Rhenium complexes comprising a ligand with a distal inverted trigonal pyramidal structural motif and use therof

Abstract

The present disclosure is directed to compounds of Formula I and pharmaceutical compositions comprising thereof. Further, use of compounds and pharmaceutical compositions in medicine, particularly prevention or treatment of a medical condition associated with pathogenic infection and cancer, are also provided.

Description

RHENIUM COMPLEXES COMPRISING A LIGAND WITH A DISTAL INVERTED TRIGONAL PYRAMIDAL STRUCTURAL MOTIF AND USE THEROFFIELD OF THE INVENTION

[0001] The present disclosure relates generally to rhenium complexes, and use thereof, e.g. as antimicrobial agents and anticancer agents.BACKGROUND OF THE INVENTION

[0002] Cisplatin or (SP-4-2)-diamminedichloridoplatinum, a metal coordination compound, is one of the most potent and widely used drugs for the treatment of various solid cancers such as testicular, ovarian, head and neck, bladder, lung, cervical cancer, melanoma, lymphomas among others. However, deleterious side effects and drug resistance development are two inherent challenges which limit the application and effectiveness of cisplatin.

[0003] The metallo-drug field is evolving, and research has been performed to design and synthesize non-platinum metal coordination compounds.

[0004] Some rhenium derivatives have been developed as anticancer drug candidates, whereas Re and Tc tricarbonyl complexes play an important role in the area of radiopharmaceuticals. In the last decade their action as antimicrobials has also raised interest.

[0005] Patent WO2017223428A1 discloses rhenium complexes and methods for treating cancer by administering the rhenium complex to a subject.

[0006] Patent US20210317151 A discloses generally to rhenium complexes and methods for treating conditions that could benefit from ER stress induction, particularly cancer, by administering the rhenium complex to a subject having such a condition.

[0007] As such, considering the foregoing, it may be appreciated that the development of new families of rhenium complexes, e.g., as effective potent antibacterial and anticancer antimicrobial agents is particularly promising.SUMMARY OF THE INVENTION

[0008] In one aspect of the disclosure, there is provided a compound or a salt thereof, wherein the compound is of Formula I:, wherein: M is a metal selected from Mn, Re, and Tc and is in the +1 oxidation state; Q is selected from B, C, N, and P; each R, R1and R2is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted alkyl, an optionally substituted alkyne group, an optionally substituted alkyne group, or any combination thereof; each R3and R4is hydrogen, or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkyne, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof; optionally, A is a linker comprising an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted cyclic or acyclic hydrocarbyl chain, an amino acid, a peptide, a peptide nucleic acid, an ethylene glycol oligomer, any derivative thereof, or any combination thereof; X is a counterion, and m is 0 or 1.

[0009] In some embodiments, the compound is of Formula la:

[0010] In some embodiments, the A comprises any of:- is a single bond or a double bond; k is 0 or 1 , n is 1 or 2; each Z1, Z2and Z3is -N-, -NH-, -NR-, -CH-, -CR-, -CH2-, -CR2-, -P-, -S-, or -O-; R5is hydrogen or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof.

[0011] In some embodiments, the compound is of Formula II:

[0012] In some embodiments, the Z1and Z2is N.

[0013] In some embodiments, the Q is C.

[0014] In some embodiments, the compound is of Formula III: n x-

[0015] In some embodiments, the Q is P.

[0016] In some embodiments, each of the R, R1and R2is selected from optionally substituted phenyl group, cyclohexyl group, or methyl group.

[0017] In some embodiments, the R3and R4is hydrogen.

[0018] In some embodiments, the M is Re.

[0019] In some embodiments, the compound is selected from the following list:

[0020] In some embodiments, the compound is for use in medicine.

[0021] In some embodiments, the compound is for use in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, a medical condition associated with cancer, pathogen infection, or a combination thereof, in a subject in need thereof.

[0022] In some embodiments, the compound is for use in labeling cancer cells, detecting cancer cells, imaging, sensitizing cancer cells, promoting cell death in cancer cells, inhibiting cell repair from DNA damage, decreasing size of a tumor, decreasing growth of a tumor, decreasing number of metastases, decreasing size of metastases, or any combination thereof, in a subject in need thereof.

[0023] In some embodiments, the cancer is selected from the group comprising: skin cancer, brain cancer, thyroid cancer, oral and oropharyngeal cancer, lung cancer, bronchial cancer, breast cancer, liver cancer, intrahepatic bile duct cancer, pancreatic cancer, gastrointestinal cancer, kidney cancer, colon cancer, rectal cancer, bladder cancer, ovarian cancer, prostate cancer, rhabdomyosarcoma, basal-cell carcinoma, glioblastoma, medulloblastoma, leukemia, lymphoma, osteosarcoma, multiple endocrine neoplasia, mesothelioma, or any combination thereof.

[0024] In some embodiments, the cancer is a solid tumor cancer.

[0025] In some embodiments, the solid tumor cancer is a cisplatin resistant tumor.

[0026] In some embodiments, the compound is for use in inhibiting or reducing a load of a microorganism in a subject, wherein the microorganism is a pathogen.

[0027] In some embodiments, the pathogen is a bacterium, preferably a Gram-positive bacterium, preferably selected from: S. aureus, B. subtilis, E. faecium, S. pneumoniae, S. epidermidis, C. difficile, or any combination thereof.

[0028] In another aspect of the disclosure, there is provided a pharmaceutical composition, comprising at least one compound according to the present disclosure, and a pharmaceutically acceptable carrier.

[0029] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent selected from: antimicrobial agent, chemotherapeutic agent, or both.

[0030] In some embodiments, the antimicrobial agent is an antibiotic selected from: penicillins, cephalosporins, sulfonamides, fluoroquinolones, macrolides, tetracyclines, aminoglycosides, carbapenems, glicopeptides, streptogramins, oxazolidinones, cyclic lipopeptides, lipoglycopeptide, or any combination thereof.

[0031] In some embodiments, the chemotherapeutic agent is selected from: cisplatin, carboplatin, etoposide, oxaliplatin, rituximab or trastuzumab, mechlorethamine, cyclophosphamide, bleomycin, doxorubicin, daunorubicin, cytarabine, methotrexate, hydroxyurea, or any combination thereof.

[0032] In some embodiments, the pharmaceutical composition further comprises a vector selected from: peptide, liposome, vesicle, polymer, mesoporous material, MOF, inorganic layered structure, nanoparticle, dendrimer, protein, plasma protein, antibody, micelle, non-woven, or any combination thereof.

[0033] In some embodiments, the pharmaceutical composition is for use in targeting a cancer cell, preferably a tumor, in a subject.

[0034] In some embodiments, the pharmaceutical composition is for use in medicine, particularly in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, even more particularly in the prevention or treatment of a medical condition associated with cancer, bacterial infection, or both, in a subject in need thereof.

