Compounds and their use in treatment of non-viral diseases and infections

Abstract

The present invention relates to compounds having a structure according to general formula I or II or III for use in the treatment of non-viral infections or diseases caused by non-viral infections. The present invention relates to compounds having a structure according to general formula III and to pharmaceutical compositions comprising at least one of said compounds. The invention also relates to methods of treating non-viral infections or diseases caused by non-viral infections.

Description

Technical Field

[0001] The present invention relates to compounds having a structure according to Formula I, II, or III for use in treating non-viral infections or diseases caused by non-viral infections. The present invention also relates to methods of treating non-viral infections or diseases caused by non-viral infections. The present invention relates to compounds having a structure according to Formula III and pharmaceutical compositions comprising at least one of said compounds. Background Art

[0002] At the 2017 G20 summit, world leaders identified the spread of antimicrobial resistance as one of the greatest challenges facing humanity (G20 Leaders Declaration: Shaping an interconnected world (2017)). In 2019, the World Health Organization (WHO) issued an urgent warning about antimicrobial resistance, calling it a global crisis that threatens a century of progress (Interagency Coordination Group on Antimicrobial Resistance: No time to wait: securing the future from drug-resistant infections, World Health Organization (2019)). The challenges associated with antimicrobial resistance are complex and multifaceted, but if action is taken now, it is not too late to overcome the threat of drug-resistant infections. The emergence of drug-resistant bacteria is mainly due to their widespread overuse and misuse, which leads to continuous selection pressure on bacteria (Davies and Davies, 2010; CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: US Department of Health and Human Services, CDC (2019)). Surprisingly, for several antibiotics in clinical use, there is a lack of scientific data on the exact mode of action and the protein targets involved. This hinders the understanding of drug resistance formation and the identification of new antibiotics for the development of next-generation drugs (Bandow et al., 2003; Ang et al., 2017).

[0003] An example of an unclear mode of action is the commonly used antibiotic metronidazole. For more than 45 years, metronidazole has been considered a standard of care for several infectious diseases (primarily due to the lack of alternatives) and is used against several protozoan infections, anaerobes (e.g., Clostridium difficile), and microaerophiles (e.g., Helicobacter pylori) ( et al., 2010). However, although metronidazole is widely used to treat Helicobacter pylori and Clostridium difficile, its exact mode of action remains to be elucidated, and alternatives with better efficacy, especially against metronidazole-resistant strains, are urgently needed.

[0004] Helicobacter pylori infection is characterized by increasing antibiotic resistance, which compromises the efficacy of current treatment options (Vakil et al., 2007; Megraud et al., 2004). In European adults, H. pylori resistance rates to clarithromycin are 18%, levofloxacin is 14%, and metronidazole is as high as 35%, and this resistance is a major cause of treatment failure (Ang et al., 2017). H. pylori is a Gram-negative, microaerophilic bacterium that causes a variety of gastrointestinal diseases, including gastritis, peptic ulcer disease, and even gastric cancer (Perez-Perez et al., 2004; Megraud et al., 2004). Furthermore, unless treated, gastric colonization in humans persists throughout life (Lehours et al., 2007). It is the first officially recognized bacterial carcinogen and a significant human pathogen, with 50% of the global population infected. In developing countries, infection rates reach as high as 80%. Of those infected, 15% will develop gastritis and 1% will develop cancer (Ang et al., 2017). Therefore, the development of new or improved drugs, improved treatment regimens, and monitoring of antibiotic resistance in H. pylori are crucial for infection management in clinical practice (Ang et al., 2017; Boucher et al., 2009; Zagari et al., 2018).

[0005] Jamshidi et al. (2022) described triazole / quinoline hybrid compounds with antifungal activity, such as against Streptococcus cervix and Candida albicans, and antiaerobic bacterial activity, such as against Escherichia coli and Staphylococcus aureus. Li et al. (2019) described indole-nitroimidazole conjugates that reduced gene expression in methicillin-resistant Staphylococcus aureus. Foroumadi et al. (2004) described the in vitro antituberculosis activity of two thiadiazole derivatives.

[0006] Therefore, there is a great need for new compounds with antibacterial activity for the treatment of non-viral diseases and infections, in particular for the treatment of bacterial diseases caused by bacteria that are resistant to commonly used antibiotic agents.

[0007] The object of the present invention is to provide novel compounds and their use in treating non-viral infections or diseases caused by non-viral infections. Summary of the Invention

[0008] According to the present invention, this object is solved by providing a compound having a structure according to general formula I or II or III or a pharmaceutically acceptable salt thereof for use in treating non-viral infections or diseases caused by non-viral infections:

[0009]

[0010] in,

[0011] R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group,

[0012] R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group,

[0013] wherein the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl is optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 is hydrogen or C1-C6 alkyl,

[0014] The conditions for compounds of formula II or III are:

[0015] When R 1 When it is methyl, then R 2 is not ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2, NH(CH3)2 or NH(CH2-CH3)2,

[0016] When R 1 When it is CF3, then R 2 C1-C4 alkyl not substituted by halogen,

[0017] When R 1 When is isopropyl, then R 2 C1-C4 alkyl which is not substituted by halogen;

[0018] The conditions for compounds of formula III are:

[0019] R 1 and R 2 Not all methyl.

[0020] According to the present invention, this object is solved by providing a method for treating non-viral infections or diseases caused by non-viral infections, the method comprising the following steps:

[0021] A compound having the general formula I, II or III according to the present invention or a pharmaceutical composition according to the present invention is administered to a subject in need thereof.

[0022] According to the present invention, this object is solved by providing a compound having a structure according to formula III or a pharmaceutically acceptable salt thereof:

[0023]

[0024] in,

[0025] R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group, and

[0026] R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group,

[0027] wherein the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl is optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 is hydrogen or C1-C6 alkyl,

[0028] The conditions are:

[0029] R 1 and R 2 Not all methyl,

[0030] When R 1 When it is methyl, then R 2 is not ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2 or NH(CH3)2,

[0031] When R 1 When it is CF3, then R 2 C1-C4 alkyl not substituted by halogen,

[0032] When R 1 When is isopropyl, then R 2 C1-C4 alkyl which is not substituted by halogen.

[0033] According to the present invention, this object is solved by providing a pharmaceutical composition comprising:

[0034] (i) at least one compound of the present invention having the structure of formula III,

[0035] (ii) optional pharmaceutically acceptable excipients and / or carriers.

[0036] According to the present invention, this object is solved by providing a compound having a structure according to formula III according to the present invention for use in medicine.

[0037] DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

[0038] Before describing the present invention in more detail below, it should be understood that the present invention is not limited to the particular methods, schemes and reagents described herein, as they may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. For purposes of the present invention, all references cited herein are incorporated by reference in their entirety.

