1 h-imidazo[4,5-c]quinoline metal-based complexes useful as medicaments

Abstract

It relates to 1H-imidazo[4,5-c]quinoline metal-based complexes which coordinate an imiquimod-derived ligand and another one or more which can be monodentate, polydentate, and haptic, pharmaceutical compositions comprising them, as well as such metal complexes for use as a medicament, in particular for use in the treatment of viral infection, or in the treatment of cancer.

Description

[0001] 1 / 7-imidazo[4,5-c]quinoline metal-based complexes useful as medicaments

[0002] This application claims the benefit of European Patent Application EP23383336 filed December 20th, 2023

[0003] Technical Field

[0004] The present invention relates to 1 H-imidazo[4,5-c]quinoline metal-based complexes useful as medicaments, in particular, imiquimod, resiquimod, gardiquimod or their derivatives metal-based complexes having HSV-1 and HSV-2 antiviral effect.

[0005] Background Art

[0006] Herpes simplex viruses are ubiquitous human pathogens represented by two distinct serotypes: herpes simplex virus (HSV) type 1 (HSV-1) and HSV type 2 (HSV-2). In the general population, adult seropositivity rates approach 90 % for HSV-1 and 20-25 % for HSV-2.

[0007] These viruses cause mainly cold sores and genital ulcers, with much less common but more severe manifestations causing death from encephalitis. The sites of primary human HSV-1 and HSV-2 infection are: HSV encephalitis, corneal disease-keratitis, oral mucosa blister (labial herpes), cutaneous ulcers, genital ulcers (genital herpes).

[0008] The therapeutic options available for the treatment of these infections aim to alleviate symptoms and postpone recurrences. Conventional treatments comprise the use of drugs such as Acyclovir (Zovirax®), Famcyclovir (Famvir®), or Valacyclovir (Valtrex®). However, the continuous use of these drugs may promote a decrease in their efficacy since their recurrent use increases the possibility of developing drug-resistant viral strains.

[0009] If drug resistance is generated, other drugs such imiquimod (Aldara®) are used, which is an immunomodulator. Imiquimod is the lead compound of the imidazoquinoline family of nucleoside analogues. The class of 1H-imidazo-[4,5-c]quinolines do not exert direct antiviral activity but show efficacy against virus-induced lesions, which is attributed to the induction of cytokines, especially interferons. Imiquimod was approved in the 90’s for the treatment of the HPV, with antiviral and antitumoral activity being used for several affections. It belongs to a new generation of medicines known as “biological response modifiers”. Imiquimod has also shown efficacy against a variety of tumors of different origin (see M. Schon et al.; “The Antitumoral Mode of Action of imiquimod and Other Imidazoquinolines", Current Medicinal Chemistry, 2007, vol. 14, pp. 681-687). This compound exerts multiple functions (which presumably synergistically contribute to the overall antitumoral activity) and given that several biologic functions of tumor cells are affected simultaneously, the development of resistance mechanisms may be limited.

[0010] Likewise, resiquimod has shown in vivo evidence of efficacy against herpes simplex virus (HSV) type2 (see J. Wu et al.; “Resiquimod: a new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses” Antiviral Research 2004, vol. 64, pp. 79-83). Gardiquimod has also been disclosed functioning as both an immune system modifier and a reverse transcriptase inhibitor and that could be used as a therapeutic agent to block systemic and mucosal transmission of HIV-1 (see M. Buitendijk et al., “Gardiquimod: A Toll-Like Receptor-7 Agonist That Inhibits HIV Type 1 Infection of Human Macrophages and Activated T Cells”, AIDs Res Hum Retroviruses 2013, vol. 29 pp. 907-918).

[0011] A 6-coordinated Zn(ll) complex of imiquimod (imq), [Zn(imq)2Ch], its synthesis by coupling of ZnCh with imiquimod in ethanol, and its characterization via molar conductance, magnetic measurement, IR, UV and thermogravimetric analyses has been disclosed by Sarwade, Shruti S.et al.; in “Synthesis and evaluation of Zn (II) imiquimod complex” Chemica Sinica, 2015, vol. 6, pp. 1-4. However, no data of activity is shown, and the techniques used for the characterization do not provide a clear structural information on how the ligand are coordinated around the Zn center.

[0012] Thus, from what is known in the art, it is derived that there is still the need of finding new strategies to combat or reduce the harmful effect of HSV viruses.

[0013] Summary of Invention

[0014] Inventors have found that, that the 1 H-imidazo[4,5-c]quinoline metal-based complexes of the invention, which, coordinate at least one imiquimod-derived ligand and another one or two ligands which can be monodentate, polydentate, and haptic, not only can show biological activity slightly better than the corresponding 1H-imidazo[4,5-c]quinoline known drugs, but advantageously, they are less toxic to virus host cells. As it is illustrated in the example, the compounds of the present invention showed full inhibition of HSV-1 replication in HFF cells, and reduced toxicity in HFF and VERO cells (non-tumoral) compared to imiquimod. Accordingly, an aspect of the present invention relates to a neutral or cationic metal complex of formula (I), wherein:

[0015] Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;

[0016] R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;

[0017] M is a metal, in particular, a transition metal,

[0018] L is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, tert-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)cyclohexane, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5-tetramethylcyclopenta- 1 ,3-dien-1 -yl)-1 , 1 '-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-

[0019] 1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-

[0020] 1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, halogen, amine, imidazole, indazole, 5-fluorouracil, triazole, maleimide, carbonyl, 1 ,3,5- triazaC-7-phosphaadamantane phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V-heterocyclic carbene, hydroxyl, water, N,N- bound ethylenediamine, pyridine monodentate ligand, 2,2'-bipyridyl derivative, 1 ,10- phenanthroline derivative, N,O-bound picolinate, 2-picolinic acid, 6-(aminomethyl)picolinic acid, 4-(hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligands; wherein: the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the triazole ligand is selected from the group consisting of 1 ,2,4-triazole, 1 H-1 ,2,3-triazole, 4-amino-1 ,2,4-triazole, 3-amino-1 H-1 ,2,4-triazole, 1 H-1 ,2,4-triazole-3-thiol, 3-amino-1 ,2,4- triazole, I H-1 ,2,3 triazole-1-ethanol, 4-methyl-4H-1 ,2,4-triazole-3-thiol, and 3-methyl-1 H- 1 ,2,4-triazole; the phosphine ligand is selected from the group consisting of 1 ,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1 ,1',4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexane methyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of isopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzyl alcohol, 2-propen-1-ol, isopropylic alcohol, and furfuryl alcohol; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine; the 2,2'-bipyridyl derivative ligand is selected from the group consisting of 2,2’-bipyridine, 4,4'-bis(di-tert-butyl)-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 6-bromo-2,2'-bipyridine, 4-bromo-2,2'-bipyridine, 5-bromo-2,2'-bipyridine, bimethyl 2,2'-bipyridine-4,4 - dicarboxylate, 2,2'-bipyridine-3,3'-diol, 5,5'-bis(trifluoromethyl)-2,2'-bipyridine, 5,5'- bimethyl-2,2'-dipyridyl, 2,2'-([2,2'-bipyridine]-5,5'-diyl)diacetonitrile, 6-chloro-2,2'-bipyridine, 6-fluoro-2,2'- bipyridine, [2,2'-bipyridine]-4-carbaldehyde, [2,2'-bipyridine]-4,4'-diamine, and 4,4'- diethynyl-2,2'-bipyridine; the 1 ,10-phenanthroline derivative is selected from the group consisting of 1 ,10- phenanthroline, 1 ,10-phenanthrolin-5-amine, 5,6-diamino-1 ,10-phenanthroline, 4,7- dihydroxy-1 ,10-phenanthroline, 4,7-dimethoxy-1 ,10-phenanthroline, 4,7-dichloro-1 ,10-phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, and dipyrido[3,2-a:2',3'-c]phenazine; the C,N bound ligand is selected from the group consisting of 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2-(2,4-difluorophenyl)pyridine, 2- (4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2-phenylbenzothiazole, 2-(2- benzo[b]thienyl)pyridine (btp), and 2-(3-methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2- thienyl)pyridine, 1-phenylisoquinoline, , 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4-difluorophenyl)-5-fluoropyridine, 2-(2,4- difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)-5-methoxypyridine; n is an integer from 1 to 4;

[0021] X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis [3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3.

[0022] This metal complex has one imiquimod or imiquimod derivative selected from resiquimod and gardiquimod coordinated to the metal center.

[0023] Another aspect of the present invention relates to a cationic metal trimer of formula (II), wherein: Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and - (CH2)-C(OH)(CH3)2;

[0024] R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3; M is a transition metal;

[0025] Li is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, tert-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)cyclohexane,(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)-1 ,1'-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-

[0026] 1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-

[0027] 1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene;

[0028] X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and. m is an integer selected from 0, 3, and 6.

[0029] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of either a metal complex as defined above or of a cationic metal trimer of formula (II), together with appropriate amounts of pharmaceutically acceptable carriers or excipients.

[0030] Another aspect of the present invention relates to either a metal complex or a cationic metal trimer of formula (II) as defined above, for use as a medicament.

[0031] Another aspect of the present invention relates to either a metal complex or a cationic metal trimer of formula (II) as defined above, for use in the treatment of a viral infection. Finally, another aspect of the present invention relates to either a metal complex or a cationic metal trimer of formula (II) as defined above, for use in the treatment of cancer in a mammal, including a human.

[0032] Brief Description of Drawings

[0033] FIG. 1A - FIG. 1E show the X-ray structure of the compound (p- Cymene)(imiquimod)ruthenium(ll) chloride hexafluorophosphate, [Ru(p- cymene)(imiquimod)CI]PF6 (RM11 , la), [Ru(n6-p-cym)(imq)(im)](PF6)2 (MAF04). [Ru(n6-p-cym)(imq)(py)](PF6)2(MAF02), [Rh(n5-C5Me5)CI(imq)]PF6 (AH12), and [Ru(n6-p-cym)(imq)]3(PF6)6 (ACC71).

[0034] FIG. 2 shows cell viability at different concentrations (1-100 pM) of compound (RM11, la), and imiquimod in HeLa, HFF, and VERO cells respectively.

[0035] FIG. 3 shows the antiviral activity of the indicated imiquimod derivatives at 25 pM against HSV-1. HeLa, HFF, and VERO cells were treated as described in the methods with the indicated compounds. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell-associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL.

[0036] FIG. 4 shows the antiviral activity of the imiquimod derivative, named herein metal complex (RM11, la) against HSV-1. HFF and HeLa cells (FIG 4A and 4B) were treated as described in the methods with different concentrations of the compound. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell- associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL. ICso values are reported.

[0037] FIG. 5 HFF or HeLa cells (FIG. 5A and 5B) were: i) pre-treated with metal complex (RM11 , la) (50 pM) for the indicated time points (2, 12, and 24 h). Later, cells were infected with HSV-1 (MOI 0.1) in the presence of the compound, and following virus adsorption (2 h at 37°C), the viral inoculum was removed, cultures were exposed to metal complex (RM11, la) or vehicle (DMSO) and incubated for 48 h; ii) pre-treated with metal complex (RM11, la) (50 pM) for the indicated time points (2, 12, and 24 h). Later, the compound was removed and cells were infected with HSV-1 (MOI 0.1), and following virus adsorption (2 h at 37°C), the viral inoculum was removed and cells were incubated for 48 h; iii) The compounds and the virus were added simultaneously on cells (2 h at 37°C) and then removed; iv) cells were infected with HSV-1 as described above and after the removal of inoculum they were treated with metal complex (RM11 , la) (50 pM) and incubated for 48 h. Supernatants were harvested, and infectivity titers were determined by standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL Bars show the means ± SEM of three independent experiments.

[0038] FIG. 6 shows the effect of the imiquimod derivative metal complex (RM11 , la) on the expression of viral proteins in HSV-1 infected HFF and HeLa cells (FIGs 6A and 6B). Protein levels of HSV-1 ICP27 and gD were assessed at different times post-infection (hpi) by Western blotting.

[0039] FIG. 7 shows the cell viability (FIG 7A) and antiviral activity (FIG 7B) of the imiquimod derivative metal complex (RM11 , la) against HSV-1 in Arpe cells.

[0040] FIG. 8 shows the antiviral activity of the imiquimod derivative metal complex (RM11 , la) against HSV-2. In FIG 8A) HeLa cells were treated as described in the methods with different concentrations of the compound. The extent of HSV-2 replication was then assessed by titrating the infectivity of supernatants and cell-associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL IC50 value is reported. FIG 8B) shows representative light microscopy images of HeLa cells infected with HSV-2 and treated with metal complex (RM11 , la) (25 pM), as described for virus yield reduction assay. Original magnification: 20*. FIG 8C) shows the effect of the imiquimod derivative metal complex (RM11 , la) on the expression of viral proteins in HSV-2 infected HeLa cells. Protein levels of HSV-2 ICP8 and gD were assessed at different times post-infection (hpi) by Western blotting.

[0041] FIG. 9 shows in FIG 9A) cell viability and in Fig. 9B) antiviral activity of (p- cymene)ruthenium(ll) chloride dimer (Ru p-cym) precursor against HSV-1 in HFF and FIG. 9C) Hela cells. HFF and HeLa cells were treated as described in the methods with different (p-cymene)ruthenium(ll) chloride dimer (Ru p-cym) precursor concentrations. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell-associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL.

[0042] FIG. 10 shows cell viability at 25 pM for imiquimod metal complexes in (a) HeLa, (b) HFF, and (c) VERO cells, in comparison with imiquimod. Cells were treated with different concentrations of the compounds ranging from 0 to 100 pM. Experiments were performed by triplicate.