[0035] In some embodiments, the pharmaceutical composition is for oral administration, topical administration, systemic administration, or any combination thereof.

[0036] In another aspect of the disclosure, there is provided a kit comprising at least one compound according to the present disclosure, or a pharmaceutical composition according to the present disclosure, and optionally at least one therapeutic agent.

[0037] In another aspect of the disclosure, there is provided a method for preparing a compound according to the present disclosure, the method comprising the steps of: a) contacting a solution of Re(C0)3(bpy)Br wherein bpy is 2, 2’ -bipyridyl, in an organic solvent with AgPFsSOs), and b) adding a ligand compound, preferably an imidazole compound or a phosphine compound.

[0038] In some embodiments, the ligand is selected from clotrimazole (Ctz), 1 -tritylimidazole (Trityllm), 1-tert-butylimidazole (tBulm), triphenylphosphine (PPhs) or tricyclohexylphosphine (PCys).

[0039] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the disclosure, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0040] Further embodiments and the full scope of applicability of the present disclosure will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Some embodiments of the disclosure are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the disclosure. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the disclosure may be practiced.

[0042] Figure 1 represents the chemical structure of synthetized / ac-[Re(CO)3(bpy)L]+complexes (all having TfO- counterion, not represented);

[0043] Figure 2 is a bar graph presenting the internalization of Re by S. aureus USA 300 JE2 and E. Coli MG1655 K12 after treatment with 4 pig / ml of ReBpyTrityllm, ReBpyPPh3 or ReBpyBr (4 pig / ml for S. aureus and 64 pig / ml for E. Coli . Means are representative of 2 biological samples. Significance is represented by * (P<0.05) and was calculated with a one-way ANOVA;

[0044] Figure 3A-B presents bar graphs of the fluorescence intensity F1 / F0 ratio of COP-1 in S. aureus USA 300 JE2 and E Coli MG1655 K12. S. aureus was treated with 4 pig / ml of ReBpyTrityllm, ReBpyPPh3 and ReBpyPCy3 or 64 pig / ml of ReBpytBulm and ReBpyBnlm (Figure 3A); E. Coli was treated with 64 pig / ml of ReBpyTrityllm, ReBpyPPh3, ReBpytBulm, ReBpyBnlm and ReBpyPCy3 (Figure 3B); Bacteria were exposed to the compounds for 15 minutes, followed by a 15-minute treatment with 1 pig / ml of fluorescent probe COP-1 . Data are representative of 3 biological samples (* p < 0.05; ** p < 0.01 ; **** p < 0.0001).

[0045] Figure 4 represents the ROS content in cells of S. aureus. Untreated cells (NT), exposed to DMSO, and incubated with, ReBpyTrityllm, ReBpyPPh3, and ReBpyCtz (10 piM). Cells were incubated with a 2', 7' - dichlorodihydrofluorescein diacetate probe sensitive to ROS, for 150 min. Fluorescence intensities were normalized to the optical density at 600 nm. Data are averages of three replicates and the errors are standard deviations (****, p < 0.0001).

[0046] Figures 5A-D are images of CO release in mammalian cells. Kidney cells (LLC-Pk1) were treated with 8 pig / ml of ReBpyTrityllm (Figure 5A), ReBpytBulm(Figure 5B), ReBpyPhlm (Figure 5C) or ReBpyPPh3 (Figure 5D) for 30 minutes, followed by a 15-minute treatment with 1 pig / ml of fluorescent probe COP-1. Images are representative of 3 biological samples.DETAILED DESCRIPTION OF THE INVENTIONAccording to some embodiments, the present disclosure provides a compound of general formula fac- [M(CO)3(bpy)L] or fac-[M(CO)3(bpy)L]+wherein M is a metal, bpy is 2,2'-bipyridyl, and L is a ligand that completes the coordination sphere of the metal with an 18-electron count, and has an inverted trigonal pyramidal structural motif at its terminal, distal end. In some embodiments, the ligand L has the general formula (RR1R2)Q-A, wherein A binds Q at the distal terminal and binds M at the other terminal. In some embodiments, L is a ligand of formula (RR1R2)Q, wherein Q is directly bound to M.

[0047] The present disclosure is based, in part, on the finding that a compound as described herein presents anticancer and antibacterial activity. The present disclosure is based, in part, on the finding that a ligand L comprising a distal inverted trigonal pyramidal structural motif consistently boosts the antibacterial and anticancer activity of the compound. The present disclosure is based, in part, on the finding that a ligand L comprising a bulky, distal inverted trigonal pyramidal structural motif consistently boosts the antibacterial activity of the compound.

[0048] The present disclosure is based, in part, on the finding that a compound as described herein has a dual mode of action. A compound as disclosed herein presents anticancer activity while liberating low concentrations of free CO gas. The compound liberates CO in the course of killing bacterial and tumoral cells. The release of CO initially reinforces their toxicological profile and later is expected to contribute to recovery of affected tissues. CO ameliorates the health of tissues recovering from tumoral aggression and contributes to suppressing metastases formation and metastases spread.

[0049] The present disclosure is based, in part, on the finding that a compound as disclosed herein has a new mode of action for delivering CO to tumors. A compound according to the present disclosure is able to kill tumor cells while releasing CO in the process. The technical effect associated, is the fact that a compound as disclosed herein is able to kill cancer cells directly without other physical or chemical mediation, with high potency and releasing cytoprotective CO.

[0050] According to some embodiments, the present disclosure provides a compound of Formula I:, wherein: M is a metal selected from Mn, Re, and Tc and is found in the +1 oxidation state. In some embodiments, Q is selected from B, C, N, and P; each R, R1and R2is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted alkyl, an optionally substituted alkene group, an optionally substituted alkyne group, or any combination thereof; each R3and R4is hydrogen, or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof. In some embodiments, A is an optional linker function which bridges the pyramidal (RR1R2)Q group and the metal fragment [M(CO)3(bpyR3R4)]+. In some embodiments, the(RR1R2)Q group forms bonds with neutral or charged atoms in A, namely C, N, P, 0 and S. In some embodiments, a second neutral or negatively charged terminal atom in A namely, C, N, P, 0 and S, binds the metal fragment [M(CO)3(bpyR3R4)]+. The overall sum of the charges of (RR1R2)Q, A and [M(CO)3(bpyR3R4)]+should result in a neutral or, preferably, monocationic (m = +1) charge for the overall octahedral complex in Formula I.

[0051] As used herein, the term "linker” refers to a chemical moiety (molecule, or compound) that connects two or more molecular entities together. It serves as a bridge between different components (functional groups or building blocks), allowing them to be chemically linked or attached in a controlled and specific manner. The properties of a linker, such as its length, flexibility, and functional groups, can be tailored to achieve specific objectives in the final linked structure. In some embodiments, a linker can incorporate cleavable bonds for controlled release of attached components.