[0039] Concentration, amount and other numerical data can be expressed or presented in range format in this article.It should be understood that the use of this range format is only for convenience and simplicity, and therefore should be flexibly interpreted as not only including the numerical values ​​clearly listed as range limits, but also including all individual numerical values ​​or subranges contained in the range, as if each numerical value and subrange were clearly listed.As an illustration, the numerical range of "1 to 20" should be interpreted as not only including the values ​​of 1 to 20 clearly listed, but also including individual values ​​and subranges within the indicated range.Therefore, included in this numerical range are individual values ​​such as 1, 2, 3, 4, 5 ... 17, 18, 19, 20, and subranges such as 2 to 10, 8 to 15, etc. The same principle also applies to recording a numerical range, such as "higher than 150 mg per day".In addition, no matter how the described range or feature breadth, this explanation should be applicable.

[0040] As used herein and throughout the specification, the term "alkyl" refers to a single radical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group contains 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms, more preferably 1 to 4 carbon atoms. In some embodiments, the alkyl groups employed in the present invention contain 1 to 6 carbon atoms (C 1-6 In another embodiment, the alkyl group employed contains 1 to 5 carbon atoms (C 1-5 In another embodiment, the alkyl group employed contains 1-4 carbon atoms (C 1-4 In another embodiment, the alkyl group employed contains 1-3 carbon atoms (C 1-3 In another embodiment, the alkyl group employed contains 1-2 carbon atoms (C 1-2Alkyl). In another embodiment, the alkyl group employed is methyl. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-propyl, butyl, isobutyl, n-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,2-dimethylpropyl, isopentyl, n-hexyl, isohexyl, sec-hexyl, and the like, which may carry one or more substituents. Alkyl group substituents include, but are not limited to, any substituent described herein that results in the formation of a stable moiety. In some embodiments, the alkyl chain is straight chain. In some embodiments, the alkyl chain is branched. In some embodiments, the alkyl chain is substituted. In some embodiments, the alkyl chain is unsubstituted. In some embodiments, the alkyl chain is straight chain and is substituted or unsubstituted. In some embodiments, the alkyl chain is branched and is substituted or unsubstituted.

[0041] As used herein and throughout the specification, the term "alkenyl" refers to a monoradical of a straight or branched hydrocarbon containing at least one double bond (-C=C-). Preferably, the alkenyl group contains 2 to 5 carbon atoms, i.e., 2, 3, 4, 5 or 6 carbon atoms, more preferably 1 to 4 carbon atoms. In some embodiments, the alkenyl groups employed in the present invention contain 2 to 6 carbon atoms (C 2-6 In another embodiment, the alkenyl group employed contains 2 to 5 carbon atoms (C 2-5 In another embodiment, the alkenyl group employed contains 2 to 4 carbon atoms (C 2-4 In another embodiment, the alkenyl group employed contains 2 to 3 carbon atoms (C 2-3 In another embodiment, the alkenyl group used contains 2 carbon atoms (C2 alkenyl). Examples of alkenyl radicals include but are not limited to allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl, etc., which may be substituted with one or more substituents. Alkenyl group substituents include but are not limited to any substituents described herein that result in the formation of a stable moiety. In some embodiments, the alkenyl chain is a straight chain. In some embodiments, the alkenyl chain is a branched chain. In some embodiments, the alkenyl chain is substituted. In some embodiments, the alkenyl chain is unsubstituted. In some embodiments, the alkenyl chain is a straight chain and is substituted or unsubstituted. In some embodiments, the alkenyl chain is a branched chain and is substituted or unsubstituted.

[0042] As used herein and throughout the specification, the term "alkynyl" refers to a group containing at least one triple bond (-C ≡C-) of a straight or branched hydrocarbon. Preferably, the alkynyl group contains 3 to 6 carbon atoms, i.e., 3, 4, 5 or 6 carbon atoms, more preferably 3 to 4 carbon atoms. In some embodiments, the alkynyl group employed in the present invention contains 3 to 6 carbon atoms (C 3-6 In another embodiment, the alkynyl group employed contains 3 to 5 carbon atoms (C 3-5 In another embodiment, the alkynyl group employed contains 3 to 4 carbon atoms (C 2-4 In some embodiments, the alkynyl group is a straight chain. In some embodiments, the alkynyl group is a branched chain. In some embodiments, the alkynyl group is substituted. In some embodiments, the alkynyl group is unsubstituted. In some embodiments, the alkynyl group is a straight chain and is substituted or unsubstituted. In some embodiments, the alkynyl group is a branched chain and is substituted or unsubstituted.

[0043] As used herein and throughout the specification, the term "haloalkyl" refers to an alkyl group substituted with one halogen substituent up to each halogen substituted. The halogen substituent is preferably fluorine. The haloalkyl is preferably a perfluoroalkyl. In some embodiments, the haloalkyl groups employed in the present invention contain 1 to 6 carbon atoms (C 1-6 In another embodiment, the haloalkyl groups employed in the present invention contain 1 to 5 carbon atoms (C 1-5 In another embodiment, the haloalkyl groups employed in the present invention contain 1 to 4 carbon atoms (C 1-4 In another embodiment, the haloalkyl groups employed in the present invention contain 1 to 3 carbon atoms (C 1-3 In another embodiment, the haloalkyl groups employed in the present invention contain 1 to 2 carbon atoms (C 1-2In some embodiments, the haloalkyl group is a C1 haloalkyl, particularly a C1 haloalkyl, ...

[0044] As used herein and throughout the specification, the term "substituted" means that a group such as an alkyl, alkenyl or alkynyl group may be substituted with one or more substituents, such as halogen, OR 3 or SR 3 One or more of 3 is hydrogen or C1-C6 alkyl. "Substituted" in reference to a group means that one or more hydrogen atoms attached to a member atom within the group are replaced by a substituent selected from defined or suitable substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution is consistent with the allowed valences of the substituted atom and the substituent and that the substitution results in a stable compound. When it is stated that a group may contain one or more substituents, one or more member atoms within the group may be substituted. In addition, a single member atom within a group may be substituted with more than one substituent, as long as such substitution is consistent with the allowed valences of the atom.

[0045] Nitroimidazole compounds for treating non-viral infections

[0046] As described above, the present invention provides a compound having the general formula I, II or III for use in treating non-viral infections or diseases caused by non-viral infections.

[0047] A compound having the general formula I, II or III or a pharmaceutically acceptable salt thereof:

[0048]

[0049] The compound is a compound wherein

[0050] R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group,

[0051] R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group,

[0052] For R 2, the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl may be optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 It is hydrogen or C1-C6 alkyl.

[0053] -Disclaimer

[0054] According to the present invention, the compounds used according to the present invention are not compounds of the general formula II or III, in which R 1 is a methyl group, and

[0055] R 2 It is ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2, NH(CH3)2 or NH(CH2-CH3)2.