[0043] FIG. 11 shows HSV-1 virus yield reduction assay for all complexes included in this patent and the imiquimod drug in (a) HeLa, (b) HFF and (c) VERO cell lines. Cells were infected with HSV-1 at MOI=1. Cells were treated with 25 pM of each compound, with the exception of AH15, ACC71 and MJ349 where the dose was reduced to 12.5 pM when working with HeLa cells and for AH 15 where the dose was reduced to 12.5 pM when working with VERO cells

[0044] FIG.12 shows HSV-1 virus yield reduction assay for all compounds MAF04, MAF09 and ACC71 at different concentrations HeLa, HFF and VERO cell lines. Cells were infected with HSV-1 at MO .

[0045] FIG 13. Western blot analysis of HeLa and VERO cells infected with HSV-1 (MOI 1) and treated with MAF09

[0046] FIG. 14. Western blot analysis of HeLa, HFF and VERO cells infected with HSV-1 (MOI 1) and treated with ACC71

[0047] Detailed description of the invention

[0048] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply throughout the description and claims.

[0049] As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise".

[0050] "As used herein, the indefinite articles “a” and “an” are synonymous with “at least one” or “one or more.” Thus, as used herein, the singular forms ”a”, “an”, and also the definite article “the” include plural referents unless the context clearly dictates otherwise".

[0051] As used herein a bidentate ligand is a ligand that has two donor sites and, therefore, it can bind a metal atom in two coordination sites. In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “amine ligand” is used to define a ligand selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine.

[0052] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “imidazole ligand” is used to define a ligand selected from the group consisting of 2-methylimidazole, 1-ethyl-1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2- carboxylic acid, 1-(2-hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4- chlorophenyl)imidazole, 1-(4-fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole.

[0053] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “triazole” ligand is used to define a ligand selected from the group consisting of

[0054] 1.2.4-triazole, 1 H-1,2,3-triazole, 4-amino-1,2,4-triazole, 3-amino-1 H-1,2,4-triazole, 1 H-

[0055] 1.2.4-triazole-3-thiol, 3-amino-1,2,4-triazole, I H-1 ,2,3 triazole-1 -ethanol, 4-methyl-4H-

[0056] 1 ,2,4-triazole-3-thiol, and 3-methyl-1 H-1,2,4-triazole.

[0057] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “phosphine ligand” is used to define a ligand selected from the group consisting of 1 ,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1-pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6- trimethylphenyl)phosphine, tris(3,5-dimethylphenyl)phosphine, and triphenylphosphine.

[0058] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “thiol ligand” is used to define a ligand selected from the group consisting of biphenyl-4-thiol, 1 , 1 ',4', 1 "-terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2-mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert- butylthiophenol, and cysteine.

[0059] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “selenol ligand" is used to define the benzeneselenol.

[0060] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “nitrile ligand” is used to define a ligand selected from the group consisting of acetonitrile, propionitrile, and benzonitrile.

[0061] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “isocyanate ligand” is used to define a ligand selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate.

[0062] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “thiocyanate ligand” is used to define a ligand selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate.

[0063] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “ether” is used to define a ligand selected from the group consisting of diisopropyl ether, butyl vinyl ether, tert-amyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether.

[0064] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “alcohol ligand” is used to define a ligand selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-propen-1-ol, isopropylic alcohol, and furfuryl alcohol.

[0065] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “pyridine monodentate ligand” is used to define a ligand selected from the group consisting of pyridine, 4-(1-aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4- methylpyridine, 3-methylpyridine, 2-methylpyridine, 2-methylpyridine-4-carboxylic acid, 5- methylpyridine-3-carbonitrile, 2-hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2- ethynyl-6-methylpyridine, and 4-phenylpyridine.

[0066] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “ 2 ,2'-bipyridyl derivative ligand” is used to define a ligand from the group consisting of 2,2’-bipyridine, 4,4’-bis(di-tert-butyl)-2,2’-bipyridine, 4,4’-dimethyl-2,2’- bipyridine, 6-bromo-2,2'-bipyridine, 4-bromo-2,2’-bipyridine, 5-bromo-2,2’-bipyridine, bimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-3,3'-diol, 5,5'-bis(trifluoromethyl)- 2,2'-bipyridine, 5,5'-bimethyl-2,2'-dipyridyl, 2,2’-([2,2’-bipyridine]-5,5’-diyl)diacetonitrile, 6- chloro-2,2’-bipyridine, 6-fluoro-2,2’-bipyridine, [2,2’-bipyridine]-4-carbaldehyde, [2,2’- bipyridine]-4,4’-diamine, and 4,4’-diethynyl-2,2’-bipyridine.

[0067] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “1,10-phenanthroline derivative” is used to define a ligand selected from the group consisting of 1 ,10-phenanthroline, 1 ,10-phenanthrolin-5-amine, 5,6-diamino-1,10- phenanthroline, 4,7-dihydroxy-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, 4,7-dichloro-1 ,10-phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, and dipyrido[3,2-a:2',3'-c]phenazine.

[0068] In the context of the metal complexes of the present invention of formula (I), and (la)-(lh), the term “C,N bound ligand” is used to define a ligand selected from the group consisting of 2-phenylpyridine, 4-bromo-2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6- phenylpyridine, 4-methyl-2-phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2- (2,4-difluorophenyl)pyridine, 2-(4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2- phenylbenzothiazole,, 2-(2-benzo[b]thienyl)pyridine (btp), and 2-(3- methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2-thienyl)pyridine, 1 -phenylisoquinoline, 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4- difluorophenyl)-5-fluoropyridine, 2-(2,4-difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)- 5-methoxypyridine.

[0069] The term “halogen” in the context of the metal complexes of the present invention of formula (I), and (la)-(lh), relates to F, Cl, Br, and I.

[0070] As mentioned above, a neutral or cationic metal complex with at least one imiquimod or imiquimod derivative coordinated to the metal center of formula (I), wherein: Ri, R2; M, L, n, X; and m are as defined above, is part of the present invention.

[0071] When in formula (I) m is 0, the metal complex is a neutral complex. When in formula (I) m is from 1 to 3, the metal complex is a cationic complex. The same applies for all the metal complexes below of formula (I a)-(lf).

[0072] In a particular embodiment, the metal complexes of formula (I) according to the present invention are those where the metal is selected from the group consisting of Ru, Fe, Co, Ir, Rh, Os, Pt, Mn, Cr, Ni, Re, Au, and Cu. In another particular embodiment, the metal complexes of formula (I) according to the present invention are those where the metal is selected from the group consisting of Ru, Fe, Co, Ir, Rh, Os, Pt, Mn, Cr, Ni, Re, Au, and Cu. In another particular embodiment, the metal complexes of formula (I) according to the present invention are those where the metal is Ru.

[0073] In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (I) according to the present invention are those where R1 is -(CH2)-CH(CH3)2 and R2 is H. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (I) according to the invention are those where R1 is and -(CH2)-C(OH)(CH3)2 and R2 is - (CH2)-O-CH2-CH3. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (I) according to the present invention are those where Ri is and -(CH2)-C(OH)(CH3)2 and R2 is -CH2-NH-CH2-CH3.

[0074] In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (I) according to the present invention are those where X is hexafluorophosphate.

[0075] In a particular embodiment, the compounds of formula (I) are those where n is an integer from 2 to 4. In another particular embodiment, the compounds of formula (I) are those where n is 2.

[0076] In a particular embodiment, the metal complex according to the present invention is a metal complex which coordinates an imiquimod-derived ligand and another one or two ligands which can be monodentate, polydentate, and haptic. It can have either a tetrahedral-like geometry i.e. , analogous to a pyramid, or a square planar geometry in which the ligands form a simple square on the x and y axes. In a particular embodiment, the metal complexes of the present invention are half sandwich compounds, also known as piano stool complexes.

[0077] In a particular embodiment the metal complexes of formula (I) have the formula (la) below: wherein: R1 is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and - (CH2)-C(OH)(CH3)2; R2 is a substituent selected from the group consisting of -H, -(CH2)-O- CH2-CH3, and -CH2-NH-CH2-CH3; M is a metal; Li is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, tert-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 , 2, 3,4,5- pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3-dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3- phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2- phenylacetate, ethyl 2-phenylacetate, ethyl 3-phenylpropanoate, N- phenethylmethanesulfonamide, N-([1 , 1 '-biphenyl]-2-yl)methanesulfonamide, 2- phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene,

[0078] 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)cyclohexane, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5-tetramethylcyclopenta-

[0079] 1.3-dien-1 -yl)-1 , 1 '-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-

[0080] 1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-

[0081] 1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene; L2 is a ligand selected from the group consisting of halogen, amine, pyridine, 2-phenylpyridine, 4- bromo-2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-

[0082] 2-phenylpyridine, imidazole, indazole, 5-fluorouracil, maleimide, carbonyl, 1 ,3,5-triaza-7- phosphaadamantane, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, hydroxyl, and water; wherein the imidazole, thiol, selenol, nitrile, isocyanate, thiocyanate, ether, and alcohol are as defined above; X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3. These metal complexes have a piano-stool geometry.

[0083] In a particular embodiment, the metal complexes of formula (la) are those where Li is a ligand selected from the group consisting of p-cymene, benzene, hexamethylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, and 1 ,5-cyclooctadiene. In another particular embodiment, the metal complexes of formula (la) are those where Li is p-cymene.

[0084] In another particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) are those where L2 is a ligand selected from the group consisting of halogen, amine, 2-phenylpyridine, 4-bromo-2-phenylpyridine, 5-chloro-2- phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2-phenylpyridine, imidazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, hydroxyl, and water; wherein the imidazole, thiol, selenol, nitrile, isocyanate, thiocyanate, ether, and alcohol are as defined above.

[0085] In another particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) are those where L2 is a ligand selected from the group consisting of halogen, pyridine, phosphine, thiol, nitril, and water. In another particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) are those where L2 is halogen.

[0086] In another particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) are those where X is an anion selected from the group consisting of hexafluorophosphate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate. In another particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) are those where m is 1.

[0087] In a particular embodiment, in combination with the embodiments above or below, the metal complexes of formula (la) according to the present invention are those where the metal is selected from the group consisting of Ru, Fe, Co, Ir, Rh, Os, Pt, Mn, Cr, Ni, Re, and Cu. In another particular embodiment, the metal complexes of formula (la) according to the present invention are those where the metal is Ru.

[0088] In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according to the present invention are those where R1 is -(CH2)-CH(CH3)2 and R2 is H. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according to the invention is that where R1 is and -(CH2)-C(OH)(CH3)2 and R2 is - (CH2)-O-CH2-CH3. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according to the present invention are those where R1 is and -(CH2)-C(OH)(CH3)2 and R2 is -CH2-NH-CH2- CH3.

[0089] In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according to the present invention are those where Li is p-cymene. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according of the present invention are those where L2 is halogen, in particular, the halogen is Cl. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes of formula (la) according to the present invention are those where X is hexafluorophosphate. In a particular embodiment the metal complexes of formula (I) have the formula (lb) below, where: Ri, R2, M, X, and m are as defined in the metal complex (la), and L3 and l_4are equal or different and are ligands independently selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V- heterocyclic carbene, hydroxyl, and water; wherein the amine, the pyridine monodentate ligand, the imidazole, the phosphine, the thiol, the selenol, the nitrile, the isocyanate, the thiocyanate, the ether, and the alcohol are as defined above. These metal complexes have a square planar or tetrahedral geometry. In a particular embodiment, the metal complexes of formula (I) have the formula (Ic) below, wherein: R1; R2; M; X, and m are as defined in the metal complex (la); Ls- Ls is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative N,O-bound picolinate, 2-picolinic acid, 6- (aminomethyl)picolinic acid,4-(Hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligand; wherein the 2,2'-bipyridyl derivative, the 1 ,10-phenanthroline derivative, and the C,N bound ligand is as defined above. These metal complexes have a square planar geometry.

[0090] In another particular embodiment, the metal complexes of formula (Ic) are those where Ls- Ls is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative N,O-bound picolinate, 2-picolinic acid, 6-(aminomethyl)picolinic acid,4-(Hydroxymethyl) picolinic acid, O,O-bound acetylacetonate, and C,N bound ligand; wherein the 2,2'-bipyridyl derivative, the 1 ,10- phenanthroline derivative, and the C,N bound ligand is as defined above. These metal complexes have a square planar geometry.

[0091] In another particular embodiment, the metal complexes of formula (Ic) are those where L5- L5 is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, 2,2’-bipyridine, 1 ,10-phenanthroline, N,O-bound picolinate, O,O-bound acetlylacetonate, and C, N-bound ligand.

[0092] The metal complex according to the present invention may also have an octahedral geometry. In a particular embodiment the metal complexes of formula (I) have the formula (Id) below: wherein: R1; R2; M; X, and m are as defined in the metal complex (la); Le-Le and L7-L7 can be equal or different and are bidentate ligands selected from the group consisting of L5- L5 is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, pyridine monodentate ligand, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative, N,O-bound picolinate, 2-picolinic acid, 6-(aminomethyl)picolinic acid 4-(hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligands; wherein the pyridine monodentate ligand, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative, and C,N bound ligand are as defined above.

[0093] In another particular embodiment, the metal complexes of formula (Id) are those where Ls- Ls and L7-L7 are equal or different and are bidentate ligands selected from the group consisting of N,N-bound ethylenediamine, 2,2’-bipyridine, 1 ,10-phenanthroline, N,O-bound picolinate, O,O-bound acetlylacetonate, and C,N-bound ligand.