[0052] Types of linkers are well known in the art and will become apparent to a skilled person in the art. Non-limiting examples include carbon chains, molecules comprising heteroatoms (such as nitrogen, oxygen, or sulfur) or functional groups that possess reactive sites.

[0053] In some embodiments, A is absent, and (RR1R2)Q is directly bonded to M.

[0054] In some embodiments, the atoms linking A to Q and to M are part of a linker structure A that comprises an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted cyclic or acyclic hydrocarbyl chain, an amino acid, a peptide, a peptide nucleic acid, an ethylene glycol oligomer, any derivative thereof, or any combination thereof. In some embodiments A is a peptide or derivative thereof. In some embodiments A is a derivative of a PNA (Peptide Nucleic Acid). In some embodiments A is a derivative of an ethylene glycol oligomer. In some embodiments, A is a self-imol ating linker. In some embodiments, X is a counterion and m is 0 or 1 . In some embodiments, X is a counterion balancing the charge in monocationic complexes (m is 1).

[0055] As used herein, the term "counterion” refers to an anion not involved in the coordination to the metal center. Such anions are well known and will become apparent to a person skilled in the art. Non limiting examples of anions X- include PFe", BFr, SOsCFs" (TfO-), SOsCeHsMe- (TsO~), SO3CH3“(MsO“), and ClOr. For simplification, some structures according to the present disclosure are presented without counterion. It will become apparent to a person skilled in the art that the metal M is in the +1 oxidation state and the overall charge of the octahedral metal complex is determined by the sum of the charges at (RR1R2)Q, A and [M(CO)3(bpyR3R4)]+.

[0056] In some embodiments, the compound is of Formula la:■=is a single bond or a double bond; k is 0 or 1 , n is 1 or 2; each Z1, Z2and Z3is -N-, -NH-, -NR-, -CH-, -CR-, -CH2-, -CR2-, -P-, -S- , or -O-; and R5is hydrogen or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof.

[0058] In some embodiments, the compound is of Formula II:

[0059] In some embodiments, Z1and Z2is N. In some embodiments, Q is C. In some embodiments, R3and R4is hydrogen.

[0060] In some embodiments, the linker A is absent and the compound is of Formula III:"I X-

[0061] In some embodiments, Q is P. In some embodiments, R3and R4is hydrogen.

[0062] In some embodiments, R, R1and R2is selected from optionally substituted phenyl group, cyclohexyl group, or methyl group.

[0063] In some embodiments, M is Re.

[0064] In some embodiments, the compound is selected from the following list:

[0065] In some embodiments, the compound is for use in medicine.

[0066] In some embodiments, the compound is for use in inhibiting or reducing a load of a microorganism in a subject.

[0067] Herein "antimicrobial activity” is referred to as an ability to inhibit (prevent), reduce or retard bacterial growth, fungal growth, biofilm formation or eradicate living bacterial cells, or their spores, or fungal cells, or viruses in a suspension or in a moist environment. Herein, inhibiting or reducing or retarding a load of a microorganism refers to inhibiting, reducing, or retarding growth of microorganisms and / or eradicating a portion or all of an existing population of microorganisms. Thus, compounds and compositions (formulations) described herein can be used both in reducing the formation of microorganisms in a subject, on or in an article, and in killing microorganisms in a subject, in or on an article, or a living tissue. The microorganism can be unicellular or multicellular (prokaryotes, archaea, bacteria, eukaryotes, protists, fungi, algae, molds, yeast, euglena, protozoan, dinoflagellates, apicomplexa, trypanosomes, amoebae and the likes), and the subject a mammal or a human. In some embodiments, the microorganism is a pathogen. As used herein, the term "pathogen” refers to any organism or agent that can produce a disease. In some embodiments, a pathogen is also referred to as an infectious agent.

[0068] In some embodiments, the microorganisms are bacteria.

[0069] In some embodiments, the bacteria are Gram-positive bacteria, preferably selected from: S. aureus, B. subtilis, E. faecium, S. pneumoniae, S. epidermidis, C. difficile, or any combination thereof.

[0070] The present disclosure is based, in part, on the finding that a bulky R, R1and R2group, influences the activity of the compounds. For example, compounds comprising bulky R, R1and R2groups present higher activity against S. aureus, compared to a control compound devoid of bulky R, R1and R2groups.

[0071] In some embodiments, the compound is for use in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, in a subject in need thereof.

[0072] In some embodiments, the compound is for use in the prevention or treatment of a medical condition associated with pathogen infection, cancer, or both, in a subject in need thereof.

[0073] In some embodiments, the compound is for use in labeling cancer cells, detecting cancer cells, imaging, sensitizing cancer cells, promoting cell death in cancer cells, inhibiting cell repair from DNA damage, decreasing size of a tumor, decreasing growth of a tumor, decreasing number of metastases, decreasing size of metastases, or any combination thereof, in a subject in need thereof.

[0074] In some embodiments, the cancer is selected from the group comprising: skin cancer, brain cancer, thyroid cancer, oral and oropharyngeal cancer, lung cancer, bronchial cancer, breast cancer, liver cancer, intrahepatic bile duct cancer, pancreatic cancer, gastrointestinal cancer, kidney cancer, colon cancer, rectal cancer, bladder cancer, ovarian cancer, prostate cancer, rhabdomyosarcoma, basal-cell carcinoma, glioblastoma, medulloblastoma, leukemia, lymphoma, osteosarcoma, multiple endocrine neoplasia, mesothelioma, or any combination thereof.

[0075] In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the solid tumor cancer is a cisplatin resistant tumor.

[0076] In another aspect of the disclosure disclosed herein, there is a pharmaceutical composition comprising a compound as described hereinabove, a pharmaceutically acceptable salt thereof or both. Nonlimiting examples of pharmaceutically acceptable salts include but are not limited to: acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (such as bromide, chloride, iodide, fluoride), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, edetate, fumarate, gluconate, and lactate or any combination thereof.

[0077] In some embodiments, the pharmaceutical composition comprises a compound according to the present disclosure and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound according to the present disclosure and the pharmaceutically acceptable carrier.

[0078] In some embodiments, the compound of the disclosure is referred to herein as an active ingredient of a pharmaceutical composition.

[0079] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the active ingredient is administered. Such carriers can be sterile liquids, such as water-based and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.

[0080] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. In some embodiments, a second therapeutic agent is selected from: an antimicrobial agent, chemotherapeutic agent, or both.