[0056] According to the present invention, the compounds used according to the present invention are not compounds of the general formula II or III, in which R 1 is CF3, and

[0057] R 2 It is a C1-C4 alkyl group substituted by halogen.

[0058] According to the present invention, the compounds used according to the present invention are not compounds of the general formula II or III, in which R 1 is isopropyl, and

[0059] R 2 It is a C1-C4 alkyl group substituted by halogen.

[0060] According to the invention, the compounds used according to the invention are not compounds of the general formula III, wherein

[0061] R 1 and R 2 They are all methyl.

[0062] In one embodiment of the compounds used according to the invention, R 1 is methyl, and the compound has Formula Ia or IIa or IIIa:

[0063]

[0064] In one embodiment of the compound used according to the invention:

[0065] R 2 It is a C1-C6 alkyl group, preferably a C1-C4 alkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-propyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a neopentyl group or an n-hexyl group.

[0066] In one embodiment of the compound for use according to the invention:

[0067] R 2 It is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl.

[0068] In one embodiment of the compound used according to the invention:

[0069] R 2 It is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl, 1-butynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl or 2-propynyl.

[0070] In one embodiment of the compound used according to the invention:

[0071] R 2 It is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group substituted by halogen.

[0072] In one embodiment of the compound used according to the invention:

[0073] R 2 is OR 3 Substituted C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl, wherein R 3 is hydrogen or methyl.

[0074] In one embodiment of the compound used according to the invention:

[0075] R 2 It was SR 3 Substituted C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl, wherein R 3 is hydrogen or methyl.

[0076] In one embodiment of the compound used according to the present invention, the compound has formula Ia

[0077] and

[0078] R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or 1-butyne; or

[0079] R 2 is a C1-C6 alkyl group, preferably a methyl group.

[0080] In one embodiment of the compound used according to the invention, the compound has the formula IIa

[0081] and

[0082] R 2 It is a C3-C6 alkynyl group, preferably a C3-C4 alkynyl group, more preferably a propargyl group or 1-butyne.

[0083] In one embodiment of the compound used according to the invention, the compound has the formula IIa

[0084] and

[0085] R 2 It is a C1-C6 alkyl group, preferably a C1-C4 alkyl group, more preferably a methyl group or an ethyl group.

[0086] In one embodiment of the compound used according to the invention, the compound has the formula IIa

[0087] and

[0088] R 2 It is a C2-C6 alkenyl group, preferably a C2-C5 alkenyl group, more preferably an allyl group, a vinyl group or a dimethylallyl group.

[0089] In one embodiment of the compound used according to the present invention, the compound has the formula IIIa

[0090] And R 2 It is a C3-C6 alkynyl group, preferably a C3-C4 alkynyl group, more preferably a propargyl group or 1-butyne.

[0091] Preferably, the compound is selected from MF-01: 1-(2-methoxyethyl)-2-methyl-5-nitro-1H-imidazole:

[0092] MF-02: 2-(methoxymethyl)-1-methyl-5-nitro-1H-imidazole:

[0093] MF-03: 1-(2-ethoxyethyl)-2-methyl-5-nitro-1H-imidazole:

[0094] MF-04: 2-(Ethoxymethyl)-1-methyl-5-nitro-1H-imidazole:

[0095] MF-05: 2-Methyl-5-nitro-1-(2-propoxyethyl)-1H-imidazole:

[0096] MF-06: 1-Methyl-5-nitro-2-(propyloxymethyl)-1H-imidazole:

[0097] MF-07: 1-(2-(allyloxy)ethyl)-2-methyl-5-nitro-1H-imidazole:

[0098] MF-08: 2-((allyloxy)methyl)-1-methyl-5-nitro-1H-imidazole: MF-09: 2-methyl-1-(2-((3-methylbutyl-2-en-1-yl)oxy)ethyl)-5-nitro-1H-imidazole:

[0099]

[0100] Metro-P2: 1-(2-methyl-5-nitro-1H-imidazol-1-yl)pentyl-4-yn-2-ol:

[0101]

[0102] Metro-P3: 2-Methyl-5-nitro-1-((prop-2-yn-1-oxy)methyl)-1H-imidazole: and Metro-P1: 2-methyl-5-nitro-1-(2-(prop-2-yn-1-oxy)ethyl)-1H-imidazole:

[0103]

[0104] More preferably, the compound is selected from

[0105]

[0106] Preferably, the non-viral infection is an infection with protozoa, anaerobic bacteria or microaerophilic bacteria.

[0107] Preferably, the protozoan infection is an infection with Trichomonas vaginalis, Giardia lamblia or Entamoeba histolytica.

[0108] More preferably, the non-viral infection is an infection with anaerobic or microaerophilic bacteria.

[0109] Preferably, the non-viral infection is an infection with Helicobacter pylori, Clostridium difficile, Fusobacterium nucleatum or Gardnerella vaginalis.

[0110] In a preferred embodiment, the non-viral infection is an infection with a strain of Helicobacter pylori that is resistant to metronidazole.

[0111] The compounds of the present invention preferably bind to thiol peroxidases, the inhibition of which can induce toxic effects on bacteria. One such thiol peroxidase is Helicobacter pylori thiol peroxidase HpTpx (025151). The compounds of the present invention also preferably bind to the Helicobacter pylori chaperone protein HpGroEL (P42383).

[0112] Treatment

[0113] As described above, the present invention provides a method for treating a non-viral infection or a disease caused by a non-viral infection.

[0114] The method comprises the step of administering to a subject in need thereof a compound having general formula I, II or III according to the present invention or a pharmaceutical composition of the present invention.

[0115] Preferably, a therapeutically effective amount of a compound having the general formula I, II or III according to the present invention or a pharmaceutical composition according to the present invention is administered to the subject.

[0116] A "therapeutic amount" or "therapeutically effective amount" (the two terms are used interchangeably herein) of a compound of the invention (i.e., a compound having Formula I or II or III) or a pharmaceutical composition of the invention is an amount that results in the desired therapeutic result.

[0117] The present invention also provides the use of a compound of the present invention (ie a compound according to formula I or II or III) or a pharmaceutical composition of the present invention for the preparation of a medicament.

[0118] Preferably, the non-viral infection is an infection with protozoa, anaerobic bacteria or microaerophilic bacteria.

[0119] Preferably, the protozoan infection is an infection with Trichomonas vaginalis, Giardia lamblia or Entamoeba histolytica.

[0120] More preferably, the non-viral infection is an infection with anaerobic or microaerophilic bacteria.

[0121] Preferably, the infection with anaerobic or microaerophilic bacteria is an infection with Helicobacter pylori, Clostridium difficile, Fusobacterium nucleatum or Gardnerella vaginalis.