[0094] In another particular embodiment the metal complexes of formula (I) have the formula (le) below, wherein: R1; R2; M; X, and m are as defined in the metal complex (la); Ls-Ls is a bidentate ligand selected from the group consisting of N,N-bound ethylenediamine, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative, N,O-bound picolinateT2-picolinic acid, 6- (aminomethyl)picolinic acid, 4-(hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligand; L9 and L10 are equal or different and are ligands selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V-heterocyclic carbene, hydroxyl, and water; wherein: the 2,2'- bipyridyl derivative ligand, 1 ,10-phenanthroline derivative, the C,N bound ligand, the amine, the pyridine monodentate ligand, the imidazole, the triazol, the phosphine, the thiol, the selenol, the nitrile, the isocyanate, the thiocyanate, the ether, and the alcohol are as defined above. These metal complexes also have an octahedral geometry.

[0095] In another particular embodiment, the metal complexes of formula (le) are those where Ls- Ls is a bidentate ligand selected from the group consisting of N,N-bound ethylenediamine, 2,2’-bipyridine, 1 ,10-phenanthroline, N,O-bound picolinate, O,O-bound acetlylacetonate, and C,N-bound ligand.

[0096] In another particular embodiment the metal complexes of formula (I) have the formula (If) below, wherein: Ri; R2; M; X, and m are as defined in the metal complex (la); Ln, L12, 13 and L14 are equal or different and are ligands selected from the group consisting of halogen, amine, pyridine derivative, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V-heterocyclic carbene, hydroxyl, and water; wherein the amine, the pyridine monodentate ligand, the imidazole, the triazole, the phosphine, the thiol, the selenol, the nitrile, the isocyanate, the thiocyanate, the ether, and the alcohol are as defined above. These metal complexes also have an octahedral geometry. In another particular embodiment, the metal complexes of formula (I) have the formula (Ig) below, wherein: R1; R2; M; X, and m are as defined in the metal complex (la); L15 is a tridentate ligand selected from the group consisting of tris(pyrazolyl)borate, 2,2':6',2"-terpyridine, 6,6"-dibromo-2,2':6',2"-terpyridine, bis(2-pyridylmethyl)amine, bis(2- diphenylphosphino)ethyl ether, bis(2-diphenylphosphino)ethyl sulfane, bis(2- diphenylphosphino)ethyl amine, 1 ,3-bis(diphenylphosphinomethylbenzene, 1 ,3-bis((1 H- imidazol-1-yl)methyl)benzene, 1 , 1 , 1 -tris(pyrid-2-yl)ethane, 1 ,4,7-trithiacyclononane, 1 ,4,7- triazacyclononane, 2,6-Bis[4-phenyl-2-oxazolinyl]pyridine, and biethylenetriamine; Lie is a ligand selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, silanol, nitrile, azide, cyanate, isocyanate, thiocyanate, ether, alcohol, carboxylate, / V-heterocyclic carbene, hydroxyl, and water; wherein: the amine, the pyridine monodentate ligand, the imidazole, the triazole, the phosphine, the thiol, the selenol, the nitrile, the isocyanate, the thiocyanate, the ether, and the alcohol are as defined above.

[0097] In another particular embodiment the metal complexes of formula (I) have the formula (Ih) below,

[0098] Ri; R2; M; X, and m are as defined in the metal complex (la); L17 is a tetradentate ligand selected from the group consisting of 1 ,2-bis[(2- quinolinemethyl)(phenyl)phosphanyl]ethane, tris(2-pyridylmethyl)amine, tris(5-methyl-2- pyridylmethyl)amine, N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1 ,2-diaminoethane, N,N'- bis(2-pyridylmethyl)-N,N'-dimethyl-trans-1 ,2-diaminocyclohexane, N,N'-bis(2-picolyl)-2,2'- bipyrrolidine, N1,N2-di(quinolin-8-yl)cyclohexane-1 ,2-diamine, N1,N2-bis(6-fluoroquinolin-8- yl)cyclohexane-1 ,2-diamine, N1,N2-bis(6-(tert-butyl)quinolin-8-yl)cyclohexane-1 ,2-diamine, triethylenetetramine.

[0099] In a particular embodiment, the complexes are selected from the following list: (p-cymene)(imiquimod)ruthenium(ll) chloride hexafluorophosphate, [Ru(p- cymene)(imiquimod)CI]PF6 (RM 11 , la); c / s-bis(2,2-bipyridine)(imiquimod)ruthenium(l I) dihexafluorophosphate compound, cis- [Ru(bpy)2(imiquimod)](PFe]2;

[0100] Ru(p-cymene)(imiquimod)Z](PF6)ncomplexes (where Z = pyridine, 1 ,3,5-triaza-7- phosphaadamantane, imidazole, indazole, 5-fluorouracil, iodide; n = 1 or 2); [Ru(n6-p-cym)(imq)(py)](PF6)2 (MAF02);

[0101] [Ru(n6-p-cym)(imq)(pta)](PF6)2 (MAF03);

[0102] [Ru(n6-p-cym)(irnq)(im)](PF6)2 (MAF04);

[0103] [Ru(n6-p-cym)(imq)(in)](PF6)2 (MAF05);

[0104] [Ru(n6-p-cym)(imq)(5-fu)]PF6(MAF09);

[0105] [Ru(n6-p-cym)(imq)(l)]PF6(MJ327);

[0106] [lr(n5-C5Me5)CI(imq)PF6 (AH11);

[0107] [Rh(n5-C5Me5)CI(imq)PF6 (AH12);

[0108] [Pt(bpy)(imq)]CI2(MJ349);

[0109] [lr(ppy)2(imq)][PF6] (AH15); and [Ru(n6-p-cym)(imq)]3(PF6)3 (ACC71).

[0110] The metal complexes of the present invention may be prepared by a process comprising for instance, reacting a (p-cymene)ruthenium(ll) halide dimer, [Ru(p-cymene)X]2 such as (p-cymene)ruthenium(ll) chloride dimer with and 1 / 7-imidazo[4,5-c]quinoline such as imiquimod, resiquimod or gardiquimod. Other complexes may be prepared analogously in view of these teachings and the examples.

[0111] The metal complexes of the present Invention may be prepared by a process comprising for instance, reacting a metal-arene halide dimer, such as [Ru(p-cymene)CI]2 ((p- Cymene)ruthenium(ll) chloride dimer) or [Rh / lr(Cp*)CI]2 (pentamethylcyclopentadienyl rhodium / iridium dichloride dimer) with and 1 / 7-imidazo[4,5-c]quinoline such as imiquimod, resiquimod or gardiquimod. Other complexes may be prepared analogously in view of these teachings and the examples.

[0112] The metal complexes of the present invention may also be prepared by a process comprising for instance reacting under reflux or microwave heating of a cis- [M(diimine)2Cl2] precursor such as c / s-bis(2,2-bipyridine) ruthenium(ll) dichloride complex, cis-[Ru(bpy)2Cl2] or c / s-bis(2,2-bipyridine) osmium(ll) dichloride complex, cis-[Os(bpy)2Cl2] with and 1 / 7-imidazo[4,5-c]quinoline such as imiquimod, resiquimod or gardiquimod.

[0113] 1 H-imidazo[4,5-c]quinoline scaffold can potentially be coordinated to a wide range of coordination and organometallic compounds using established procedures that an expert in the field could readily reproduce or adapt. Thus, for instance, the complexes of the invention can be prepared following the teachings of the examples, as well as several synthesis disclosed in the art that can be adapted to obtain imiquimod-based metal complexes with different geometries.

[0114] The complexes of formula (la) can be prepared by the processes disclosed in the examples.

[0115] Complexes of formula (lb) of different transition metals can be prepared following the process described by Temerova et al. (Inorg. Chem. 2022, vol. 61, pp. 19220-19231) on page 19222 using imiquimod as a bidentate ligand and one of the following metal salts ZnBr2, CdBr2 or PbBr2. Alternatively, Au complexes of type (lb) can be obtained following Cinellu et al. (Organometallics 2009, vol. 28, pp. 7015-7024) using imiquimod and Na[AuCl4]32H2O as described at page 7021.

[0116] Complexes of formula (Ic) can be prepared analogously to [Pt(bpy)(imq)]Ch] (MJ349) (see Example 18).

[0117] They can be prepared by employing imiquimod and its derivatives in the preparation of the Cu complexes as reported by Lei Wang et al.; “Changing Directions: Influence of Ligand Electronics on the Directionality and Kinetics of Photoinduced Charge Transfer in Cu(l)Diimine Complexes” Inorganic Chemistry, 2023, vol. 62, pp. 14368-14376.

[0118] Complexes of formula (Id) can be prepared analogously to [Ru(bpy)2(lmiquimod)][PF6]2 (Example 2) and [lr(ppy)2(lmq)][PFe] (AH15) (see Example 19).

[0119] Complexes of formula (le) can be obtained following the procedure reported by Ooyama et al. (Journal of Organometallic Chemistry 2003, vol. 665, pp. 107 - 113 ) on page 108, using imiquimod and [Ru(bpy)(CO)2Ch].

[0120] Complexes of formula (If) can be prepared following the procedure described by Battistin et al. (Eur. J. Inorg. Chem. 2016, pp. 2850-2860 ) at page 2858 using the precursor cis- [RuCh(PTA)4] (where PTA = 1,3,5-triaza-7-phosphaadamantane) and imiquimod as chelating ligand.

[0121] Complexes of formula (Ig) can be prepared following the procedure described by Lameijer et al. (Chem. Eur. J. 2018, vol. 24, pp. 2709 - 2717 ) at page 2 of the Supporting Information section employing [Ru(tpy)Ch] (where tpy = 2,2':6',2"-terpyridine) and imiquimod as reactants. Complexes of formula (Ih) can be prepared following the procedure described by Garcia- Lopez et al. (Dalton Trans., 2018, vol. 47, pp. 9156-9163 ), the expert can prepare Fe complexes of type 1h using Fe(CIC>4)2 x H2O, imiquimod and is(2-pyridylmethyl)amine as reactants (page 9161).

[0122] A pharmaceutical composition comprising a therapeutically effective amount of a metal complex as defined above, together with appropriate amounts of pharmaceutically acceptable excipients or carriers is also part of the invention.

[0123] The term “therapeutically effective amount” as used herein, refers to the amount of a compound that, when administered, is enough to prevent development of, or alleviate to some extent, one or more symptoms of the disease which is addressed. The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the via of administration, the particular condition being treated, and similar considerations.

[0124] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism.

[0125] The terms “pharmaceutically acceptable excipients or carriers” refers to pharmaceutically acceptable material, composition, or vehicle. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must be also suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a benefit / risk ratio.

[0126] In a particular embodiment, the pharmaceutically acceptable excipients or carriers may include diluents, disintegrants, stabilizers, preservatives, buffers, emulsifiers, flavouring agents, colouring agents, sweetening agents, thickeners, dissolution aids and other additives such as water, vegetable oil, alcohol (e.g., ethanol or benzyl alcohol, etc.), polyethylene glycol, glyceryl triacetate, and the like.

[0127] An important feature of the compounds of the present invention is their biological activity equal to or, even better than the corresponding 1 H-imidazo[4,5-c]quinoline known drugs while are less toxic to virus host cells. Thus, a metal complex as defined above for use as a medicament is also part of the invention. Likewise, a metal complex as defined above for use in the treatment of viral infection is also part of the invention. This aspect can also be formulated as use of the metal complex according as defined above for the preparation of a medicament for the treatment of a viral infection in a mammal, including a human. The invention also relates to a method of treatment of a mammal, including a human, suffering from a viral infection, said method comprising the administration to said patient of a therapeutically effective amount of a compound of a metal complex as defined above, together with pharmaceutically acceptable excipients or carriers.

[0128] The term “patient” refers to a person who is designated to receive a medical treatment, therapy, or service. The term patient may be extended to an animal when used within the context of the animal receiving veterinary treatment or services.

[0129] The treatment in the context of the present invention may include inhibition of the virus replication, reducing severity of the virus infection.

[0130] In a particular embodiment, in combination with any of the embodiments above or below, the metal complexes for use as defined above are those where the treatment is of a viral infection caused by a virus selected from the group consisting of Herpes Simplex Virus (HSV), ocular virus, Human Papillomavirus (HPV), Molluscum Contagiosum, Respiratory Syncytial Virus, and Arthropod-borne viruses. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes for use as defined above are those where it is for treating a viral infection caused by the Herpes Simplex Virus (HSV).

[0131] In a particular embodiment, in combination with any of the embodiments above or below, the metal complexes for use as defined above are those where the Herpes Simplex Virus is Herpes Simplex Virus, type 1. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes for use as defined above are those where the Herpes Simplex Virus is Herpes Simplex Virus, type 2. The HSV-1 and HSV-2 are the main responsible of the following primary human infections: HSV encephalitis, corneal disease-Keratitis, oral mucosa blister (labial herpes), cutaneous ulcers, and genital ulcers (genital herpes).

[0132] Particularly good results are obtained with the metal complex (p- cymene)(imiquimod)ruthenium(ll)chloride, [Ru(p-cymene)(imiquimod)CI]PF6 (RM11, la) for use in the treatment of viral infections, in particular, for Herpes Simplex Virus, type 1. Furthermore, such metal complex (RM11, la) has resulted to be less toxic than imiquimod in the hosting cells, particularly in non-tumoral cell lines (HFF, VERO), and showed a slightly higher antiviral activity than its well-known antiviral imiquimod precursor at 25 pM in two cell lines infected with the virus. Thus, the metal complex (RM11 , la) at 50 pM is a more potent antiviral agent than imiquimod, while being less cytotoxic in HFF cells.

[0133] Cationic metal trimer of formula (II), wherein: Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)-C(OH)(CH3)2; 2 is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2-NH-CH2-CH3; M is a transition metal; Li is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, tert-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 '- b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)cyclohexane,(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)-1 ,1'-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-

[0134] 1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-

[0135] 1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer selected from 0, 3, and 6, are also part of the invention.