[0081] Antimicrobial agents, more specifically antibacterial agents are well known in the art and will become apparent to a skilled person in the art. Non-limiting examples of anti-bacterial agents include: penicillins, cephalosporins, sulfonamides, fluoroquinolones, macrolides, tetracyclines, aminoglycosides, carbapenems, glicopeptides, streptogramins, oxazolidinones, cyclic lipopeptides, lipoglycopeptide, or any combination thereof. Chemotherapeutic agents are well known in the art and will become apparent to a skilled person in the art. Non-limiting examples of chemotherapeutic agents include: cisplatin, carboplatin, etoposide, oxaliplatin, rituximab or trastuzumab, mechlorethamine, cyclophosphamide, bleomycin, doxorubicin, daunorubicin, cytarabine, methotrexate, hydroxyurea, or any combination thereof.

[0082] In some embodiments, the pharmaceutical composition further comprises a vector. In some embodiments, the vector is a biocompatible vector. In some embodiments, the vector is a non-viral vector. Vectors are well known in the art and non-limiting examples include: peptide, liposome, vesicle, polymer, mesoporous material, MOF, inorganic layered structure, nanoparticle, dendrimer, protein, plasma protein, antibody, micelle, non-woven, or any combination thereof.

[0083] In some embodiments, the pharmaceutical composition as described herein comprising a vector, is for use in targeting a cancer cell, preferably a tumor, in a subject.

[0084] According to the present disclosure, a pharmaceutical composition as described herein comprising a vector, prevents killing healthy cells on the way to a tumor. A compound and a carrier as described herein and pharmaceutical composition comprising a compound and a carrier as described herein arrive and accumulate at the target tumor where they are triggered to exert their cell killing activity.

[0085] In some embodiments, the pharmaceutical composition as described herein is for use in medicine, particularly in inhibiting or reducing the formation of load of a microorganism in a subject, more particularly in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, even more particularly in the prevention or treatment of a medical condition associated with pathogen infection, cancer, or both, in a subject in need thereof.

[0086] It should be understood that according to the scope of the present disclosure, all uses of a compound as described hereinabove, apply for a pharmaceutical composition as described herein.

[0087] In some embodiments, the pharmaceutical composition is for oral administration, topical administration, systemic administration, or any combination thereof.

[0088] According to some embodiments, the present disclosure provides a method for treating or preventing development of a medical condition associated with pathogen infection, cancer, or both, in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described hereinabove.In some embodiments, administering is oral administration, topical administration, systemic administration, or any combination thereof.

[0089] In some embodiments, the methods of the invention further comprise monitoring the effect of the pharmaceutical composition on at least one symptom selected from, without being limited thereto, growth or angiogenesis of a metastatic tumor, presence of circulating tumor cells, and appearance of a new metastasis.

[0090] In some embodiments, the monitoring further comprises measuring a decrease of a symptom of the cancer or metastasis progression. In some embodiments, the symptom is selected from, without being limited thereto, size of a tumor, growth of a tumor, number of metastases, size of metastases, number of circulating tumor cells in blood, vascularization in tissue adjacent to the tumor, or metastases, vascularization of tumor or metastases, or, a weight loss of the subject. In some embodiment, the treating is inhibiting or reducing the proliferation of a cancer cell.

[0091] As used herein, the term "preventing", indicates that the growth rate of cells is essentially nullified or is reduced by at least 20 %, at least 30 %, at least 40 %, at least 50 %, at least 60 %, at least 70 %, at least 80 %, at least 90 %, including any value therebetween, of the appearance of a microorganism cells or cancer cells in a comparable situation lacking the presence of a compound or composition described herein. Alternatively, preventing means a reduction to at least 15%, 10%, or 5% of the appearance of the microorganism cells or cancer cells in a comparable situation lacking the presence of a compound or composition described herein. Methods for determining a level of appearance of microorganism cells and cancer cells are known in the art.

[0092] According to some embodiments, the present disclosure provides a kit comprising at least one compound according to the present disclosure. According to some embodiments, the present disclosure provides a kit comprising at least one pharmaceutical composition according to the present disclosure. In some embodiments, the kit comprises at least one therapeutic agent as described herein.

[0093] In some embodiments, the disclosure provides kits useful for uses and methods disclosed herein. For example, a kit may include a container having a sterile reservoir that houses any compound or composition disclosed herein. In some embodiments, the kit further includes instructions. For example, a kit may include the instructions for administering the compound or composition to a subject (e.g., indication, dosage, methods etc.).

[0094] According to some embodiments, the present disclosure provides a method for preparing a compound as disclosed hereinabove, the method comprising the steps of: a) contacting a solution of Re(CO)3(bpy)Br wherein bpy is 2, 2’ -bipyridyl, in an organic solvent with AgPFsSOs), and b) adding a ligand compound, preferably an imidazole compound or a phosphine compound.

[0095] In some embodiments, the ligand is selected from clotrimazole (Ctz), 1 -tritylimidazole (Trityllm), 1-tert-butylimidazole (tBulm), triphenylphosphine (PPhs) or tricyclohexylphosphine (PCys).

[0096] In some embodiments, contacting comprises stirring, high shear mixing, ultrasonication, overhead stirring, homogenizing, or any combination thereof.

[0097] In some embodiments, contacting is performed at a temperature from 20 °C to 80 °C. In some embodiments, contacting is performed in the dark.

[0098] Compounds and compositions of the present disclosure may, if desired, be presented in a pack or dispenser device, such as an U.S. Food and Drug Administration (FDA) approved kit, or as a diagnostic kit which may contain one or more unit dosage forms containing the disclosed compound or composition. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the FDA for prescription drugs or of an approved product insert.

[0099] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0100] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (S-) configuration. The compounds provided herein may either be enantiomerically pure, or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R-) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S-) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0101] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0102] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded and the resulting compound is stable. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. Astable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.

[0103] Any suitable group may be present on a "substituted" or "optionally substituted" position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0104] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 21 to 100 carbon atoms, and more preferably 21 -50 carbon atoms. Whenever a numerical range; e.g., "21-100", is stated herein, it implies that the group, in this case the alkyl group, may contain 21 carbon atoms, 22 carbon atoms, 23 carbon atoms, etc., up to and including 100 carbon atoms. In the context of the present disclosure, a "long alkyl" is an alkyl having at least 20 carbon atoms in its main chain (the longest path of continuous covalently attached atoms). A short alkyl therefore has 20 or less main-chain carbons. The alkyl can be substituted or unsubstituted, as defined herein.

[0105] The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.

[0106] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0107] The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0108] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring ( / .e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or unsubstituted, as indicated herein.

[0109] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0110] The term "alkoxy" describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein.[01 1 1] The term "aryloxy" describes an -O-aryl, as defined herein.

[0112] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, alkoxy, nitro, amine, hydroxyl, thiol, thioalkoxy, thiohydroxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0113] The term "halide", "halogen" or "halo" describes fluorine, chlorine, bromine or iodine.