[0122] In a preferred embodiment, the non-viral infection is an infection with a strain of Helicobacter pylori that is resistant to metronidazole.

[0123] Nitroimidazole compounds

[0124] As mentioned above, the present invention provides a compound having the general formula III.

[0125] A compound of formula III or a pharmaceutically acceptable salt thereof:

[0126]

[0127] The compound is a compound wherein

[0128] R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group, and

[0129] R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group,

[0130] wherein the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl is optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 It is hydrogen or C1-C6 alkyl.

[0131] -Disclaimer

[0132] According to the present invention, the compound of the present invention no Such a compound, wherein

[0133] R 1 and R 2 They are all methyl compounds.

[0134] According to the present invention, the compound of the present invention no Compounds with the following structure:

[0135]

[0136] According to the present invention, the compound of the present invention no Such a compound, wherein

[0137] R 1 is a methyl group, and

[0138] R 2 It is ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2 or NH(CH3)2.

[0139] According to the present invention, the compound of the present invention no Such a compound, wherein

[0140] R 1 is CF3, and

[0141] R 2It is a C1-C4 alkyl group substituted by halogen.

[0142] According to the present invention, the compound of the present invention no Such a compound, wherein

[0143] R 1 is isopropyl, and

[0144] R 2 It is a C1-C4 alkyl group substituted by halogen.

[0145] According to the present invention, the compound of the present invention no Compounds having any of the following structures:

[0146]

[0147] In one embodiment, the compound of Formula III has the structure wherein,

[0148] R 1 is methyl, and the compound has the formula IIIa

[0149]

[0150] In one embodiment, a compound of Formula III has the structure wherein,

[0151] R 2 It is a C1-C6 alkyl group, preferably a C1-C4 alkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-propyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a neopentyl group or an n-hexyl group.

[0152] In one embodiment, the compound of Formula III has the structure wherein,

[0153] R 2 It is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl.

[0154] In one embodiment, the compound of Formula III has the structure wherein,

[0155] R 2 It is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl, 1-butynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl or 2-propynyl.

[0156] In one embodiment, the compound of Formula III has the structure wherein,

[0157] R 2 It is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group substituted by halogen.

[0158] In one embodiment, the compound of Formula III has the structure wherein,

[0159] R 2 is OR 3 substituted C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl, and

[0160] R 3 is hydrogen or methyl.

[0161] In one embodiment, the compound of Formula III has the structure wherein,

[0162] R 2 It was SR 3 substituted C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl, and

[0163] R 3 is hydrogen or methyl.

[0164] In a preferred embodiment, the compound has the formula IIIa

[0165] and

[0166] R 2 It is a C3-C6 alkynyl group, preferably a C3-C4 alkynyl group, more preferably a propargyl group or 1-butyne.

[0167] Preferred compounds of formula III are

[0168]

[0169] (Metro-P2: 1-(2-methyl-5-nitro-1H-imidazol-1-yl)pentyl-4-yn-2-ol).

[0170] As described above, the present invention provides a pharmaceutical composition comprising:

[0171] (i) at least one compound of the general formula III according to the invention,

[0172] (ii) optional pharmaceutically acceptable excipients and / or carriers.

[0173] As stated above, the present invention provides compounds of general formula III according to the invention for use in medicine.

[0174] The pharmaceutical composition or formulation can be selected according to the present invention from the group consisting of tablets, layered tablets, coated tablets, pills, soft or hard capsules, microcapsules, oral delayed-release drug forms, transdermal systems, suppositories, microcrystalline and nanocrystalline formulations, liposomal formulations, drops, nasal drops, sprays, emulsions, dispersions, solutions, sterile solutions, lyophilizates, powders and inhalation sprays.

[0175] The application or use of the pharmaceutical composition or formulation according to the invention is preferably selected from oral, peroral, sublingual, buccal, subcutaneous, intravenous, dermal, pulmonary or nasal application or use.

[0176] The pharmaceutical compositions or formulations are preferably provided in the form of sterile solutions or lyophilizates, parenteral, oral and oral delayed release drug forms, transdermal systems, microcrystalline and nanocrystalline formulations, liposomal formulations, microcapsules, emulsions, dispersions and are particularly suitable for subcutaneous, intravenous, dermal, transdermal, oral, peroral or pulmonary use or application.

[0177] Lactose, starch, sorbitol, mannitol, sucrose, ethanol and water can be used, for example, as pharmacologically and chemically compatible carriers, solvents or adjuvants.

[0178] In addition, starch, modified starch, gelatin, natural sugar, natural or synthetic polymers such as gum arabic, guar gum, sodium alginate, carboxymethyl cellulose or polyethylene glycol can be included as binders. Cyclodextrin, modified cyclodextrin and benzoate, chloride, acetate, tartrate can be included as stabilizers and stearate, polyethylene glycol, amino acids such as leucine can be used as adjuvants usually at a concentration of 0.05% to 15%.

[0179] Liquid preparations include solutions, dispersions, and emulsions. Liquid preparations for parenteral use are sterile and contain water or water and a solubilizing agent, such as propylene glycol, micelles, and mixed micelle forming agents. Starch or modified starch, alginates, aluminates, bentonite, or microcrystalline cellulose can be used as liquid preparations in concentrations typically between 2% and 30% by weight.

[0180] Sugars, sugar alcohols, corn, rice, or potato starch, gelatin, gum arabic, tragacanth, calcium ammonium alginate, carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and inorganic substances can be used as adjuvants at concentrations generally between 1% and 30% by weight. Pharmaceutical preparations for subcutaneous, intravenous, and transdermal use, as well as parenteral and oral sustained-release dosage forms, are claimed as preferred preparations. Such preparations generally comprise a matrix, particularly one with a polymer (in many cases a biodegradable polymer) as a shaping or structural additive, into which at least one compound of the invention is incorporated.

[0181] As used herein, the term "pharmaceutically acceptable salt" includes salts of compounds of Formula III prepared using relatively non-toxic (i.e., pharmaceutically acceptable) acids or bases, depending on the specific substituents found on the compounds of the invention. For example, if the compounds of the invention contain acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. If the compounds of the invention contain basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. The limiting examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, partially neutralized phosphoric acid, sulfuric acid, partially neutralized sulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also include salts of amino acids such as arginine, etc., and salts of organic acids such as glucuronic acid or galacturonic acid, etc. Some specific compounds of the present invention can contain alkaline and acidic functional groups simultaneously, which allows the compound to be converted into base addition salts or acid addition salts. Salt is contacted with an alkali to regenerate the neutral form of the compound of the present invention or acid, and the parent compound is separated in a conventional manner. The parent form of the compound is different from various salt forms in certain physical properties such as solubility in polar solvents, but in other respects, for the purposes of the present invention, these salts are equivalent to the parent form of the compound. The compounds of the present invention can have chirality or asymmetric carbon atoms (optical centers) and / or double bonds. The present invention includes racemates, diastereomers, geometric isomers and independent optical isomers. The compounds of the present invention can exist in unsolvated forms and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are also included in the present invention. The compounds of the present invention can also exist in multiple crystalline or amorphous forms.