[0136] Particular embodiments, of Ri, R2, M, Li, X, and m provided for the metal complexes of formula (I) above, are considered also particular embodiments of the cationic metal trimer of formula (II).

[0137] The metal complexes of the invention present inhibition of the HSV virus in HeLa and HFF cells. The antiviral activity of the metal complexes of formula (I) of the present invention is extended to ocular cell lines (ARPE, a spontaneously arising retinal pigment epithelial (RPE) cell line) which is of relevance for the treatment of HSV (IG.5).

[0138] In another particular embodiment, in combination with any of the particular embodiments above or below, the metal complexes for use as defined above are those where the treatment comprises the administration of the compounds in the adsorption or postinfection virus phase, particularly, in the post-infection virus phase.

[0139] In a particular embodiment, in combination with any of the embodiments above or below, the metal complexes of the present invention as defined above for use as defined above, are those where they are administered simultaneously, sequentially or separately, together with one or more known antiviral agents such as valacyclovir or acyclovir.

[0140] It is also part of the invention, a metal complex as defined above for use in the treatment of cancer in a mammal, including a human. This aspect can also be formulated as use of the metal complex according as defined above for the preparation of a medicament for the treatment of cancer in a mammal, including a human. The invention also relates to a method of treatment of a mammal, including a human, suffering from cancer, said method comprising the administration to said patient of a therapeutically effective amount of a compound of a metal complex as defined above, together with pharmaceutically acceptable excipients or carriers.

[0141] In a particular embodiment, the metal complex for use in the treatment of cancer are those where the cancer is selected from the group consisting of primary skin cancer (cutaneous tumors) and cutaneous metastasis. Cutaneous primary and metastasis tumors include basal cell carcinomas, keratoacanthomas, actinic keratoses, Bowen’s disease, melanoma in situ, cutaneous metastases of melanoma, and cutaneous T cell lymphomas. Cancer treatment with the compounds of the present invention also includes cutaneous neoplasias, for instance, in organ transplant patients under immunosuppressive therapy or xeroderma pigmentosum patients suffering from rapid development of multiple UV- induced cutaneous malignancies, and transplantable tumors.

[0142] In a particular embodiment, the metal complex for use in the treatment of cancer is the complex (p-cymene)(imiquimod)ruthenium(ll)chloride, [Ru(p-cymene)(imiquimod)CI]PF6 (RM11 , la). As it is illustrated in the examples this complex is less toxic than imiquimod in the hosting cells, particularly in non-tumoral cell lines (HFF, VERO).

[0143] The metal complexes of the present invention can be used in the same manner as other known chemotherapeutic agents, i.e., in combination with other treatments, either simultaneously or sequentially, depending on the condition to be treated. In a particular embodiment, in combination with any of the embodiments above or below, the metal complexes (I) of the present invention for use in the treatment of cancers as defined above, are administered in combination with a chemotherapeutic agent. In another particular embodiment, in combination with any of the embodiments above or below, the compounds of the invention are administered simultaneously with the chemotherapeutic agent. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes (I) of the present invention and the chemotherapeutic agent are administered separately, in any order, within a therapeutically effective interval. In another particular embodiment, in combination with any of the embodiments above or below, the metal complexes (I) of the present invention and the chemotherapeutic agent are administered simultaneously or sequentially. In a more particular embodiment, the metal complexes (I) of the present invention are administered in combination with a chemotherapeutic agent. Examples of these chemotherapeutic agents include, 5-fluorouracil, tazarotene, sorafenib, or anti-PD-1 antibody.

[0144] The metal complexes of the present invention for use in the previous therapeutic applications may be administered by topically or by systemic administration including enteral or parenteral administration. In a particular embodiment, the metal complexes are administered by topical cutaneous administration.

[0145] The topical administration includes administration to the nasopharyngeal area. For these purposes the metal complexes of the present invention may be delivered for instance in a nasal spray.

[0146] The cationic metal trimer of formula (II) for use in any of the previous uses mentioned for the metal complexes are also part of the invention. Any of the particular embodiments mentioned above for the metal complexes with respect to such uses are also particular embodiment for the cationic metal trimer of formula (II) for the intended use.

[0147] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

[0148] Examples

[0149] General methods

[0150] Cells and viruses: Human foreskin fibroblasts (HFF; American Type Culture Collection, ATCC SCRC-1041), the cervix adenocarcinoma cell line HeLa (ATCC CCL-2), African green monkey kidney cells (VERO, ATCC CCL-81), Adult Retinal Pigment Epithelial cells (Arpe-19) cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (Sigma- Aldrich, St. Louis, MO, USA), supplemented with 10% heat-inactivated fetal bovine serum (FBS), 2 mM glutamine, 1 mM sodium pyruvate, 100 U / mL penicillin, and 100 pg / mL streptomycin sulfate (Sigma-Aldrich, St. Louis, MO, USA). The clinical isolate of human herpes simplex virus type 1 (HSV-1) and human herpes simplex virus type 2 (HSV-2) was used for the study. HSV-1 and HSV-2 were propagated and titrated by plaque assay on VERO cells, as previously described.

[0151] Antiproliferative activity: The antiproliferative activity of the investigated compounds was evaluated by using a system based on the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide compound (MTT). To determine the antiproliferative activity of the compounds, HFF, HeLa, and VERO cells were seeded in a 96-well culture plate at a density of about 4 x 104cells / well in 100 pL of the medium. After overnight incubation at 37°C in a 5% CO2 humidified atmosphere, the medium from the wells was removed, and cells were exposed to increasing concentrations of the compounds or vehicle (DMSO), in a final volume of 100 pl / well. After 48 hours of incubation, the number of viable cells was determined using an MTT assay. The MTT solution (500 pg / mL in serum-free medium, Sigma-Aldrich was added to each well, and the plates were incubated for 2 h. At the end of the incubation period, the medium was removed, and the formazan product was dissolved in 50 pL of DMSO. The cell viability was evaluated by measurement of the absorbance at 570 nm, using a VICTORS 1420 multilabel counter (Perkin-Elmer). All experiments were made in triplicate. The readings were converted to the percentage of control (% cell survival). ICsowas defined as the concentration of each compound that reduced the cell viability to 50% compared to untreated cells, producing 50% cell death (htps: / / www.aatbio.com / tools / ic50-calculator).

[0152] Virus yield reduction assay: VERO cells were seeded in 24-well plates and after 24 h subjected to the time of addition assays with different concentrations of complexes or the vehicle control (DMSO), as described in the Results section. Cells were infected with HSV-1 or HSV-2 at MOI of 1 PFU / cell, and the cells and supernatants were then harvested and disrupted using three freezes (liquid nitrogen) / thaw (37°C) cycles. The extent of virus replication was subsequently assessed by titrating the infectivity of the supernatants of the cell suspensions in VERO cells by standard plaque assay, as previously described. Plaques were microscopically counted, and the mean plaque counts for each drug concentration were expressed as PFU / mL.

[0153] Western Blotting: After treatment, the cells were washed with phosphate-buffered saline (PBS), and cell lysis was carried out using radioimmunoprecipitation assay (RIPA) buffer to obtain total cell lysate. An equal amount of the cell extracts was fractionated by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels and transferred to Immobilon-P membranes (Bio-Rad, Milan, Italy). After blocking with 5% nonfat dry milk in TBS-Tween 0.05%, the membranes were incubated overnight at 4 °C with the appropriate primary antibodies. The following primary antibodies were used: mouse monoclonal antibodies anti-HSV-1 ICP27 monoclonal antibody (MAb) (clone H1113, Virusys Corporation), mouse anti-HSV-2 ICP8 MAb (clone 4E6, Virusys Corporation), mouse anti- HSV-1 / 2 gD MAb (clone 2C10, Virusys Corporation) and anti-Actin (clone C4, MAB1501) (Sigma-Aldrich, Milan, Italy) (all at 1 :1000 dilution in 5% nonfat dry milk, TBS-Tween 0.05%). After washing with TBST buffer (500 mM NaCI, 20 mM Tris pH 7.4, 0.05% Tween 20), the membrane was incubated with an HRP-conjugated anti-mouse secondary antibody (GE Healthcare, Chicago, IL, USA) for 1 h at room temperature, and visualized using an enhanced chemiluminescence detection kit (SuperSignal West Pico Chemiluminescent Substrate, Thermo SCIENTIFIC, Waltham, MA, USA).

[0154] Example 1 : (p-cymene)(imiquimod)ruthenium(ll) chloride hexafluorophosphate, [Ru(p- cymene)(imiquimod)CI1PF6 (RM11 , la)

[0155] (p-cymene)ruthenium(ll) chloride dimer, [Ru(p-cymene)Cl2]2 (20 mg, 0.0326 mmol) was dissolved in 0.5 mL of dichloromethane and a solution of imiquimod (15 mg, 0.0652 mmol) in MeOH (4 mL) was added dropwise. The reaction mixture was left stirring to react for 12 hours at 60°C. Ammonium hexafluorophosphate (5 eq) was added to the solution and sonicated for 10 min. The reaction mixture was dried under vacuum to half-volume and left to crystalize in the freezer. After approximately 12 h, a crystalline burgundy precipitate was collected by filtration, washed with Et20 and dried under vacuum. Some of the crystals were suitable for X-ray measurements. Yield: 89%. MS(ESI+): m / z calcd for C24H3oCIN4Ru[M]+: 511.1197; found: 511.1166;1H NMR: (300 MHz, Methanol-d4) 5 8.83 (s, 1 H), 7.87 (d, J = 8.1 , 1 H), 7.54 - 7.45 (m, 1 H), 7.39 - 7.30 (m, 2H), 5.97 - 5.85 (m, 2H), 5.75 - 5.58 (m, 2H), 4.42 (d, J = 7.5 Hz, 2H), 2.90 - 2.71 (m, 1 H), 2.25 (s, 3H), 2.24- 2.27 (m, 1 H), 1.22 (d, J = 6.9 Hz, 6H), 1.05 (d, J = 6.7 Hz, 6H).13C NMR: (75 MHz, Methanol-d4) 5 153.48, 146.81 , 139.21 , 131.59, 130.83, 124.72, 123.19, 118.61 , 113.72, 103.62, 100.77, 83.54, 83.26, 82.17, 81.05, 56.30, 32.45, 30.46, 22.62, 22.33, 19.65, 19.02.

[0156] Table 1 :

[0157] Formula C48H58CI2N8P2F12RU Ru1-CI1 2.393(3)

[0158] M 1310 Ru1-N1 2.120(6)

[0159] Crystal System Triclinic Ru1-N2 2.119(6) Space group P-1 Ru1-C1 2.152(9) T [K] 170 Ru1-C2 2.179(7)

[0160] See also FIG. 1A.

[0161] Example 2: Preparation of c / s-bis(2,2-bipyridine)(imiquimod)ruthenium(ll) dihexafluorophosphate compound, cis-[Ru(bpy)2(imiquimod)](PF6)2 c / s-bis(2,2-bipyridine) ruthenium(ll) dichloride complex, cis-[Ru(bpy)2Cl2] (30 mg, 0.06 mmol) and imiquimod (16.5 mg, 0.069 mmol) were added in 6 mL of ethylene glycol forming a purple suspension. After 30 min of microwave irradiation (Anton Paar, Monowave 400) at 150°C and subsequent cooling to room temperature, the reaction mixture turned to a dark red solution. The reaction crude was washed with Et20 (10 x 3 mL), and 10 mL of distilled water were added. Ammonium hexafluorophosphate (5 eq) was added to the aqueous solution and a crystalline red precipitate was collected by filtration, washed with Et20 and dried under vacuum. Yield: 96%.1H NMR: (300 MHz, Acetonitrile-cfe) 6 10.03 (s, 1 H), 8.93 (d, J = 5.7 Hz, 1 H), 8.54 - 8.39 (m, 4H), 8.25 - 8.17 (m, 1 H), 8.12 - 8.00 (m, 2H), 7.99 - 7.85 (m, 4H), 7.84 - 7.79 (m, 1H), 7.59 - 7.46 (m, 4H), 7.43 - 7.34 (m, 2H), 7.28 (m, 2H), 6.10 (s, 1 H), 4.18 (d, J = 7.5 Hz, 2H), 2.27-2.10 (m, 1 H), 0.97 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H).13C NMR: (75 MHz, Acetonitrile- d3) 5 159.91, 159.77, 158.79, 158.71 , 153.96, 153.75, 153.67, 153.23, 153.04, 145.80, 139.12, 137.50, 137.38, 137.26, 137.07, 130.74, 127.95, 127.93, 127.23, 127.11 , 124.32, 124.27, 124.22, 124.18, 123.25, 113.83, 55.95, 29.82, 19.68, 19.40.

[0162] Example 3: Toxicity assay

[0163] The cell cytotoxicity of the complex (p-cymene) (imiquimod)ruthenium(ll) chloride hexafluorophosphate, [Ru(p-cymene)(imiquimod)CI]PF6_(RM11 , la) against HFF, HeLa, and VERO cells was evaluated.

[0164] Cells were seeded in a P96-well plate. After 24 h, the cells were treated with different drug dilutions, or mock-treated using the same amount of vehicle solution (DMSO), ranging from 1 to 100 pM. After 48 h of treatment, cell viability was determined using the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (see Mosman, T., “Rapid Colorimetric Assay for Cellular Growth and Survival: Application to proliferation and Cytotoxicity Assays” J. Immunol. Methods, 1983, vol. 65, pp.55-63)

[0165] It was found that metal complex (RM11, la) did not produce significant toxicity up to 25 pM in all cell lines tested (70-80% cell viability). The compound was considered non-toxic only if it maintained at least 70% cell viability after 48 h of treatment. Importantly, the metal complex (RM11, la) showed reduced toxicity in HFF and VERO cells (non-tumoral) compared to imiquimod, whereas the toxicity of this Ru complex was comparable to imiquimod in HeLa (cervical carcinoma) cells (see FIG. 2).