[0114] The term " haloalky I" describes an alkyl group as defined herein, further substituted by one or more halide(s).

[0115] The term "haloalkoxy" describes an alkoxy group as defined herein, further substituted by one or more halide(s).

[0116] The term "hydroxyl" or "hydroxy" describes a -OH group.

[0117] The term "thiohydroxy" or "thiol” describes a -SH group. The term "thioalkoxy" describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein. The term "thioaryloxy" describes both an -S-aryl and a -S-heteroaryl group, as defined herein.

[0118] The term "amino” or "amine” describes a -NR'R” group, with R' and R” as described herein.

[0119] The term "heteroaryl" describes a monocyclic or fused ring ( / .e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine and the like.

[0120] The term "heteroalicyclic" or "heterocyclyl" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.

[0121] The term "carboxy" or "carboxylate" describes a -C(=O)-OR' group, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon) or heteroalicyclic (bonded through a ring carbon) as defined herein.

[0122] The term "carbonyl” or "keto” describes a -C(=0)-R' group, where R' is as defined hereinabove.

[0123] The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0124] The term "thiocarbonyl" describes a — C(=S)-R' group, where R' is as defined hereinabove. A "thiocarboxy" group describes a -C(=S)-OR' group, where R' is as defined herein. A "sulfinyl" group describes an -S(=0)-R' group, where R' is as defined herein. A "sulfonyl" or "sulfonate" group describes an -S(=O)2-R' group, where Rx is as defined herein. A "sulfonyl" or "sulfonate” group describes an -S(O)3R' group, where R' is as defined herein. A "sulfone" group describes an -S(O)2R' group, where R' is as defined herein.

[0125] A "carbamyl" or "carbamate” group describes an -OC(=O)-NR'R" group, where R' is as defined herein and R" is as defined for R'.

[0126] A "nitro" group refers to a -NO2 group. A "cyano" or "nitrile" group refers to a -C=N group. As used herein, the term "azide" refers to a -N3 group.

[0127] The term "sulfonamide" refers to a -S(=O)2-NR'R" group, with R' and R" as defined herein.

[0128] The term "alkylaryl" describes an alkyl, as defined herein, which substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0129] The term "heteroaryl" describes a monocyclic or fused ring (i.e. rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine and the like.

[0130] The term "vinyl" refers to a -CH=CH2 group.

[0131] The term "allyl" refers to a -CH2-CHOH2 group.

[0132] The term "thioalkyl" describes an alkyl group as defined above, further substituted by one or more mercapto group(s).

[0133] The term "alkylhydroxy" describes an alkyl group as defined above, further substituted by one or more hydroxy group(s).

[0134] As used herein the term "about" refers to ± 10 %.

[0135] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

[0136] The word "exemplary" is used herein to mean "serving as an example, instance or illustration". Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0137] The word "optionally" is used herein to mean "is provided in some embodiments and not provided in other embodiments". Any particular embodiment of the disclosure may include a plurality of "optional” features unless such features conflict.

[0138] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0139] Throughout this application, various embodiments of this disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0140] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging / ranges between” a first indicate number and a second indicate number and "ranging / ranges from” a first indicate number "to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0141] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0142] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the disclosure. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.EXAMPLES

[0143] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the disclosure in a non-limiting fashion.Synthesis of carbonyl complexes

[0144] Synthesis of fac-[Re(CO)3(bpy)(1-tritylimidazole)][OTf] (compound 2): To a yellow solution of Re(CO)3(bpy)Br (105.8 mg, 0.21 mmol) in acetone (30 mL), Ag CFsSOs) (53.3 mg, 0.21 mmol) was added and the mixture left stirring at room temperature for 3 hours in the dark. The solution was filtered to discard AgBr and after addition of 1 -tritylimidazole (65,2 mg, 0.21 mmol) the suspension was left stirring overnight, at room temperature. The solution was then evaporated to dryness and the solid froth washed with diethyl ether to leave a bright yellow powder which was dissolved in 5 ml CH2CI2, filtered to separate some solid impurities, concentrated to ca. 3 ml, layered with 20 ml Et20 and kept at -30°C. The yellow powder obtained after decantation was recrystallized from CF CL^O (1 :8), at -30°C for 3 days. The needle-like yellow crystals were separated by filtration and dried (120 mg, 68 %).

[0145] Synthesis of fac-[Re(CO)3(bpy)(1-diphenylmethylimidazole)][OTf) (compound 3): To a yellow solution of Re(CO)3(bpy)Br (100.2 mg, 0.20 mmol) in acetone (30 mL), Ag(CF3SO3) (50.8 mg, 0.20 mmol) was added, and the mixture left stirring at room temperature for 3 hours, in the dark. The solution was filtered to discard AgBr and after addition of 1- diphenylmethylimidazole (93.8 mg, 0.4 mmol) the solution was left stirring overnight, at room temperature. The solution was then evaporated to dryness and the waxy solid washed with diethyl ether (4x5ml) to remove excess 1 -diphenylmethylimidazole and leave a bright yellow powder which was dissolved in 10 ml CH2CI2, concentrated to ca 5 ml, layered with 30 ml Et20 and kept at-30°C for 5 days. A yellow precipitate formed was isolated by decantation and dried under vacuum. Yield (102 mg, 63 %).

[0146] Synthesis of fac-[Re(CO)3(bpy)(1-benzylimidazole)][OTf) (compound 4): To a yellow solution of Re(CO)3(bpy)Br (105.6 mg, 0.21 mmol) in acetone (30 mL), Ag CFsSOs) (53,0 mg, 0.21 mmol) was added, and the mixture left stirring at room temperature for 3 hours, in the dark. The solution was filtered to discard AgBr and after addition of 1 - benzylimidazole (66,4 mg, 0.42 mmol) the solution was stirred overnight, at room temperature. After evaporation to dryness the waxy solid was washed with Et20 (4x 5ml) to remove excess 1 -benzylimidazole and leave a bright yellow powder which was recrystallized from CH2Cl2 / Et2O (1 :8), at -30°C for 3 days, and dried (128 mg, 87 %).

[0147] Synthesis of fac-[Re(CO)3(bpy)(1-phenylimidazole]OTf (compound 5): To a yellow solution of Re(CO)3(bpy)Br (105.5 mg, 0.20 mmol) in acetone (30 mL), Ag(CF3SO3) (53.5 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 3 hours, in the dark. The solution was filtered to discard AgBr and after addition of 1- phenylimidazole (58 mg, 0.40 mmol) the reaction was left stirring overnight, at room temperature. After evaporation to dryness the waxy solid was washed with hexane and Et20 (3x5ml) to leave a bright waxy solid. This was dissolved in 10 ml CH2CI2. The solution was filtered and concentrated to ca. 5 ml, layered with 30 ml Et20 and kept overnight at -30°C. The yellow powder was isolated by filtration and recrystallized from CH2Cl2 / Et2O (1 :8), at -30°C for 6 days, decanted and dried (110 mg; 77 %).