[0182] The compounds of the present invention can also be in the form of so-called prodrugs. Prodrugs of the compounds of the present invention are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an isolated environment. For example, when placed in a transdermal patch reservoir, for example, together with a suitable enzyme or chemical reagent, prodrugs can slowly be converted into compounds of the present invention.

[0183] Further Description of the Preferred Embodiments

[0184] Disclosed are novel antibiotic compounds based on a nitroimidazole scaffold that exhibit >60-fold enhanced activity against Helicobacter pylori compared to the parent compound, metronidazole. Furthermore, they exhibit moderate activity against resistant isolates. Modifications to enhance activity primarily occur at the free alcohol of the N-1 hydroxyethyl chain or at the C2-hydroxymethyl chain to form an ether bond.

[0185] Mode of action studies suggest binding to the chaperone protein HpgGroEL and enhanced binding to thiol peroxidase (compared to metronidazole), with inhibition of thiol peroxidase triggering toxic effects on bacteria due to suppression of the overall oxidative stress response. The compound is non-toxic to human cells, exhibits suitable plasma stability, and has favorable ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic properties, making it a prime candidate for antibiotic use.

[0186] Disclosed herein are nitroimidazole compounds with enhanced antimicrobial activity for the treatment of Helicobacter pylori infection and other anaerobic or microaerophilic bacterial or protozoal infections. Cytotoxicity was evaluated in human cells, which demonstrated that these compounds were non-cytotoxic. Therefore, nitroimidazole compounds are potential drug candidates with an appropriate safety profile.

[0187] The following examples and figures illustrate the present invention but do not limit it. BRIEF DESCRIPTION OF THE DRAWINGS

[0188] Figure 1 Compounds of the present invention are shown.

[0189] Figure 2 Shown are exemplary results of an MTT assay for determining IC50 values ​​of compounds of the invention in HeLa cells. The values ​​obtained after the MTT readout of the nitroimidazole compounds were normalized to the DMSO control value (DMSO ctrl = 100% cell viability after 24 hours of culture). The MTT assay was performed in a concentration range of 10 μM to 1 mM.

[0190] Figure 3 The in vitro stability of the compounds of the present invention in mouse plasma is shown.

[0191] Figure 4 Shown are modifications of recombinantly expressed Helicobacter pylori thiol peroxidase (HpTpx) with metronidazole or Metro-P3, identified by intact protein mass spectrometry analysis after protein purification. H. pylori thiol peroxidase was overexpressed in E. coli in the presence of 500 μM metronidazole or Metro-P3, then purified by affinity chromatography, analyzed by IP-MS, and compared to the unmodified HpTpx enzyme.

[0192] Figure 5The results of peroxidase assay using thiol peroxidase HpTpx are shown. It can be seen that as the degree of Metro or Metro-P3 modification increases, the activity decreases.

[0193] Figure 6 IP-MS studies showing improved efficacy of Metro-P3. Metro-P3 bound to HpTpx more readily (~8-fold) than metronidazole, suggesting that Metro-P3 has enhanced affinity compared to metronidazole.

[0194] Figure 7 shows the different binding modes of metronidazole to Metro-P3 in HpTpx crystallographic studies. Metro-P3 binds to HpTpx in its reduced state, which is the more stable and prevalent form of HpTpx in the cytoplasm.

[0195] Figure 8 Pharmacokinetic data for various nitroimidazole compounds of the present invention are shown. DETAILED DESCRIPTION

[0196] Example 1 Materials and Methods

[0197] 1.1 Reagents and solvents

[0198] Unless otherwise stated, commercial reagents and starting materials were from Sigma Aldrich, TCI Europe, VWR, Roth, BLDpharm and Alfa Aesar, and starting compounds were used without further purification and stored as indicated. Technical solvents used for purification were used after simple distillation.

[0199] All air- and moisture-sensitive reactions were performed using standard Schlenk techniques in flame-dried glassware under an argon atmosphere. Argon-flushed syringes were used to transfer anhydrous solvents and water-sensitive liquid chemicals.

[0200] 1.2 Thin layer chromatography (TLC)

[0201] For thin layer chromatography (TLC), silica-coated plates (aluminum, Merck, silica 60F254) were used. For visualization, spots were detected using ultraviolet light (254 nm and 366 nm) or by staining with potassium permanganate solution (3.00 g KMNO4, 20.0 g K2CO3 and 5.00 mL 5% NaOH (aq.) dissolved in 300 mL water) and then heat-treated. Column chromatography was performed using silica gel from Merck (40 to 63 μm (Si 60)).

[0202] 1.3 High-pressure liquid chromatography (HPLC) analysis

[0203] If necessary, compounds were purified using preparative reversed-phase HLPC using a Waters 2545 quaternary gradient module equipped with a fraction collector on a YMC Triart C18 column (250×10 mm, 5 μm). ddH 2 O and HPLC-grade acetonitrile (TFA-free) were used as the mobile phase, and the gradients are listed in Table 1.

[0204] Table 1: Gradients used for HPLC purification.

[0205]

[0206] 1.4 Nuclear Magnetic Resonance Spectroscopy (NMR)

[0207] Nuclear magnetic resonance (NMR) spectra were measured at room temperature on a Bruker AVHD-400 or AVHD-300. Chemical shifts are given as δ values ​​in ppm (parts per million) and are calibrated based on the residual proton signal of the solvent relative to the internal standard tetramethylsilane:

[0208] Chloroform-d1( 1 H-NMR: δ=7.26ppm, 13 C-NMR: δ = 77.2 ppm)

[0209] NMR multiplicity is expressed as singlet (s), doublet (d), triplet (t), quartet (q), pseudo-sextet (ps), or multiplet (m). Coupling constants, J, are expressed in Hertz (Hz). 1 H-NMR and 13 The assignment of C-NMR signals was determined by two-dimensional NMR spectroscopy (COSY, HSQC, HMBC).

[0210] 1.5 Mass spectrometry (MS)

[0211] High-resolution mass spectrometry (HR-MS) was performed on an LTQ-FT Ultra mass spectrometer (Thermo Fisher Scientific). ESI was used as the ionization method. Low-resolution LC-MS measurements were performed on an MSQ Plus mass spectrometer (Thermo Fisher Scientific). Mass spectrometry data were processed using Xcalibur 2.2 (Thermo Fisher Scientific).