[0166] Example 4: Antiviral activity vs. HSV-1 (Herpes Simplex Virus, type 1)

[0167] Ru-imiquimod-based compound (RM11, la) was evaluated for its antiviral activity against HSV-1 at 25 pM, which was the minimum effective dose that did not show pronounced cytotoxicity (based on MTT results).

[0168] HeLa, HFF, and VERO were seeded at a density of 40,000 cells / well. After 24 h, cells were pretreated with 25 pM of the indicated metal complexes or vehicle (DMSO) for 2 h. Later, cell cultures were infected with HSV-1 at a multiplicity of infection (MOI) of 1. The MOI represents the ratio of the number of virus particles to the number of host cells in a given infection medium. A value of MOI = 1 implies that on average there is a single host cell for a single virus particle. Following virus adsorption (2 h at 37°C), the viral inoculum was removed, and cultures were exposed to the compound for 48 h. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell- associated viruses using a standard plaque assay in VERO cells (see Toscani, A. et al.; “Synthesis and Biological Evaluation of Amidinourea Derivatives against Herpes Simplex Viruses. Molecules, 2021, vol.26, p. 4927). Plaques were microscopically counted, and the mean plaque counts for each drug concentration were expressed as plaque-forming units per milliliter (PFU / mL) (FIG. 3).

[0169] Complex (RM11, la) and imiquimod presented inhibition of the virus in HeLa and HFF cells. Interestingly, metal complex (RM11, la) showed a slightly higher antiviral activity than its well-known antiviral imiquimod precursor at 25 pM. metal complex. The tested compound did not exert inhibition of HSV-1 in VERO cells.

[0170] A more detailed analysis with serial dilutions of the compounds revealed an IC50 of 15.35 and 7.69 pM for metai complex (RM11, la) in HFF and HeLa cells, respectively (FIG. 4). Importantly, the metal complex (RM11, la) exerts full inhibition of HSV-1 replication at 100 pM in HFF cells. In contrast, imiquimod is toxic at such a concentration (FIG. 2). Direct comparison between the metal complex (RM11, la) and imiquimod can be obtained at 50 pM, where the Ru agent is 1-2 orders of magnitude more potent, depending on the cell line. In the cancerous HeLa cell line, the metal complex (RM11, la) was more potent than imiquimod.

[0171] Example 5: A time-of-addition drug assay

[0172] To better understand which phase of the HSV-1 replication cycle is inhibited by the imiquimod -based metal complex (la). A time-of-addition drug assay (see Biolatti, M. et al.; “Strigolactones as Broad-Spectrum Antivirals against p-Coronaviruses through Targeting the Main Protease Mpro.” ACS Infect. Dis. 2023, vol. 9, pp.1310-1318). Metal complex (RM11 , la) was added into the cells during the pre-adsorption stage, the adsorption stage, or after the removal of inoculum (post-adsorption stage). The results reported in FIG.5 revealed that adding metal complex (RM11, la) before infection could not significantly reduce the relative virus yield compared to full treatment and / or post-infection treatment. These results indicated that metal complex (RM11, la) can inhibit HSV-1 at the late stages of the viral life cycle, and this effect is even more pronounced in HeLa cells.

[0173] Additionally, to identify the phase of HSV replication that is affected by metal complex (RM11 , la), the effect of this compound on viral protein expression was investigated in HSV-1 infected cells. The total protein cell extracts were prepared from HSV-infected (MOI 1) HFF and HeLa cells treated with metal complex (RM11, la) and harvested at different time post-infection. The expression patterns of HSV-1 ICP27 and gD were used as a reflection of immediate-early (ICP27) and late (gD) viral products, respectively. As shown in FIG. 6, an overall decrease in viral proteins was observed at 48 hpi (postinfection). These results indicated that metal complex (RM11, la) interferes with a molecular event that occurs in an early stage of the HSV replication cycle, following the viral attachment and entry phases.

[0174] Example 6: Antiviral activity of metal complex (RM11 , la) in ocular cell lines

[0175] The antiviral activity of metal complex (I) can be extended to ocular cell lines (ARPE, a spontaneously arising retinal pigment epithelial (RPE) cell line) which is of relevance for the treatment of HSV (FIG.7A).

[0176] Example 7: Antiviral properties of metal complex (RM 11 , la) against different viruses

[0177] Imiquimod has shown promising antiviral properties against different viruses, including Human Papillomavirus (HPV), Molluscum Contagiosum (MC), Respiratory Syncytial Virus (RSV), and Arthropod-borne viruses (arboviruses). The antiviral properties of the metal complex (RM11, la) are extended to other viruses, the Herpes Simplex Virus type 2 (HSV- 2) model has been included. HSV-2 is the most common cause of genital herpes, making the development of topical treatments for inhibiting HSV-2 replication strongly envisaged. As shown in FIG. 7, the metal complex (RM11, la) impairs HSV-2 replication in a dosedependent manner (ICso= 12.55 pM) and affect immediate-early (ICP8) and late (gD) viral protein expression (FIG. 8, panel C). These results show the antiviral activity of metal coordinated imiquimod according to the invention in other types of viruses.

[0178] Example 8: Effect of the ruthenium scaffold without imiquimod coordinated

[0179] The metal complex evaluated [Ru(p-cymene)Cl2]2 has the following formula: The results show that the ruthenium scaffold did not show any antiviral activity without imiquimod coordinated (comparative Example (I)). In fact, the structurally related metal complex [Ru(p-cymene) Ch]2 of formula above does not display any antiviral activity in one of the cell lines tested (HFF and HeLa) (see FIG. 9).

[0180] Example 9: Preparation of [Ru(p- cvmene)(imiquimod)Z1(PF6)ncomplexes (where Z = pyridine, 1 ,3,5-triaza-7-phosphaadamantane, imidazole, indazole, 5-fluorouracil, iodide; n = 1 or 2). General Procedure:

[0181] In a round-bottom flask, compound (RM11 , la) (1.0 eq) is dissolved in methanol (MeOH) under magnetic stirring. Next, a solution of silver nitrate (AgNO3, 0.95 eq) is added, and the reaction is stirred at room temperature for 16-24 hours. After that time, the reaction mixture is filtered using a syringe filter (0.2 pm) to remove the silver salts (AgCI). The resulting solution is transferred to another round-bottom flask, and the corresponding monodentate ligand (1.2-1.5 eq) is added. The reaction mixture is stirred overnight at room temperature. Subsequently, an excess of NH4PF6(5.0 eq) is added, and the volume is reduced to one-fourth of its original volume under reduced pressure using a rotary evaporator. This solution is allowed to crystallize at 4°C for approximately 24 hours. The solid is isolated by decanting the supernatant, washed three times with diethyl ether, and dried under reduced pressure.

[0182] Example 10: Preparation of fRu(n6-P-cvm)(imq)(py)1(PF6)2 (MAF02). Following the general procedure of Example 9, for the preparation of complex MAF02, compound (RM11 , la) (29.5 mg, 0.045 mmol), AgNO3(9.3 mg, 0.055 mmol), pyridine (py) (37.0 pL, 0.0684 mmol) as the monodentate ligand, and NH4PF6(40.0 mg, 0.245 mmol) were used. The compound was obtained as a yellow solid (30.0 mg, 78.9% yield).

[0183] Crystals suitable for X-ray diffraction were obtained by crystallization in methanol at 298 K.

[0184] 1H NMR (300 MHz, Methanol-d4) 6 9.12 (s, 1 H), 8.59 (d, J = 5.0 Hz, 2H), 7.95 - 7.87 (m, 2H), 7.60 - 7.52 (m, 1 H), 7.49 - 7.34 (m, 4H), 6.21 (dd, J = 27.0, 6.4 Hz, 2H), 5.88 (dd, J = 14.9, 6.0 Hz, 2H), 4.50 (dd, J = 7.6, 4.2 Hz, 2H), 2.63 (hept, J = 13.9, 6.7 Hz, 1 H), 2.24 (hept, J = 13.3, 6.5 Hz, 1 H), 1.86 (s, 3H), 1.13 - 1.03 (m, 9H), 0.97 (d, J = 6.6 Hz, 3H).13C NMR (126 MHz, Methanol-d4) 6 155.08, 154.02, 147.88, 140.92, 139.12, 135.70, 132.50, 131.48, 127.64, 125.35, 123.44, 119.12, 113.42, 105.15, 104.09, 87.29, 86.15, 83.94, 81.79, 56.72, 32.40, 30.25, 22.71 , 22.37, 19.62, 18.06. MS (ESI+): m / z calcd para C29H35N5RU [M - py - H]+: 475.1430; found: 475.1440.

[0185] Example 11 : fRu(n6-P-cym)(imq)(pta)1(PF6)2 (MAF03).

[0186] Following the general procedure of Example 9, to obtain complex MAF03, compound (RM11 , la) (29.5 mg, 0.045 mmol), AgNO3(7.1 mg, 0.042 mmol), 1 ,3,5-triaza-7- phosphaadamantane (pta) (8.9 mg, 0.054 mmol) as a monodentate ligand, and NH4PF6(39.2 mg, 0.225 mmol) were used. The compound is obtained as a light yellow solid (36.5 mg, 87.9%). Crystals suitable for X-ray diffraction were obtained by crystallization in methanol at 298 K

[0187] MAF03

[0188] 1H N MR (400 MHz, Acetone-cfe) 6 8.86 (s, 1 H), 8.16 (d, J = 9.0 Hz, 1 H), 7.66 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.58 (dd, J = 8.4, 1.2 Hz, 1 H), 7.48 (ddd, J = 8.3, 7.2, 1.3 Hz, 1 H), 6.31 (d, J = 6.2 Hz, 1 H), 6.28 - 6.18 (m, 2H), 6.17 (d, J = 6.2 Hz, 1 H), 4.65 (dd, J = 7.6, 2.5 Hz, 2H), 4.43 (s, 6H), 4.20 (s, 6H), 2.95 (hept, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.09 (dd, J = 6.6, 2.0 Hz, 6H). A multiplet corresponds to the CH signal of imiquimod below the singlet at 2.41 ppm.13C NMR (126 MHz, Acetone-cfe) 5 206.19, 152.74, 148.78, 138.71 , 136.44, 132.98, 131.34, 125.20, 123.53, 119.00, 113.65, 112.52, 104.14, 89.34, 89.32, 89.28, 89.25, 88.83, 88.81 , 87.19, 87.16, 72.96 (d, JPC= 7.7 Hz), 56.39, 52.04 (d, JPC= 14.9 Hz), 32.08, 23.03, 22.99, 19.73, 19.66, 19.11.31P NMR(126 MHz, Acetone-d6) 5 -33.55 (s, 1 P, pta), -143.57 (hept, JPF = 708.8 Hz, PF6). MS (ESI+): m / z calcd para C30H42N7PRU [M - H]+: 632.2199; found: 632.2211.

[0189] Example 12: Preparation of rRu(n6-P-cym)(imq)(im)1(PF6)2 (MAF04).

[0190] Following the general procedure of Example 9, to obtain complex MAF04, compound (RM11 , la) (30 mg, 0.046 mmol), AgNO3(7.4 mg, 0.043 mmol), imidazole (im) (3.7 mg, 0.0543 mmol) as a monodentate ligand, and NH4PF6(36.7 mg, 0.225 mmol) were used. The compound is obtained as a light yellow solid (35.2 mg, 93.8%). Crystals suitable for X-ray diffraction were obtained by crystallization in methanol at 298 K.

[0191] 1H NMR (300 MHz, Metanol-d4) 5 8.99 (s, 1 H), 7.90 (d, J = 8.1 Hz, 1H), 7.83 (s, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.45 (d, J = 8.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.09 (s, 1 H), 6.97 (s, 1 H), 6.19 (d, J = 5.9 Hz, 1 H), 6.08 (d, J = 6.0 Hz, 1H), 5.84 (dd, J = 10.0, 6.2 Hz, 2H), 4.46 (dd, J = 7.6, 3.8 Hz, 2H), 2.61 (hept, J = 6.5 Hz, 1H), 2.21 (hept, J = 7.4 Hz, 1H), 1.90 (s, 3H), 1.15 - 1.01 (m, 10H), 0.96 (d, J = Q.Q Hz, 3H).13C NMR (75 MHz, Metanol-d4) 5 153.83, 147.64, 139.77, 139.12, 135.86, 132.19, 131.28, 130.62, 125.13, 123.33, 119.54, 118.97, 113.44, 111.39, 105.20, 103.55, 86.69, 85.45, 83.19, 81.15, 56.55, 32.42, 30.27, 22.76, 22.40, 19.62, 19.57, 18.26. MS (ESI+): m / z calcd para C27H34N6Ru [M - H]+: 543.1810; found: 543.1826.

[0192] Example 13: Preparation of fRu(n6-P-cym)(imq)(in)1(PF6)2 (MAF05).

[0193] Following the general procedure of Example 9, the synthesis of complex MAF05 was carried out using compound (RM11, la) (20.0 mg, 0.030 mmol), AgNO3(4.7 mg, 0.028 mmol), indazole (in) (5.32 mg, 0.045 mmol) as a monodentate ligand, and NH4PF6(24.3 mg, 0.150 mmol). The compound was obtained as a light yellow solid (26.5 mg, 87.5%). Crystals suitable for X-ray diffraction were obtained by crystallization in methanol at 298 K.