[0148] Purification of fac-[Re(CO)s(bpy)(imidazole]OTf (compound 6): This compound was prepared following the same methodology described for the other imidazole derivatives. The reaction product was recrystallized from acetone layered with Et20 and placed in at -30°C for 22 hours. The crystals formed were separated by decantation and dried under vacuum.

[0149] Synthesis of [Re(CO)3(bpy)PPh3]OTf (Compound 7) A yellow solution of Re(CO)3(bpy)Br (107 mg; 0.21 mmol) in THF (30 ml was treated with Ag(CFsSO3) (53. 3mg; 0. 21 mmol) and refluxed in the dark for 6 hours. The precipitate formed upon cooling to room temperature was filtered off and the yellow solution treated with a 10-fold excess of PPhs (524,0 mg; 10-fold excess) and the mixture left refluxing for 18 hours, in the dark. The reaction mixture was then taken to dryness and the residue formed washed with Et20 (3x 5 ml). The yellow washings were discarded while the remaining residue was dissolved in CH2CI2 (10 ml), concentrated to ca. 5ml and layered with Et20 (ca 30 ml). After 5 days at -30°C, the yellow mother liquor was decanted, and the yellow crystals dried under vacuum (142 mg; 81 %).

[0150] Synthesis of fac-[Re(CO)3(bpy)PCys]OTf (compound 8): The reaction was done exactly like the previous one using 593 mg (10-fold excess) of PCys and a reflux time of 24 hours. The residue obtained after the evaporation of the THF to dryness was orange and was washed with Et20 (3x 5ml). The orange washings were discarded, and the remaining residue dissolved in CH2CI2 (10 ml) concentrated to ca. 5ml, layered with Et20 (ca. 25 ml) and left at -30°C for 5 days. The mother liquor was decanted, and the yellow crystals dried under vacuum (156 mg; 90 %).

[0151] Synthesis offac-[Re(CO)3(bpy)(1-tert-butylimidazole)][OTf] (compound 9): To a yellow solution of Re(C0)3(bpy)Br (105.4 mg, 0.21 mmol) in acetone (30 ml), Ag CFsSOs) (53.3 mg, 0.21 mmol) was added, and the mixture left stirring at 40°C for 3 hours, in the dark. The solution was filtered to discard AgBr and after addition of 1-tert-butylimidazole (0.1ml; excess) the suspension was left stirring 40 hours, at room temperature in the dark. The solution was then evaporated to dryness and the oil washed with pentane (5x5ml) and then Et20 (3x5ml) to leave a bright yellow powder which was dissolved in 5 ml CH2CI2, concentrated to ca. 3 ml, layered with 20 ml Et20 and kept at -30°C for 3 days. The yellow crystals were decanted and dried (123 mg, 88 %).

[0152] Minimum Inhibitory Concentration Determination:MICs of the compounds against Escherichia coll MG1655 K12 and Staphyloccocus aureus USA300 JE2 (MRSA) (NARSA, Chantilly, VA, United States), grown in cation-adjusted Mueller-Hinton broth, were determined through the microdilution method and according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). A 2-fold serial dilution of the compound was incubated with bacterial inoculum of 5*105colony-forming units (CFU) per ml. Following 18 hours of incubation at 37 °C, the lowest compound concentration preventing visible bacterial growth was taken as the MIC. The MIC values were determined for at least three biological samples analyzed in triplicate.

[0153] Mammalian Cell Cytotoxicity Assays:Cells lines of porcine kidney epithelial cell line (LLC-PK1), human colorectal adenocarcinoma (HT-29), and human breast adenocarcinoma (MDA-MB-231) were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% (v / v) heat-inactivated fetal bovine serum and 1 % (v / v) penicillin-streptomycin mixture. Cells seeded, at a final cellular density of 10,000 cells / well, were treated with compounds, and the IC50 values were determined, according to the standard procedures described in the literature, for at least three biological samples analyzed in triplicate.

[0154] Metal Internalization in bacteria:E. coll and S. aureus were inoculated in Luria-Bertani broth to an optical density at 600 nm of 0.1 , grown to 0.3, and treated with the compounds, at a final concentration of 4 pig / ml in 1 % (v / v) of the respective solvent, for 15 minutes at 37°C. Cells were collected, and the biomass dried overnight in a 60 °C dry oven, and in a water bath of 100°C for 2 hours and kept at -80°C. Re content was determined by ICP-AES (Inductively Coupled Plasma-Atomic Emission Spectrometry), for at least three biological samples analyzed in triplicate.

[0155] Intracellular Carbon Monoxide release in porcine kidney cell line and bacteria:Determination of the CO released intracellularly was done using the carbon monoxide probe-1 (COP-1) according to the method described in the literature. Porcine kidney cell line LLC-PK1 was maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum and 1 % penicillinstreptomycin at 37°C in 5% CO2. LLC-PK1 seeded cells were treated with the compounds for 30 minutes and after were exposed to COP-1 for 15 minutes. Bacterial cells, grown aerobically in Luria-Bertani broth to an ODeoo of 0.3, were incubated with the selected compounds for 15 min at 37 °C and treated with 1 pMCOP-1 for 15 min. All cells are analyzed in a fluorescence microscope, with a phase contrast Uplan F1 10x objective (100x for bacteria) and a CCD Ixon camera (Andor Technologies). Samples were excited at 488 nm Ar laser, and the emission was collected using a META detector at 525 nm. The microscope images were analyzed using Imaged software version 2.3.0 / 1 ,53f. Images represent three biological samples, and in total, at least 300 cells per condition. etermination of ROS in bacterial cells incubated with selected CORMs. The evaluation of the intracellular ROS content in S. aureus JE2 USA300 was determined as follows. JE2 cells grown in 20 mL Luria-Bertani (LB) medium to an ODeoonm of 0.3 were treated for 1 h with 10 piM ReBpyTrityllm and ReBpyPPh3. Untreated cells, cells exposed to DMSO and ReBpyCtz (10 piM) were also tested. Cells were harvested by centrifugation, washed, and resuspended in phosphate- buffered saline (PBS), and the ODeoonm of each cell suspension was determined. The probe 2', 7' - dichlorodihydrofluorescein diacetate (Enzo, Ref ALX-610-022-M050) was added to the cell suspensions at a final concentration of 5 pM and the fluorescence intensity (Fl) was monitored every 30 min for 2.5 h in 96 black well plates. The data was collected at an excitation wavelength (Aex) of 485 nm and emission wavelength (Aem) of 528 nm, with an optimal (100%) gain of 60 in a Tecan Infinite M Nano+Monochromator equipment with a 96-well plate reader.EXAMPLE 1 SYNTHESIS