[0212] Example 2 Synthesis

[0213] 2.1Metro-P1 (2-methyl-5-nitro-1-(2-(prop-2-yn-1-oxy)ethyl)-1H-imidazole)

[0214]

[0215] To a suspension of metronidazole (200 mg, 1.17 mmol, 1.00 eq.) and Cs CO (838 mg, 2.57 mmol, 2.20 eq.) in DMF (4 mL) was added propargyl bromide solution (80% in toluene, 0.30 mL, 2.78 mmol, 2.40 eq.) and heated to 50° C. for 96 hours. The reaction mixture was quenched by the addition of H O (5 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were then washed with 5% LiCl solution (aq., 15 mL) and brine (20 mL), dried over Na SO, and the solvent removed in vacuo. The crude product was further purified by column chromatography (EtOAc 100%) and high performance liquid chromatography (HPLC) to yield 74.4 mg of the desired probe (30%, 1.17 mmol) as a white solid.

[0216] TLC:R f =0.45(EtOAc)[UV].

[0217] 1 H NMR (400MHz, CDCl3) δ (ppm) = 2.39 (t, 4 J=2.3Hz,1H,H-12),2.52(s,3H,H-6),3.86(t, 3 J=4.9Hz,2H,H-8),4.08(d, 4 J=2.3Hz,2H,H-10),4.51(t, 3 J=4.9Hz,2H,H-7),7.96(s,1H,H-4).

[0218] 13 C NMR (101MHz, CDCl3) δ (ppm) = 14.8 (C-6), 46.6 (C-7), 58.7 (C-10), 68.6 (C-8), 75.3 (C-12), 78.8 (C-11), 133.4 (2×C, C-4 / C-5) 152.0 (C-2).

[0219] HR-MS (ESI): m / z = calc. [M+H] + :210.0878, found:210.0874.

[0220] 2.2 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)acetaldehyde (part of Metro-P2 synthesis)

[0221]

[0222] Under an argon atmosphere, 2.00 mL (20.0 mmol, 1.10 eq.) of oxalyl chloride was added dropwise to 160 mL of CH Cl. The solution was cooled to -78°C, and 10 mL of DMSO was added dropwise to the stirred solution. After 20 minutes, 3.42 g (20 mmol, 1.00 eq.) of metronidazole was dissolved in 15 mL of DMSO. After stirring for another 20 minutes, 33 mL (240 mmol, 12.0 eq.) of NEt was added. The reaction mixture was stirred at 78°C for another 10 minutes and then warmed to room temperature. The mixture was diluted with EtOAc (400 mL) and washed with water (4 × 75 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na SO, and the solvent was removed in vacuo. The crude residue was purified by flash chromatography on silica gel (CH 2 Cl 2 / MeOH 40:1 v / v) to afford the title compound (1.20 g, 7.09 mmol, 32%) as an orange viscous oil.

[0223] TLC:R f =0.78(CH2Cl2 / MeOH 10:1)[UV].

[0224] 1 H NMR (400MHz, CDCl3) δ (ppm) = 2.41 (s, 3H, H-6), 5.21 (s, 2H, H-7), 7.99 (s, 1H, H-4), 9.75 (s, 1H, H-8).

[0225] 13 C NMR (101MHz, CDCl3) δ (ppm) = 14.0 (C-6), 54.8 (C-7), 132.8 (C-4), 132.9 (C-5), 150.4 (C-2), 191.6 (C-9).

[0226] LR-MS: m / z = calc. [M+H] + :170.06, found:170.11.

[0227] Metro-P2 (1-(2-methyl-5-nitro-1H-imidazol-1-yl)pentyl-4-yn-2-ol)

[0228]

[0229] A mixture of 620 mg (25.5 mmol, 1.78 eq.) of magnesium turnings, 3.56 g (15.8 mmol, 1.10 eq.) of ZnBr and iodine (5 mol%) in dry THF (5 mL) was stirred at room temperature for 15 minutes. A solution of propargyl bromide (1.55 mL, 80% toluene, 14.4 mmol, 1.00 eq.) in dry THF (15 mL) was then added dropwise. When the reaction mixture began to reflux, it was cooled to 0° C. After complete addition of the bromide, the reaction mixture was stirred at room temperature for 1 hour. Complete conversion was assumed and the crude material was used directly in the subsequent step.

[0230] Metronidazole aldehyde (500 mg, 2.96 mmol, 1.00 eq.) was dissolved in dry THF (8 mL), and 5.30 mL (3.84 mmol, 1.30 eq.) of the previously synthesized Grignard reagent was added. The mixture was stirred at room temperature for 2 hours and then poured into ice water. Saturated aqueous NH4Cl solution (20 mL) was added to dissolve the precipitate, and the organic layer was separated. The aqueous layer was extracted with Et2O (3×30 mL). The combined organic extracts were washed with brine (2×20 mL) and dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography (EtOAc 100%) and HPLC to obtain 34 mg (5%, 0.16 mmol) of the desired probe Metro-P2.

[0231] TLC:R f =0.41(EtOAc)[UV].

[0232] 1 H NMR (300MHz, CDCl3) δ (ppm) = 2.18 (t, 4 J=2.7Hz,1H,H-12),2.56–2.60(m,2H,H-10),2.72(s,3H,H-6),4.14–4.36(m,2H,H-8,H-9)4.77(d, 3 J=11.8Hz,1H,H-8),8.06(s,1H,H-4).

[0233] 13 C NMR (75MHz, CDCl3) δ (ppm) = 14.6 (C-6), 25.4 (C-10), 50.7 (C-8), 69.0 (C-9), 72.3 (C-12), 78.5 (C-11), 132.7 (C-4), 140.2 (C-5), 152.1 (C-2).

[0234] HR-MS (ESI): m / z = calc. [M+H] +:210.0878, found:210.0874.

[0235] 2.3Metro-P3 (2-methyl-5-nitro-1-((prop-2-yn-1-oxy)methyl)-1H-imidazole)

[0236]

[0237] To a suspension of (2-methyl-5-nitro-1H-imidazol-1-yl)methanol (250 mg, 1.59 mmol, 1.00 eq.) and CsCO (1.20 g, 3.91 mmol, 2.30 eq.) in THF (10 mL) was added a solution of propargyl bromide (80% in toluene, 0.40 mL, 3.66 mmol, 1.20 eq.) and heated to 70 ° C for 96 hours. The reaction mixture was quenched by adding dH O (5 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were then washed with brine (20 mL) and water (20 mL), dried over Na SO, and the solvent removed in vacuo. The crude product was further purified by column chromatography (hexane / EtOAc 1: 1) and high performance liquid chromatography (HPLC) to obtain 136.5 mg of the desired probe Metro-P3 (44%, 0.70 mmol) as a white solid.

[0238] TLC:R f =0.36(EtOAc)[UV].