[0194] 1H NMR (300 MHz, Methanol-d4) 6 9.04 (s, 1H), 8.19 (s, 1H), 7.88 (d, J = 8.2 Hz, 1 H), 7.68 (d, J = 8.3 Hz, 1H), 7.59 - 7.42 (m, 4H), 7.41 - 7.32 (m, 1H), 7.17 (t, J = 7.5 Hz, 1 H), 6.36 (d, J = 5.8 Hz, 1 H), 6.22 (d, J = 6.0 Hz, 1 H), 6.00 (t, J = 6.1 Hz, 2H), 4.47 (d, J = 7.6 Hz, 2H), 2.69 - 2.51 (m, 1 H), 2.32 - 2.10 (m, 1H), 1.91 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H).13C NMR (75 MHz, Methanol-d4) 6 148.07, 143.28, 140.40, 139.02, 135.67, 132.56, 131.46, 130.35, 125.38, 124.13, 123.70, 123.45, 121.53, 119.08, 113.42, 111.40, 110.79, 105.61 , 104.27, 87.25, 86.07, 84.01 , 81.94, 56.67, 32.50, 30.23, 22.77, 22.23, 19.55, 18.42. MS (ESI+): m / z calcd para CaiHaeNeRu [M - H]+: 593.1961 ; found: 593.1966.

[0195] Example 14: Preparation of fRu(n6-P-cym)(imq)(5-fu)1PF6 (MAF09).

[0196] Following the general procedure of Example 9, the synthesis of complex MAF09 was carried out using compound (RM11, la) (50.0 mg, 0.076 mmol), AgNO3(12.1 mg, 0.072 mmol), and potassium salt of 5-fluorouracil (5-Fll, 15.21 mg, 0.0812 mmol) as a monodentate ligand. The compound was obtained as a yellow solid (33.30 mg, 82.7%).

[0197] Following a slightly modified procedure (described by X. Wang et al.; J. Inorg. Biochem. 2003, vol.94, pp.186-192), the potassium 5-Fll salt was also obtained by reacting equimolar amounts of 5-Fll (100.0 mg, 0.768 mmol) and KOH (46.2 mg, 0.823 mmol) in MeOH (2 mL) under magnetic stirring at room temperature for 2 hours. After this time, a crystalline white solid was obtained, filtered, and washed three times with cold MeOH (~ 4 °C). Once dried under reduced pressure, it was ready for use without further purification.

[0198] MAF09

[0199] 1H NMR (300 MHz, Acetone-cfe) 6 8.99 (s, 1H), 7.92 (d, J = 6.8 Hz, 1 H), 7.56 - 7.42 (m, 2H), 7.32 (t, J = 7.2 Hz, 2H), 6.19 (d, J = 5.0 Hz, 1 H), 6.01 (d, J = 6.0 Hz, 1H), 5.84 (t, J = 4.8 Hz, 2H), 4.59 - 4.29 (m, 2H), 2.90 - 2.74 (m, 1H), 2.20 (s, 3H), 2.18 - 2.10 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.6 Hz, 3H).13C NMR (75 MHz, Acetone-cfe) 6 158.92 (d, JFC= 25.2 Hz), 157.55, 152.95, 148.69, 142.82 (d, JFC= 225.9 Hz), 140.83 (d, JFC= 26.5 Hz), 138.50, 135.70, 130.95, 130.66, 124.72, 123.12, 118.75, 113.55, 104.47, 102.09, 84.76, 84.08, 83.89, 81.24, 55.76, 31.90, 22.99, 22.24, 19.47, 19.34, 18.76. A multiplet corresponds to the CH signal of imiquimod below the singlet at 2.41 ppm. MS (ESI+): m / z calcd para C28H32FN6O2RU [M]+605.1609; found 605.1621. Example 15: Preparation of fRu(n6-P-cym)(imq)(l)1PF6 (MJ327).

[0200] Following the general procedure of Example 9, to obtain complex MJ327, compound (RM11 , la) (20 mg, 0.03 mmol), AgNO3(6.7 mg, 0.039 mmol), and KI (15 mg, 0.09 mmol) as a monodentate ligand were used. The compound was obtained as a dark reddish solid (21 mg, 89.1 %).

[0201] 1H N MR (300 MHz, Methanol-cU) 6 8.81 (s, 1 H), 7.92 (dd, J = 8.1 , 1.3 Hz, 1 H), 7.54 (ddd, J = 8.5, 7.2, 1 .3 Hz, 1 H), 7.47 - 7.29 (m, 2H), 5.88 (td, J = 4.4, 2.2 Hz, 2H), 5.81 - 5.56 (m, 2H), 4.47 (qd, J = 14.4, 7.6 Hz, 2H), 2.98 (m, 1 H), 2.40 (s, 3H), 2.30 - 2.17 (m, 1 H), 1.34 - 1 .24 (m, 6H), 1 .05 (dd, J = 18.7, 6.6 Hz, 6H) ppm. MS (ESI+): m / z calcd for C24H29N4 U [M-l-H]+475.1430; found 475.1435.

[0202] Example 16. Preparation of Sinthesis de nrfn^CsMesICKImiquimodllfPFsl (where M = Ir, Rh and CsMes = 1 ,2,3,4,5-pentamethylcyclopentadienyl) General Procedure:

[0203] In a Schlenk flask under an inert atmosphere, the corresponding dimer [M(n5-C5Me5)CI]2 (M = Ir or Rh) (1.0 eq), imiquimod (2.0 eq) and NH4PF6 (2.0 eq) are dissolved in 1 mL of MeOH and 2 mL of CH2CI2. The reaction mixture is stirred for 16 h at room temperature. After this time, the solvent is evaporated, and the residue is washed with diethyl ether (2 x 3 mL). Finally, the product is dried under vacuum. Example 17. Preparation of nr(n5-C5Me5)CI(imq)1PF6 (AH11). Following the general procedure of Example 16, compound AH11 was prepared using [lr(n5-C5Me5)CI]2 (500 mg, 0.6 mmol), imq (302 mg, 1.3 mmol), and NH4PF6(205 mg, 1.3 mmol). The compound was obtained as a light brown solid with a 73% yield.

[0204] 1H NMR (300 MHz, DMSO) 8 8.35 (s, 1 H), 8.10 (d, 1 H, J= 8.06), 7.74 (d, 1 H, J= 8.31), 7.58 (dd, 1 H), 7.43 (dd 1 H), 7.15 (s, 2H), 4.45 (d, 2H, J= 7.42), 2.17 (m, 1 H), 1.63 (s, 15H), 0.93 (d, 6H, J= 6.64).13C NMR (75 MHz, DMSO) 8 150.7, 144.8, 132.9, 128.2,

[0205] 127.2, 123.1 , 122.7, 121.2, 113.9, 109.9, 92.1 53.5, 28.4, 19.3, 8.2. MS (ESI+): m / z calcd for C24H29N4RU [M]+603.1852; found 603.1861.

[0206] Example 18. Preparation of (AH12). AH12

[0207] Following the general procedure of Example 16, compound AH12 was synthesized using [Rh(n5-C5Me5)CI]2 (500 mg, 0.8 mmol), imq (389 mg, 1.6 mmol), and NH4PF6(264 mg, 1.6 mmol). The compound was obtained as an orange solid with an 81% yield.1H NMR (300 MHz, DMSO) 58.30 (s, 1H), 8.07 (d, 1 H, J= 8.17), 7.70 (d, 1 H, J= 8.16), 7.54 (dd ancho, 1H), 7.38 (dd ancho, 1H), 7.16 (s, 2H), 4.44 (d, 2H, J= 7.36), 2.16 (m, 1H), 1.62 (s, 15H), 0.93 (d, 6H, J= 6.71).13C (75 MHz, DMSO) 5 150.8, 144.6, 132.7, 128.0, 127.2, 123.1, 122.9, 121.1, 114.0, 109.5, 98.8, 53.5, 28.4, 19.3, 8.6. MS (ESI+): m / z calcd for C24H29N4Ru [M]+513.1279; found 513.1287.

[0208] Example 19: Preparation and characterization of new imiquimod-based metal complexes of the type (Ic), fPt(bpy)(imq)1CI2(MJ349).

[0209] The precursor Pt(bpy)CI2(described by M. Grehl et al.; Inorg.Chem. 1994, vol. 33, pp.3877-3885) (40 mg, 0.095 mmol) was suspended in 5 mL of deionized water, and silver nitrate (AgNCh, 34 mg, 0.209 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours. Following the reaction period, the mixture was centrifuged to remove the precipitated silver chloride, and the supernatant containing [Pt(bpy)(H2O)2] was retained for further steps. Imiquimod (27 mg, 0.114 mmol, 1.2 eq) was added to the filtrate, and the reaction mixture was stirred at 50°C for 48 hours. After completion of the reaction, the suspension was filtered to remove any solid impurities and the filtrate was concentrated under reduced pressure to yield a solid residue. This residue was dissolved in methanol (MeOH) and precipitated by the addition of diethyl ether (Et2O, 3 x 5 mL), resulting in the formation of a dark yellowish solid (15 mg, 23.8%).

[0210] 1H NMR (300 MHz, D2O) 5 8.88 (d, J = 6.0 Hz, 1 H), 8.46 (m, 2H), 8.13 (m, 2H), 7.98 - 7.85 (m, 2H), 7.71 - 7.24 (m, 5H), 7.20 - 6.97 (m, 1H), 4.26 (d, J = 7.5 Hz, 2H), 2.21 - 2.00 (m, 1 H), 0.86 (d, J = 6.6 Hz, 6H). MS (ESI+): m / z calcd for C24H23N6Pt [M-H]+590.1626; found 590.1634.

[0211] Example 20 Preparation and characterization of new imiquimod-based metal complexes of the type (ld) lr(ppy)2(imq)irPF6l (AH15). In a Schlenk flask under an inert atmosphere, [lr(ppy)2(NCMe)2]PF6(35 mg, 0.05 mmol) and imiquimod (14 mg, 0.06 mmol) were added and dissolved in CH2CI2 and MeOH. The reaction was stirred for 3 hours. After this time, the product was filtered, washed with ether, and dried under vacuum. The compound was obtained as a yellow solid with a 64% yield.

[0212] 1H NMR (300 MHz, DMSO) 6 11.57 (s, 1 H), 8.66 (d, 1 H, J= 5.21), 8.21 (m, 2H), 7.92 (m, 5H), 7.81 (m, 2H), 7.56 (d, 2H, J= 3.89), 7.30 (m, 2H), 7.19 (m, 2H), 6.89 (m, 2H), 6.76 (m, 2H), 6.26 (d, 1 H, J= 7.16), 6.20 (d, 1 H, J= 7.09), 4.37 (d, 2H, J= 7.32), 2.05 (m, 1 H), 0.88 (d, 3H, J = 6.48), 0.68 (d, 3H, J = 6.44).13C NMR (75 MHz, DMSO) 8 167.7, 167.2,

[0213] 153.8, 149.6, 148.9, 148.6, 147.4, 144.8, 144.3, 143.8, 142.7, 138.1 , 137.9, 137.8, 134.9,

[0214] 131.8, 131.5, 129.5, 129.2, 129.1 , 124.6, 124.2, 123.2, 123.1 , 123.0, 122.1 , 121.2, 121.0, 119.2, 119.1 , 117.6, 112.2, 53.6, 28.4, 19.0, 18.7. MS (ESI+): m / z calcd for C24H29N4RU [M]+741.2372; found 741.2312.

[0215] Example 21 : Preparation and characterization of imiquimod-Ru trimer clusters Preparation of fRu(n6-P-cvm)(imq)]3(PF6)6 (ACC71).

[0216] In a round-bottom flask, compound (RM11 , la) (23.0 mg, 0.035 mmol) is dissolved in methanol (MeOH) under magnetic stirring. Next, a solution of silver nitrate (AgNO3, 5.6 mg, 0.033 mmol) is added, and the reaction is stirred, protected from light at room temperature for 16-24 hours. After that time, the reaction mixture is filtered using a syringe filter (0.2 pm) to remove the silver salts (AgCI). The resulting solution is transferred to another round-bottom flask, and 1 -aminoadamantane (8.0 mg, 0.053 mmol) is added. The reaction mixture changed from orange to red instantaneously and, after 1 h stirring started to precipitate. The reaction mixture is left to stir for and addition 1.5 h and then is kept in the fridge overnight. The bright orange solid is isolated by decanting the supernatant, washed three times with diethyl ether, and dried under reduced pressure (9.2 mg, 34%). Crystals suitable for X-ray diffraction were obtained by crystallization in methanol at 298 K.1H NMR (300 MHz, Acetone-cfe) 6 9.28 (s, 1 H), 8.94 (d, J = 8.9 Hz, 1 H), 7.63 - 7.50 (m, 2H), 7.06 (t, J = 8.1 Hz, 1 H), 6.92 (d, J = 7.0 Hz, 1 H), 6.79 (d, J = 5.9 Hz, 1 H), 6.71 (d, J = 5.7 Hz, 1 H), 5.97 (d, J = 5.8 Hz, 1 H), 4.37 (dd, J = 14.4, 6.4 Hz, 1 H), 4.18 (dd, J = 14.4, 8.6 Hz, 1 H), 1.98 (s, 3H), 1.96 - 1.89 (m, 1 H), 1.07 (dd, J = 10.0, 7.0 Hz, 6H), 0.91 (d, J = Q.7 Hz, 3H), 0.49 (d, J = 6.6 Hz, 3H). A multiplet corresponding to a CH p-cym is under the residual solvent peak.13C NMR (75 MHz, Acetone-cfe) 5 160.51 (C), 147.88(CH), 147.81 (C), 135.27(C), 130.01 (C), 128.62(CH), 128.19(CH), 122.45(CH), 122.05(CH), 116.04(C), 88.63(CH), 86.08(CH), 84.68(CH), 79.31 (CH), 56.08(CH2), 32.36(CH), 29.41 (CH, inside residual peak), 22.75(CH3), 19.58(2xCH3), 19.10(CH3). Two missing quaternary carbons are located between 100-106 ppm, assigned by correlations on1H-13C HMBC experiment. MS (ESI+): m / z calcd para C24H29N4RU [M - py - H]+: 475.1430; found: 475.1440

[0217] Example 22: X ray data of some of the complexes:

[0218] See FIGs1 B-E and the following Table 2: Table 2:

[0219] Example 23: Cell viability experiments

[0220] The cell viability experiments have been performed in three different cell lines (HeLa, HFF and VERO). For all three cell lines, the viability has been determined at 25 pM under the same experimental conditions using the MTT assay. Experiments were performed as reported in the “General methods” section of the document. The most active compounds in the HeLa tumoral cell line were AH 15 and ACC71. All derivatives showed modest toxicity in non-tumoral cell lines (HFF and VERO). Striking is the case of ACC71 , which is significantly less toxic than imiquimod. FIG. 10 shows cell viability at 25 pM for the second generation of imiquimod metal complexes in HeLa, HFF, and VERO cells, in comparison with (RM11, la) and imiquimod.