[0156] To study the effect of structural variations in the clotrimazole (ctz) ligand space of the complex fac-[Re(CO)3(bpy)(ctz)]+, a library of / ac-[Re(CO)3(bpy) L]+complexes was prepared (Figure 1 ). The fragment fac-[Re(CO)3(bpy)]+is kept constant while the structure of the L ligand (also called axial ligand) is systematically varied. The initial reference compound with clotrimazole (compound 1) is successively modified by removing the phenyl substituents all the way down to the cationic imidazole (complex 6). The complexes were prepared by the classical route employed in all the studies with these compounds: fac- [Re(CO)3(bpy)Br] was reacted with AgOTf and, after separation of AgBr, the intermediate fac- [Re(CO)s(bpy)(OTf)] was reacted with the imidazole derivative to give the desired compounds. After recrystallization pure samples were obtained in good yields. Most complexes are stable in DMSO solution under air and under ordinary light for several months. The only exception is complex 8 which slowly oxidizes in air and light as a solid or in DMSO solution.EXAMPLE 2ANTIMICROBIAL ACTIVITY

[0157] Prepared compounds were tested against S. aureus and E. coli as model bacteria for Grampositive and Gram-negative bacteria, respectively. The Minimum Inhibitory Concentrations (MIC; pig / ml) values observed for the series of complexes are depicted in Table 1 .Table 1. Minimum inhibitory concentrations MIC (pig / ml) of synthesized compounds to Gram-positive and Gram-negative bacteria, namely Staphylococcus aureus and Escherichia coli, respectively.literature values

[0158] For S. aureus, the maximum activity was found for the 1 -tritylimidazole derivative (ReBpyTrityllm, compound 2) that is very close to the activity of the clotrimazole derivative (ReBpyCtz, compound 1) taken here as the reference lead. This activity drops abruptly when one of the phenyl rings of the trityl substituent is removed, as in compound 3 (ReBpyPh2lm). When two phenyl groups are removed the activity of the 1- benzylimidazole derivative (compound 4, ReBpyBnlm), is again very low just like in the 1 -phenyl imidazole (compound 5, ReBpyPhlm) or the imidazole species (compound 6, ReBpylm). These results suggested that an inverted cone structure at the distal end of the axial ligand, like that of the 1 -tritylimidazole or the clotrimazole ligands is decisive for the high activity. The activity of the triphenylphosphine complex (compound 7, ReBpyPPh3) was tested, and it is similar to that of compound 2 and compound 1 complexes (ReBpyTrityllm and ReBpyCtz, respectively) against S. aureus. It seems that the imidazole is not playing any role in controlling the bactericidal activity of these complexes against S. aureus. The important structural motif appears to be the PhsQ (Q = P) or QA = C-lmidazole) moiety bound to the fac-[Re(CO)3(bpy)]+fragment. To confirm this suggestion, the tricyclohexyl phosphine complex (compound 8, ReBpyPCy3) was prepared and found that it is also as potent as the PPhs analogue. In contrast, the tri-substituted 1 -tertbutylimidazole derivative (compound 9 ReBpytBulm), was innocuous.

[0159] Internalization studies carried out to evaluate the intake of some of these molecules by the bacterial cells are presented in Figure 2.

[0160] The results show that the neutral ReBpyBr ( / ac-[Re(CO)3(bpy)Br] is taken up by both bacteria without promoting any growth inhibition. On the contrary, both compound 2 (ReBpyTrityllm) and compound 7 (ReBpyPPh3) are not taken up by S. aureus which they efficiently kill. In the case of E. coli, compound 2accumulates in small amounts whereas compound 7 does not. So, for S. aureus the CORM intake is not correlated to toxicity whereas in E. coli such correlation may be present since higher uptake of compound 2 corresponds to higher toxicity when compared to compound 7, for which neither uptake nor toxicity are observed.

[0161] As graphically displayed in Figures 3A-D, all compounds tested promoted CO release in the presence of S. aureus. The decreasing order of the increase in CO cytoplasmic levels relative to control is ReBpyTrityllm > ReBpyPPh3 « ReBpyPCy3 « ReBpyBnlm > ReBpytBulm. Clearly, CO release does not depend on the uptake of the complexes, since those that produced the higher amounts of CO are those that weren't taken up in the cells, according to Figure 2.

[0162] It was also checked whether the interaction of ReBpyTrityllm and ReBpyPPh3 with S. aureus induces the generation of ROS. The data revealed a significant increase of ROS content in cells exposed to ReBpyTrityllm, ReBpyPPh3 and ReBpyCtz relative to the DMSO control (Figure 4), providing evidence that ROS are involved in the interaction of these CORMs with S. aureus. The origin of ROS is not clear yet a high concentration of ROS contributes to bacterial death.EXAMPLE 3

[0163] Compounds were also tested against mammalian cells (Table 2).Table 2. Half maximum inhibitory dose (IC-50, piM) of the compounds to proximal tubular cell line derived from normal pig kidney (LLC-Pk1), breast cancer cells (MDA-MB-231), and colon cancer cells (HT29), evaluated after 24 hours of incubation.literature data; nd: not determined;

[0164] Since literature values vary widely with experimental conditions, for the case of cisplatin vs HT- 29, a determination was made under the same experimental conditions as described in the present disclosure, for a more accurate comparison.

[0165] From this table it can be seen that all complexes with L having a terminal inverted trigonal pyramidal structure (CPt^CsH^I (clotrimazole, compound 1), CPhs (trityl, compound 2), C(CH3)3 (tert-Butyl, compound 9), PPhs (triphenylphosphine, compound 7) have potent cytotoxicity against porcine LLC-PK1 and breast cancer cells, whereas the 1 -Ph-imidazole ligand, compound 5, produces a much less toxiccomplex. Importantly, all these complexes promote CO release in LLC-PK1 cells as can be seen in Figures 5A-D. Furthermore, they are significantly more toxic than cisplatin.

[0166] For colon cancer cells (HT29), it seems that complexes comprising a ligand L comprising a bulky inverted trigonal pyramidal structure (such as clotrimazole compound 1, trityl compound 2, and triphenylphosphine compound 7, have a higher cytotoxicity.

[0167] In summary, it was identified a molecular feature of the axial ligand L in the fac-[Re(C0)3(bpy)L]+complexes (Figure 1) that imparts high cytotoxicity against Gram-positive bacteria and mammalian cells in a process accompanied by intracellular CO release. The high cytotoxicity to animal cells limits the use of these compounds as antimicrobials but at the same time opens the door to their use as anti-tumoral drugs.