[0239] 1 H NMR (300MHz, CDCl3) δ (ppm) = 2.51 (t, 4 J=2.4Hz,1H,H-11),4.05(s,3H,H-6),4.25(d, 4 J=2.4Hz,2H,H-9),4.79(s,2H,H-7),7.97(s,1H,H-4).

[0240] 13 C NMR (75MHz, CDCl3) δ (ppm) = 34.2 (C-6), 58.5 (C-9), 63.2 (C-7), 76.2 (C-11), 78.2 (C-10), 129.6 (2×C, C-4, C-5), 147.8 (C-2). .

[0241] HR-MS (ESI): m / z = calc. [M+H] + :196.0717, found:196.0715.

[0242] 2.4MF-01 (1-(2-methoxyethyl)-2-methyl-5-nitro-1H-imidazole)

[0243]

[0244] Cs CO (1.71 g, 5.28 mmol, 4.50 eq.) is added to metronidazole (200 mg, 1.17 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 minutes. Methyl iodide (582 μ L, 1.33 g, 9.36 mmol, 8.00 eq.) is added and the solution is stirred at room temperature for 21 hours. The solvent is removed under reduced pressure and the remaining residue is dissolved in EtOAc, then filtered. The crude product is purified by flash silica gel chromatography (SiO , hexane / EtOAc=1 / 1, 2.5 × 20 cm) and HPLC to obtain MF-01 (28.4 mg, 153 μ mol, 13%) as a white solid.

[0245] TLC:R f =0.35(EtOAc)[UV].

[0246] HPLC:t R =5.0 minutes

[0247] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 2.75 (s, 3H, H-6), 3.30 (s, 3H, H-9), 3.73 (t, 3 J=4.8Hz,2H,H-8),4.59(t, 3 J=4.8Hz,2H,H-7),8.07(s,1H,H-4).

[0248] 13 C-NMR (101MHz, CDCl3): δ [ppm] = 13.6 (q, C-6), 47.6 (t, C-7), 59.4 (q, C-9), 70.7 (t, C-8), 126.9 (d, C-4), 136.6 (s, C-5), 150.8 (s, C-2).

[0249] HR-MS (ESI): m / z = calc. [M+H] + :186.0873, found:186.0871.

[0250] 2.5MF-02 (2-(methoxymethyl)-1-methyl-5-nitro-1H-imidazole)

[0251]

[0252] Cs CO (1.04 g, 3.18 mmol, 2.50 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (200 mg, 1.27 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 minutes. Methyl iodide (560 μL, 1.26 g, 8.89 mmol, 7.00 eq.) was added and the solution was stirred at room temperature for 21 hours. The solvent was removed under reduced pressure and the remaining residue was dissolved in EtOAc and then filtered. The crude product was purified by flash silica gel chromatography (SiO , hexane / EtOAc=1 / 1) and HPLC to obtain MF-02 (84.8 mg, 495 μmol, 39%) as a white solid.

[0253] TLC:R f =0.48(EtOAc)[UV].

[0254] HPLC:t R =6.6 minutes.

[0255] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 3.41 (s, 3H, H-8), 4.04 (s, 3H, H-6), 4.65 (s, 2H, H-7), 7.98 (s, 1H, H-4).

[0256] 13 C-NMR (101MHz, CDCl3): δ [ppm] = 34.4 (q, C-6), 58.9 (q, C-8), 66.3 (t, C-7), 130.2 (d, C-4), 148.5 (s, C-5), 157.3 (s, C-2).

[0257] 2.6MF-03 (1-(2-ethoxyethyl)-2-methyl-5-nitro-1H-imidazole)

[0258]

[0259] 200mg metronidazole (1.00eq., 1.17mmol) and 457mg cesium carbonate (1.20eq., 1.40mmol) are suspended in 5mL dry THF. 0.20mL ethyl bromide (2.40eq., 306mg, 2.80mmol) is slowly added to the suspension and then heated to reflux. Over 60 hours, 4.80 equivalents of ethyl bromide (612mg, 5.60mmol) and 1 equivalent of cesium carbonate (380mg, 1.16mmol) are added. The suspension is quenched with 20mL distilled water. The reaction mixture is extracted with ethyl acetate (3×20mL). The combined organic layer is washed with 20mL saturated NaCl solution and dried over sodium sulfate. Excess solvent is removed in vacuo. The crude product is subjected to chromatographic separation (SiO 2 , hexane / EtOAc=1:5) to obtain an orange-brown solid (37.8mg, 0.19mmol, 16%).

[0260] TLC:R f =0.30 (hexane / EtOAc 1:5) [UV].

[0261] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 1.10 (t, 3 J=7.0Hz,3H,H-10),2.58(s,3H,H-6),3.41(q, 3 J=7.0Hz,2H,H-9),3.73(t, 3 J=5.0Hz,2H,H-8),4.51(t, 3 J=5.0Hz,2H,H-7),7.98(s,1H,H-4).

[0262] 13 C-NMR (100MHz, CDCl3): δ [ppm] = 14.4 (C-6), 15.1 (C-10), 47.1 (C-7), 67.1 (C-9), 69.1 (C-8), 131.6 (C-4), 138.4 (C-5), 151.7 (C-2).

[0263] HR-MS (ESI): m / z = calc. [M+H] + :200.1030, found:200.1029.

[0264] 2.7 MF-04 2-(Ethoxymethyl)-1-methyl-5-nitro-1H-imidazole (MF-RP-09)

[0265]

[0266] CsCO (2.49 g, 7.64 mmol, 4.00 eq.) and tetrabutylammonium iodide (TBAI, 317 mg, 0.45 mol%) were added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (300 mg, 1.91 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 minutes. Ethyl bromide (0.56 mL, 7.64 mmol, 4.00 eq.) was added and the solution was stirred at reflux for 21 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The crude product was dissolved in EtOAc, filtered and purified by flash silica gel chromatography (SiO, hexane / EtOAc=1 / 2) and then subjected to HPLC purification. Pure MF-04 (80.0 mg, 1.11 mmol, 58%) was obtained as a yellow oil.

[0267] TLC:R f =0.44 (hexane / EtOAc 2:1) [UV].

[0268] HPLC:t R =7.7 minutes

[0269] 1 H NMR (400MHz, CDCl3) δ [ppm] = 1.22 (t, 3 J=7.1Hz,3H,H-9),3.57(q, 3 J=7.1Hz,2H,H-8),4.04(s,3H),4.66(s,2H),7.95(s,1H).

[0270] 13 C NMR (100MHz, CDCl3) δ = 15.1 (C-9), 33.9 (C-6), 64.7 (C-8), 66.8 (C-7), 130.8 (C-4), 139.7 (C-5), 149.0 (C-2).

[0271] HR-MS (ESI): m / z = calc. [M+H] + :186.0873, found:186.0872.