[0221] Example 24: Antiviral activity

[0222] To determine the antiviral activity of the complexes included in this patent, an HSV-1 virus yield reduction assay have been performed in different cell lines (HeLa, HFF and VERO). A 25 pM concentration of dose for the complexes based on the MTT assays was selected to do not compromise the cell viability while performing the experiment, with the exception of AH15, ACC71 and MJ349 where the dose was reduced to 12.5 pM when working with HeLa cells and for AH 15 where the dose was reduced to 12.5 pM when working with VERO cells. Experiments were performed as reported in the “General methods” section of the patent. The most active second-generation derivatives against HSV-1 in HeLa cells were ACC71, MAF09, AH15 and MJ349. In HFF and in VERO, ACC71 and AH15 were confirmed as very active. FIG. 11 shows the antiviral activity of the second-generation metal imiquimod derivatives at 25 pM against HSV-1 with the exception of AH15, ACC71 and MJ349 where the dose was reduced to 12.5 pM when working with HeLa cells and for AH 15 where the dose was reduced to 12.5 pM when working with VERO cells. HeLa, HFF, and VERO cells were treated as described in the methods with the indicated compounds. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell-associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL.

[0223] It is important to highlight that MJ349 (Pt square planar complex) and AH15 (Ir octahedral complex) show antiviral activity higher than imiquimod in all the cell lines demonstrating that other types of complexes with different geometries than (RM11 , la) can be active. This confirms the generality of the approach of the present invention.

[0224] Example 25 : Antiviral activity against HSV-1 at different concentrations of the drug candidates.

[0225] Compounds MAF04, MAF05 and ACC71 to further explore the antiviral activity against HSV-1 at different concentrations of the drug candidates. FIG. 12 shows the antiviral activity of three selected compounds of the second-generation imiquimod derivatives, named herein metal complex MAF04, MAF09, ACCC71 against HSV-1. HeLa and HFF cells were treated as described in the methods with different concentrations of the compound. The extent of HSV-1 replication was then assessed by titrating the infectivity of supernatants and cell- associated viruses using a standard plaque assay in VERO cells. Plaques were microscopically counted, and the mean plaque counts for each molecule were expressed as PFU / mL. The three complexes MAF04, MAF09 and ACC71 display a concentration dependent capacity to inhibit the replication of the HSV-1 virus, with MAF09 and ACC71 being the most potent in HeLa and HFF cells.

[0226] Example 26: mechanism of action (affecting the virus replication)

[0227] FIG. 13 shows the effect of the imiquimod derivative MAF09 on the expression of viral proteins in HSV-1 infected HeLa and VERO cells. Protein levels of HSV-1 ICP4, VP16 and gD were assessed at different times post-infection (hpi) by Western blotting.

[0228] FIG. 14 shows the effect of the imiquimod derivative ACC71 on the expression of viral proteins in HSV-1 infected HeLa, HFF and VERO cells. Protein levels of HSV-1 ICP4, VP16 and gD were assessed at different times post-infection (hpi) by Western blotting.

[0229] MAF09 and ACC71 impairs HSV-1 replication, affecting the expression of early (ICP4), and late (VP16 and gD) viral proteins .

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Claims

Claims1 . A neutral or cationic metal complex of formula (I),wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2.R2 is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;L is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, t-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)cyclohexane, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5-tetramethylcyclopenta- 1 ,3-dien-1 -yl)-1 , 1 '-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-aminehydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, halogen, amine, imidazole, indazole, 5-fluorouracil, triazole, maleimide, carbonyl, 1 ,3,5- triazaC-7-phosphaadamantane phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V-heterocyclic carbene, hydroxyl, water, N,N- bound ethylenediamine, pyridine monodentate ligand, 2,2’-bipyridyl derivative, 1 ,10- phenanthroline derivative, N,O-bound picolinate?2-picolinic acid, 6-(aminomethyl)picolinic acid, 4-(Hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligands; the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the triazole ligand is selected from the group consisting of 1 ,2,4-triazole, 1 H-1 ,2,3-triazole, 4-Amino-1 ,2,4-triazole, 3-amino-1 H-1 ,2,4-triazole, 1 H-1 ,2,4-triazole-3-thiol, 3-amino-1 ,2,4- triazole, I H-1 ,2,3 triazole-1-ethanol, 4-methyl-4H-1 ,2,4-triazole-3-thiol, and 3-methyl-1 H- 1 ,2,4-triazole; the phosphine ligand is selected from the group consisting of 1 ,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1 ,1',4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol;the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl isocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, furfuryl alcohol; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine; the 2,2'-bipyridyl derivative ligand is selected from the group consisting of 2,2’-bipyridine, 4,4'-bis(di-t-butyl)-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 6-bromo-2,2'-bipyridine, 4- bromo-2,2'-bipyridine, 5-bromo-2,2'-bipyridine, bimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-3,3'-diol, 5,5'-bis(trifluoromethyl)-2,2'-bipyridine, 5,5'-bimethyl-2,2'-dipyridyl, 2,2'-([2,2'-bipyridine]-5,5'-diyl)diacetonitrile, 6-chloro-2,2'-bipyridine, 6-fluoro-2,2'- bipyridine, [2,2'-bipyridine]-4-carbaldehyde, [2,2'-bipyridine]-4,4'-diamine, and 4,4'- diethynyl-2,2'-bipyridine; the 1 ,10-phenanthroline derivative is selected from the group consisting of 1 ,10- phenanthroline, 1 ,10-Phenanthrolin-5-amine, 5,6-Diamino-1 ,10-phenanthroline, 4,7- dihydroxy-1 ,10-phenanthroline, 4,7-dimethoxy-1 ,10-phenanthroline 4,7-dichloro-1 ,10-phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, and dipyrido[3,2-a:2',3'-c]phenazine;the C,N bound ligand is selected from the group consisting of 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2-(2,4-difluorophenyl)pyridine, 2- (4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2-phenylbenzothiazole, 2-(2- benzo[b]thienyl)pyridine (btp), and 2-(3-methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2- thienyl)pyridine, 1-phenylisoquinoline, 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4-difluorophenyl)-5-fluoropyridine, 2-(2,4- difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)-5-methoxypyridine; n is an integer from 1 to 4;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis [3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3.

2. The metal complex according to claim 1 , wherein the metal is selected from the group consisting of Ru, Fe, Co, Ir, Rh, Os, Pt, Mn, Cr, Ni, Re, Au, and Cu.

3. The metal complex according to any of the claims 1-2, having the formula (la),wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2 is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2-NH-CH2-CH3;M is a transition metal;Li is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, t-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1,3-dien-1-yl)cyclohexane, (2,3,4,5-tetramethylcyclopenta-1,3-dien-1-yl)benzene,4-(2,3,4,5-tetramethylcyclopenta-1.3-dien-1 -yl)-1 , 1 '-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1,3-dien-1- yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5- tetramethylcyclopenta-1,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1,3-diene;L2is a ligand selected from the group consisting of halogen, amine, pyridine, 2- phenylpyridine, 4-bromo-2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6- phenylpyridine, 4-methyl-2-phenylpyridine, imidazole, indazole, 5-fluorouracil, maleimide, carbonyl, 1 ,3,5-triaza-7-phosphaadamantane, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, hydroxyl, and water; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the phosphine ligand is selected from the group consisting of 1,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine,tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1,T,4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, and furfuryl alcohol;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and. m is an integer from 0 to 3.

4. The metal complex according to claim 3, wherein Li is a ligand selected from the group consisting of p-cymene, benzene, hexamethylbenzene, cyclopentadiene, 1 , 2, 3,4,5- pentamethylcyclopentadiene, and 1,5-cyclooctadiene.

5. The metal complex according to any of the claim 3-4, wherein L2 is a ligand selected from the group consisting of halogen, pyridine, phosphine, thiol, nitril, and water.

6. The metal complex according to any of the claims 1-2, having the formula (lb), (lb) wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;L3 and l_4 are equal or different and are ligands independently selected from the group consisting of halogen, amine, pyridine derivative, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanate, isocyanate, thiocyanate, ether, alcohol, / V- heterocyclic carbene, hydroxyl, and water; the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the phosphine ligand is selected from the group consisting of 1 ,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine;the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1 ,T,4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, and furfuryl alcohol;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3.

7. The metal complex according to any of the claims 1-2, having the formula (Ic),(Ic) wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;Ls- L5 is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, 2,2'-bipyridyl derivative, 1 ,10-phenanthroline derivative, N,O-bound picolinate?2-picoli nic acid, 6-(Aminomethyl)picolinic acid, 4-(Hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, and C,N bound ligands; the 2,2'-bipyridyl derivative ligand is selected from the group consisting of 2,2’-bipyridine, 4,4’-bis(di-t-butyl)-2,2’-bipyridine, 4,4’-dimethyl-2,2’-bipyridine, 6-bromo-2,2'-bipyridine, 4- bromo-2,2’-bipyridine, 5-bromo-2,2’-bipyridine, bimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-3,3'-diol, 5,5'-bis(trifluoromethyl)-2,2'-bipyridine, 5,5'-bimethyl-2,2'-dipyridyl, 2,2’-([2,2’-bipyridine]-5,5’-diyl)diacetonitrile, 6-chloro-2,2’-bipyridine, 6-fluoro-2,2’- bipyridine, [2,2’-bipyridine]-4-carbaldehyde, [2,2’-bipyridine]-4,4’-diamine, and 4,4’- diethynyl-2,2’-bipyridine; the 1 ,10-phenanthroline derivative ligand is selected from the group consisting of 1 ,10- phenanthroline, 1 ,10-phenanthrolin-5-amine, 5,6-diamino-1,10-phenanthroline, 4,7- dihydroxy-1 ,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, 4,7-Dichloro-1 ,10- phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, and dipyrido[3,2-a:2',3'-c]phenazine; the C,N bound ligand is selected from the group consisting of 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2-(2,4-difluorophenyl)pyridine, 2- (4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2-phenylbenzothiazole,, 2-(2- benzo[b]thienyl)pyridine (btp), and 2-(3-methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2- thienyl)pyridine, 1-phenylisoquinoline, 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4-difluorophenyl)-5-fluoropyridine, 2-(2,4- difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)-5-methoxypyridine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), tris(tetrachlorobenzenediolato)phosphate), and m is an integer from 0 to 3.