[0168] Although the disclosure has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

CLAIMS1 . Compound or a salt thereof, wherein said compound is of Formula I:wherein:M is a metal selected from Mn, Re, and Tc in the +1 oxidation state;Q is selected from B, C, N, and P; each R, R1and R2is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted alkyl, an optionally substituted alkyne group, an optionally substituted alkyne group, or any combination thereof; each R3and R4is hydrogen, or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkyne, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof; optionally, A is a linker comprising an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted bicyclic heteroaryl, an optionally substituted bicyclic aryl, an optionally substituted bicyclic heterocyclyl, an optionally substituted bicyclic cycloalkyl, an optionally substituted cyclic or acyclic hydrocarbyl chain, an amino acid, a peptide, a peptide nucleic acid, an ethylene glycol oligomer, any derivative thereof, or any combination thereof;X is a counterion, and m is 0 or 1 .

2. Compound according to claim 1 , wherein said compound is of Formula la:to any one of claims 1 to 2, wherein said A comprises any of:wherein:- is a single bond or a double bond; k is 0 or 1, n is 1 or 2; each Z1, Z2and Z3is -N-, -NH-, -NR-, -CH-, -CR-, -CH2-, -CR2-, -P-, -S-, or -O-;R5is hydrogen or a substituent comprising a halogen, an optionally substituted alkyl, an optionally substituted alkene, an optionally substituted alkyne, an alkoxy group, an amino group, an amide group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, a cyano group, a haloalkyl group, a nitro group, an azo group, a sulfonate group, a sulfinyl group, a vinyl group, an allyl group, an alkylhydroxy group, a keto group, an ether group, an ester group, a sulfone group, or any combination thereof.

4. Compound according to any one of claims 1 to 3, wherein said compound is of Formula II:

5. Compound according to the previous claim, wherein said Z1and Z2is N.

6. Compound according to any one of claims 4 to 5, wherein said Q is C.

7. Compound according to claim 1, wherein said compound is of Formula III:

8. Compound according to the previous claim, wherein said Q is P.

9. Compound according to any one of claims 1 to 8, wherein each of said R, R1and R2is selected from optionally substituted phenyl group, cyclohexyl group, or methyl group.

10. Compound according to any one of claims 1 to 9, wherein said R3and R4is hydrogen.

11. Compound according to any one of claims 1 to 10, wherein said M is Re.

12. Compound according to any one of claims 1 to 11 , wherein said compound is selected from the following list:

13. Compound according to any one of claims 1 to 12, for use in medicine.

14. Compound according to any one of claims 1 to 12, for use in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, a medical condition associated with cancer, pathogen infection, or a combination thereof, in a subject in need thereof.

15. Compound according to any one of claims 1 to 12, for use in labeling cancer cells, detecting cancer cells, imaging, sensitizing cancer cells, promoting cell death in cancer cells, inhibiting cell repair from DNA damage, decreasing size of a tumor, decreasing growth of a tumor, decreasing number of metastases, decreasing size of metastases, or any combination thereof, in a subject in need thereof.

16. Compound according to any one of claims claim 14 to 15, wherein said cancer is selected from the group comprising: skin cancer, brain cancer, thyroid cancer, oral and oropharyngeal cancer, lung cancer, bronchial cancer, breast cancer, liver cancer, intrahepatic bile duct cancer, pancreatic cancer,gastrointestinal cancer, kidney cancer, colon cancer, rectal cancer, bladder cancer, ovarian cancer, prostate cancer, rhabdomyosarcoma, basal-cell carcinoma, glioblastoma, medulloblastoma, leukemia, lymphoma, osteosarcoma, multiple endocrine neoplasia, mesothelioma, or any combination thereof..

17. Compound according to any one of claims 14 to 16, wherein said cancer is a solid tumor cancer.

18. Compound according to the previous claim, wherein said solid tumor cancer is a cisplatin resistant tumor.

19. Compound according to any one of claims 1 to 12, for use in inhibiting or reducing a load of a microorganism in a subject, wherein the microorganism is a pathogen.

20. Compound according to the previous claim, wherein said pathogen is a bacterium, preferably a Gram-positive bacterium, preferably selected from: S. aureus, B. subtilis, E. faecium, S. pneumoniae, S. epidermidis, C. difficile, or any combination thereof.21 . Pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier.

22. Pharmaceutical composition according to the previous claim, further comprising a second therapeutic agent selected from: antimicrobial agent, chemotherapeutic agent, or both.

23. Pharmaceutical composition according to the previous claim, wherein said antimicrobial agent is an antibiotic selected from: penicillins, cephalosporins, sulfonamides, fluoroquinolones, macrolides, tetracyclines, aminoglycosides, carbapenems, glicopeptides, streptogramins, oxazolidinones, cyclic lipopeptides, lipoglycopeptide, or any combination thereof.

24. Pharmaceutical composition according to claim 22, wherein said chemotherapeutic agent is selected from: cisplatin, carboplatin, etoposide, oxaliplatin, rituximab or trastuzumab, mechlorethamine, cyclophosphamide, bleomycin, doxorubicin, daunorubicin, cytarabine, methotrexate, hydroxyurea, or any combination thereof.

25. Pharmaceutical composition according to any one of claims 21 to 24, further comprising a vector selected from: peptide, liposome, vesicle, polymer, mesoporous material, MOF, inorganic layered structure, nanoparticle, dendrimer, protein, plasma protein, antibody, micelle, non-woven, or any combination thereof.

26. Pharmaceutical composition according to the previous claim, for use in targeting a cancer cell, preferably a tumor, in a subject.

27. Pharmaceutical composition according to any one of claims 21 to 25, for use in medicine, particularly in the prevention or treatment of a medical condition in a subject that benefits from the therapeutic action of CO, even more particularly in the prevention or treatment of a medical condition associated with cancer, pathogenic infection, or both, in a subject in need thereof.

28. Pharmaceutical composition according to any one of claims 21 to 25, for oral administration, topical administration, systemic administration, or any combination thereof.

29. A kit comprising at least one compound according to any one of claims 1 to 12, or a pharmaceutical composition according to any one of claims 21 to 25, and optionally at least one therapeutic agent.

30. Method for preparing a compound according to any one of claims 1 to 12, the method comprising the steps of: a) contacting a solution of Re(CO)3(bpy)Br wherein bpy is 2, 2’ -bipyridyl, in an organic solvent with AgCCFsSOs), and b) adding a ligand compound, preferably an imidazole compound or a phosphine compound.

31. Method according to claim 30, wherein said ligand is selected from clotrimazole (Ctz), 1- tritylimidazole (Trityllm), 1 -tert-butylimidazole (tBulm), triphenylphosphine (PPh3) or tricyclohexylphosphine (PCy3).

Images