8. The metal complex according to any of the claims 1-2, which is selected from the group consisting ofa) metal complex having the formula (Id),wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;Le-Le and L7-L7 are equal or different and are bidentate ligands selected from the group consisting of N, N-bound ethylenediamine, 2,2’-bipyridine, 4,4'-bis(di-t-butyl)-2,2'- bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 6-bromo-2,2'-bipyridine, 4-bromo-2,2'-bipyridine, 5-bromo-2,2'-bipyridine, bimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-3,3'- diol, 5,5'-bis(trifluoromethyl)-2,2'-bipyridine, 5,5'-bimethyl-2,2'-dipyridyl, 2,2'-([2,2'-bipyridine]-5,5'-diyl)diacetonitrile, 6-chloro-2,2'-bipyridine, 6-fluoro-2,2'- bipyridine, [2,2'-bipyridine]-4-carbaldehyde, [2,2'-bipyridine]-4,4'-diamine, 4,4'-diethynyl- 2,2'-bipyridine, 1 ,10-phenanthroline, 1 ,10-phenanthrolin-5-amine, 5,6-Diamino-1 ,10- phenanthroline, 4,7-dihydroxy-1 ,10-phenanthroline, 4,7-dimethoxy-1 ,10-phenanthroline 4,7-dichloro-1 ,10-phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, dipyrido[3,2- a:2',3'-c]phenazine, N,O-bound picolinate?2-picolinic acid, 6-(Aminomethyl)picolinic acid 4-(Hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, and C,N bound ligands;the C,N bound ligand is selected from the group consisting of 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2-(2,4-difluorophenyl)pyridine, 2- (4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2-phenylbenzothiazole, 2-(2- benzo[b]thienyl)pyridine (btp), and 2-(3-methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2- thienyl)pyridine, 1-phenylisoquinoline, 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4-difluorophenyl)-5-fluoropyridine, 2-(2,4- difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)-5-methoxypyridine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3; b) a metal complex of formula le;wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;LS-I-8 is a bidentate ligand selected from the group consisting of N, N-bound ethylenediamine, 2,2'-bipyridyl derivatives, 1 ,10-phenanthroline derivative, N,O-bound picolinate?2-picoli nic acid, 6-(aminomethyl)picolinic acid, 4-(hydroxymethyl) picolinic acid, O,O-bound acetlylacetonate, 2-phenylpyridine, 4-bromo-2-phenylpyridine, 5-chloro-2- phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2-phenylpyridine, and C,N bound ligands;Lg and L are equal or different and are ligands selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanate, isocyanate, thiocyanate, ether, alcohol, / V- heterocyclic carbene, hydroxyl, and water; the 2,2'-bipyridyl derivative ligand is selected from the group consisting of 2,2’-bipyridine, 4,4’-bis(di-t-butyl)-2,2’-bipyridine, 4,4’-dimethyl-2,2’-bipyridine, 6-bromo-2,2'-bipyridine, 4- bromo-2,2’-bipyridine, 5-bromo-2,2’-bipyridine, bimethyl 2,2'-bipyridine-4,4'-dicarboxylate, 2,2'-bipyridine-3,3'-diol, 5,5'-bis(trifluoromethyl)-2,2'-bipyridine, 5,5'-bimethyl-2,2'-dipyridyl, 2,2’-([2,2’-bipyridine]-5,5’-diyl)diacetonitrile, 6-chloro-2,2’-bipyridine, 6-fluoro-2,2’- bipyridine, [2,2’-bipyridine]-4-carbaldehyde, [2,2’-bipyridine]-4,4’-diamine, and 4,4’- diethynyl-2,2’-bipyridine; the 1 ,10-phenanthroline derivative ligand is selected from the group consisting of 1 ,10- phenanthroline, 1 ,10-phenanthrolin-5-amine, 5,6-diamino-1 ,10-phenanthroline, 4,7- dihydroxy-1 ,10-phenanthroline, 4,7-dimethoxy-1 ,10-phenanthroline, 4,7-Dichloro-1 ,10-phenanthroline, 1 ,10-phenanthroline-5, 6-dione, neocuproine bathophenanthroline, bathocuproine, pyrazino[2,3-f] [1 ,10]phenanthroline, and dipyrido[3,2-a:2',3'-c]phenazine; the C,N bound ligand is selected from the group consisting of 2-phenylpyridine, 4-bromo- 2-phenylpyridine, 5-chloro-2-phenylpyridine, 2-methyl-6-phenylpyridine, 4-methyl-2- phenylpyridine, 2-[2,4-bis(trifluoromethyl)phenyl]pyridine, 2-(2,4-difluorophenyl)pyridine, 2- (4-fluorophenyl)pyridine, 2-phenylbenzoxazole, 2-phenylbenzothiazole, 2-(2- benzo[b]thienyl)pyridine (btp), and 2-(3-methoxyphenyl)pyridine, benzo(h)quinoline, 2-(2- thienyl)pyridine, 1-phenylisoquinoline, 7,8-benzoquinoline, 2-(2,4-difluorophenyl)pyridine, 4-chloro-2-phenylquinoline, 2-(2,4-difluorophenyl)-5-fluoropyridine, 2-(2,4- difluorophenyl)pyridine, and 2-(2,4-difluorophenyl)-5-methoxypyridine;the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the triazole ligand is selected from the group consisting of 1 ,2,4-triazole, 1 H-1 ,2,3-triazole, 4-Amino-1 ,2,4-triazole, 3-amino-1 H-1 ,2,4-triazole, 1 H-1 ,2,4-triazole-3-thiol, 3-amino-1 ,2,4- triazole, 1 H-1 , 2, 3 triazole-1-ethanol, 4-methyl-4H-1 ,2,4-triazole-3-thiol, and 3-methyl-1 H- 1 ,2,4-triazole; the phosphine ligand is selected from the group consisting of 1 ,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1 ,1',4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether;the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, furfuryl alcohol; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3; and c) a metal complex of formula (If):wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;Ln , L12, L13 and L are equal or different and are ligands selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, nitrile, azide, cyanide, isocyanate, thiocyanate, ether, alcohol, / V-heterocyclic carbene, hydroxyl, and water; the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the triazole ligand is selected from the group consisting of 1 ,2,4-triazole, 1 H-1 ,2,3-triazole, 4-Amino-1 ,2,4-triazole, 3-amino-1 H-1 ,2,4-triazole, 1 H-1 ,2,4-triazole-3-thiol, 3-amino-1,2,4- triazole, I H-1,2,3 triazole-1-ethanol, 4-methyl-4H-1 ,2,4-triazole-3-thiol, and 3-methyl-1 H- 1 ,2,4-triazole; the phosphine ligand is selected from the group consisting of 1,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1,1',4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine; the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate;the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, furfuryl alcohol; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and Tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3; d) A metal complex of formula (Ig):Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2 is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;L15 is a tridentate ligand selected from the group consisting of tris(pyrazolyl)borate, 2,2':6',2"-terpyridine, 6,6"-dibromo-2,2':6',2"-terpyridine, bis(2-pyridylmethyl)amine, bis(2- diphenylphosphino)ethyl ether, bis(2-diphenylphosphino)ethyl sulfane, bis(2- diphenylphosphino)ethyl amine, 1 ,3-bis(diphenylphosphinomethylbenzene, 1 ,3-bis((1 H- imidazol-1-yl)methyl)benzene, 1 , 1 , 1 -tris(pyrid-2-yl)ethane, 1 ,4,7-trithiacyclononane, 1 ,4,7- triazacyclononane, 2,6-Bis[4-phenyl-2-oxazolinyl]pyridine, and biethylenetriamine;Lie is a ligand selected from the group consisting of halogen, amine, pyridine monodentate ligand, imidazole, triazole, maleimide, carbonyl, phosphine, thiol, selenol, silanol, nitrile, azide, cyanate, isocyanate, thiocyanate, ether, alcohol, carboxylate, / V- heterocyclic carbene, hydroxyl, and water; the amine ligand is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, and isopropyl amine; the imidazole ligand is selected from the group consisting of 2-methylimidazole, 1-ethyl- 1 H-imidazole, 4-(4-fluorophenyl)-1 H-imidazole, imidazole-2-carboxylic acid, 1-(2- hydroxyethyl)imidazole, 1 -(trimethylsilyl)imidazole, 1-(4-chlorophenyl)imidazole, 1-(4- fluorophenyl)imidazole, and 1-(3-aminopropyl)imidazole; the triazole ligand is selected from the group consisting of 1 ,2,4-triazole, 1 H-1 ,2,3-triazole, 4-Amino-1 ,2,4-triazole, 3-amino-1 H-1 ,2,4-triazole, 1 H-1 ,2,4-triazole-3-thiol, 3-amino-1 ,2,4- triazole, I H-1 ,2,3 triazole-1-ethanol, 4-methyl-4H-1 ,2,4-triazole-3-thiol, and 3-methyl-1 H- 1 ,2,4-triazole; the phosphine ligand is selected from the group consisting of 1 ,3,5-triaza-7- phosphatricyclo[3.3.1.13,7]decane, tri(o-tolyl)-phosphine, tris(trimethylsilyl)phosphine, tris(4-trifluoromethylphenyl)phosphine, tris(hydroxypropyl)phosphine, tris(1 - pyrrolidinyl)phosphine, tri(p-tolyl)phosphine, tris(2,4,6-trimethylphenyl)phosphine, tris(3,5- dimethylphenyl)phosphine, and triphenylphosphine; the thiol ligand is selected from the group consisting of biphenyl-4-thiol, 1 ,1',4',1"- terphenyl-4-thiol, 2-propene-1 -thiol, methanethiol, ethanethiol, 2-propanethiol, 2- mercaptobenzothiazole, 2-methyl-1 -butanethiol, and 4-tert-butylthiophenol, and cysteine;the selenol ligand is benzeneselenol; the nitrile ligand is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile; the isocyanate ligand is selected from the group consisting of isocyanate, benzyl isocyanate, phenyl isocyanate, methyl isocyanate, butyl isocyanate, ethyl isocyanate, pentyl isocyanate, phenethyl isocyanate, cyclohexanemethyl isocyanate, and isopropyl isocyanate; the thiocyanate ligand is selected from the group consisting of thiocyanate, methyl thiocyanate, butyl thiocyanate, ethyl thiocyanate, and benzyl thiocyanate; the ether is selected from the group consisting of diisopropyl ether, butyl vinyl ether, tertamyl methyl ether, allyl methyl ether, and 2-chloroethyl vinyl ether; the alcohol ligand is selected from the group consisting of methanol, ethanol, propanol, butanol, benzylalcohol, 2-Propen-1-ol, isopropylic alcohol, furfuryl alcohol; the pyridine monodentate ligand is selected from the group consisting of pyridine, 4-(1- aminoethyl)pyridine, 4-(dimethylamino)pyridine, 4-methylpyridine, 3-methylpyridine, 2- methylpyridine, 2-methylpyridine-4-carboxylic acid, 5-methylpyridine-3-carbonitrile, 2- hydroxy-5-methylpyridine, 2-ethynyl-5-methylpyridine, 2-ethynyl-6-methylpyridine, and 4- phenylpyridine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3; and e) A metal complex of formula (Ih):R1 is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2 is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;L17 is a tetradentate ligand selected from the group consisting of 1 ,2-bis[(2- quinolinemethyl)(phenyl)phosphanyl]ethane, tris(2-pyridylmethyl)amine, tris(5-methyl-2- pyridylmethyl)amine, N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1 ,2-diaminoethane, N,N'- bis(2-pyridylmethyl)-N,N'-dimethyl-trans-1 ,2-diaminocyclohexane, N,N'-bis(2-picolyl)-2,2'- bipyrrolidine, N1,N2-di(quinolin-8-yl)cyclohexane-1 ,2-diamine, N1,N2-bis(6-fluoroquinolin-8- yl)cyclohexane-1 ,2-diamine, N1,N2-bis(6-(tert-butyl)quinolin-8-yl)cyclohexane-1 ,2-diamine, triethylenetetramine;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl]borate), and tris(tetrachlorobenzenediolato)phosphate); and m is an integer from 0 to 3.

9. The metal complex according to any of the claims 1-8, wherein: a) R1 is -(CH2)-CH(CH3)2 and R2is H; b) R1 is and -(CH2)-C(OH)(CH3)2 and R2is -(CH2)-O-CH2-CH3; Or c) R1 is and -(CH2)-C(OH)(CH3)2 and R2is -CH2-NH-CH2-CH3.

10. A cationic metal trimer of formula (II),wherein:Ri is a substituent selected from the group consisting of -(CH2)-CH(CH3)2 and -(CH2)- C(OH)(CH3)2;R2is a substituent selected from the group consisting of -H, -(CH2)-O-CH2-CH3, and -CH2- NH-CH2-CH3;M is a transition metal;Li is either a mono or a polydentate ligand which is independently selected from the group consisting of p-cymene, benzene, toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, mesitylene, cumene, t-butylbenzene, hexamethylbenzene, styrene, allylbenzene, ethynylbenzene, cyclopentadiene, 1 ,2,3,4,5-pentamethylcyclopentadiene, phenylmethanol, 2-phenylethan-1-ol, 3-phenylpropan-1-ol, anisole, ethoxybenzene, 2,3- dihydro-1 H-indene, 2,3-dihydro-1 H-inden-2-ol, 3-phenylpropanoic acid, 2-phenylacetic acid, methyl 2-phenylacetate, methyl 2-phenylacetate, ethyl 2-phenylacetate, ethyl 3- phenylpropanoate, N-phenethylmethanesulfonamide, N-([1 , 1 b i ph eny l]-2- yl)methanesulfonamide, 2-phenylethan-1 -amine, 2-aminobiphenyl, 1 ,5-cyclooctadiene, 1 ,2,3,4-tetramethyl-1 ,3-cyclopentadiene,1-ethyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 1-isopropyl-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, ((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl) methyl)benzene, (2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1- yl)cyclohexane,(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene,4-(2,3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)-1 ,1'-biphenyl, 2-((2,3,4,5-tetramethylcyclopenta-1 ,3- dien-1-yl)methyl)pyridine, 2-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)ethan-1-amine hydrochloride, 1-fluoro-4-(2,3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)benzene, 4-(2, 3,4,5-tetramethylcyclopenta-1 ,3-dien-1-yl)phenol, 1-(tert-butyl)-2,3,4,5-tetramethylcyclopenta-1.3-diene, 1-(3,3-dimethylbutyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene, 8-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)quinoline, N, N-dimethyl-2-(2, 3,4,5- tetramethylcyclopenta-1 ,3-dien-1-yl)aniline, 4-methyl-2-(2,3,4,5-tetramethylcyclopenta-1.3-dien-1-yl)phenol, 1-(2-methoxyethyl)-2,3,4,5-tetramethylcyclopenta-1 ,3-diene;X is an anion selected from the group consisting of hexafluorophosphate, chloride, bromide, tetrafluoroborate, tetraphenylborate, trifluoromethanesulfonate, tetrakis[3,5- bis(trifluoromethyl)phenyl] borate), and tris(tetrachlorobenzenediolato)phosphate); and. m is an integer selected from 0, 3, and 6.11 . A pharmaceutical composition comprising a therapeutically effective amount either of a metal complex as defined in any of the claims 1-9 or of a cationic metal trimer of formula (II) as defined in claim 10, together with appropriate amounts of pharmaceutically acceptable carriers or excipients.

12. A metal complex according to any of the claims 1-9, or a cationic metal trimer of formula (II) as defined in claim 10, for use as a medicament.

13. A metal complex according to any of the claims 1-9, or a cationic metal trimer of formula (II) as defined in claim 10, for use in the treatment of viral infection.

14. The metal complex, or the cationic metal trimer of formula (II) as defined in claim 10, for use according to claim 12, wherein the treatment is of a viral infection caused by a virus selected from the group consisting of Herpes Simplex Virus, ocular virus, Human Papillomavirus, Molluscum Contagiosum, Respiratory Syncytial Virus, and Arthropod- borne viruses.

15. The metal complex, or the cationic metal trimer of formula (II) as defined in claim 10, for use according to claim 13, wherein the virus is Herpes Simplex Virus and is selected from Herpes Simplex Virus, type 1 and Herpes Simplex Virus, type 2.

16. A metal complex according to any of the claims 1-9 or the cationic metal trimer of formula (II) as defined in claim 10, for use in the treatment of cancer in a mammal, including a human.

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