[0272] 2.8MF-05 (2-methyl-5-nitro-1-(2-propoxyethyl)-1H-imidazole)

[0273]

[0274] Cs CO (1.14 g, 3.51 mmol, 4.99 eq.) was added to a solution of metronidazole (150 mg, 876 μmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 minutes. Propyl iodide (0.85 mL, 8.76 mmol, 10.0 eq.) was added and the solution was stirred under reflux overnight. The reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography (SiO , hexane / EtOAc=1 / 2) to obtain MF-05 (38.5 mg, 184 μmol, 21%) as a yellow oil.

[0275] TLC:R f =0.23 (hexane / EtOAc 1:2) [UV].

[0276] 1 H NMR (400MHz, CDCl3) δ [ppm] = 0.83 (t, 3 J=7.1Hz,3H,H-11),1.49(ps, 3 J=7.1Hz,2H,H-10),2.58(s,3H,H-6),3.31(t, 3 J=7.1Hz,2H,H-9),3.73(t, 3 J=4.5Hz,2H,H-8),4.52(t, 3 J=4.5Hz,2H,H-7),7.99(s,1H,H-4).

[0277] 13 C NMR (100MHz, CDCl3) δ [ppm] = 10.6 (C-11), 14.4 (C-6), 22.9 (C-10), 47.1 (C-7), 69.3 (C-9), 73.4 (C-8), 131.9 (C-4), 138.3 (C-5), 151.6 (C-2).

[0278] HR-MS (ESI): m / z = calc. [M+H] + :214.1186, found:214.1184.

[0279] 2.9MF-06 (1-methyl-5-nitro-2-(propyloxymethyl)-1H-imidazole)

[0280]

[0281] Cs CO (3.32 g, 7.64 mmol, 4.00 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (400 mg, 2.55 mmol, 1.00 eq.) dissolved in THF (10 mL) and stirred at room temperature for 30 minutes. Propyl iodide (1.59 mL, 15.3 mmol, 6.00 eq.) was added and the solution was stirred under reflux overnight. The reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography (SiO , hexane / EtOAc=1 / 2) to obtain pure MF-06 (57.6 mg, 281 μmol, 11%) as a yellow oil.

[0282] TLC:R f =0.57 (hexane / EtOAc 1:3) [UV].

[0283] 1 H NMR (400MHz, CDCl3) δ [ppm] = 0.91 (t, 3 J=7.2Hz,3H,H-10),1.61(ps, 3 J=7.2Hz,2H,H-9),3.44(t, 3 J=7.2Hz,2H,H-8),4.02(s,3H,H-6),4.62(s,2H,H-7),7.93(s,1H,H-4).

[0284] 13 C NMR (100MHz, CDCl3) δ [ppm] = 10.6 (C-10), 22.9 (C-9), 33.8 (C-6), 65.3 (C-8), 73.0 (C-7), 131.6 (C-4, C-5), 149.2 (C-2).

[0285] HR-MS (ESI): m / z = calc. [M+H] + :200.1030, found:200.1028.

[0286] 2.10MF-07 (1-(2-(allyloxy)ethyl)-2-methyl-5-nitro-1H-imidazole)

[0287]

[0288] 200mg metronidazole (1.17mmol, 1.00eq.) and 762mg cesium carbonate (2.34mmol, 2.00eq.) were suspended in 10mL dry THF. 0.30mL allyl bromide (2.80mmol, 3.00eq.) was slowly added to the suspension and then heated to 70°C. After 23 hours, the suspension was quenched with 20mL distilled water. The reaction mixture was extracted with ethyl acetate (3×20mL). The combined organic layers were washed with 20mL saturated NaCl solution and dried over sodium sulfate. Excess solvent was removed in vacuo. The crude product was subjected to chromatography (1:5 hexane / ethyl acetate) to obtain pure MF-07 (74.5mg, 0.35mmol, 30%) as a golden brown solid.

[0289] TLC:R f =0.40 (hexane / EtOAc 1:5) [UV].

[0290] 1 H NMR (400MHz, CDCl3) δ [ppm] = 2.57 (d, 3 J=2.6Hz,3H,H-6),3.75(t, 3 J=5.1Hz,2H,H-8),3.84–3.93(m,2H,H-9),4.52(t, 3 J=5.1Hz,2H,H-7),5.09–5.20(m,2H,H-11),5.66–5.81(m,1H,H-10),7.98(d, 3 J = 2.6 Hz, 1H, H-4).

[0291] 13 C-NMR (100MHz, CDCl3): δ [ppm] = 14.5 (C-6), 46.9 (C-7), 68.7 (C-8), 72.3 (C-9), 117.7 (C-11), 132.0 (C-4), 133.8 (C-10), 138.4 (C-5), 151.7 (C-2).

[0292] HR-MS (ESI): m / z = calc. [M+H] + :212.1030, found:212.1030.

[0293] 2.11MF-08 (2-((allyloxy)methyl)-1-methyl-5-nitro-1H-imidazole)

[0294]

[0295] Cs CO (1.56 g, 4.77 mmol, 3.00 eq.) was added to (1-methyl-5-nitro-1H-imidazol-2-yl)methanol (250 mg, 1.59 mmol, 1.00 eq.) dissolved in THF (12 mL) and stirred at room temperature for 30 min. Allyl iodide (0.44 mL, 4.77 mmol, 3.00 eq.) was added and the solution was stirred at reflux for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography (SiO , hexane / EtOAc=1 / 1) and HPLC to obtain pure MF-08 (138 mg, 700 μmol, 44%) as a colorless oil.

[0296] TLC:R f =0.40 (hexane / EtOAc 1:1) [UV].

[0297] 1 H NMR (400MHz, CDCl3) δ [ppm] = 4.02–4.06 (m, 5H, H-6, H-8), 4.66 (s, 2H, H-7), 5.20–5.37 (m, 2H, H-10), 5.77–5.96 (m, 1H, H-9)), 7.95 (s, 1H, H-4).

[0298] 13 C NMR (100MHz, CDCl3) δ [ppm] = 33.9 (C-6), 64.1 (C-8), 72.0 (C-7), 118.8 (C-10), 131.0 (C4, C5), 133.3 (C-9), 148.8 (C-2).

[0299] HR-MS (ESI): m / z = calc. [M+H] + :198.0873, found:198.0872.

[0300] 2.12MF-09 (2-methyl-1-(2-((3-methylbut-2-en-1-yl)oxy)ethyl)-5-nitro-1H-imidazole)

[0301]

[0302] 200 mg of metronidazole (1.17 mmol, 1.00 eq.) and 762 mg of cesium carbonate (2.34 mmol, 2.00 eq.) were suspended in 9 mL of dry THF. 0.40 mL of 3,3-dimethylallyl bromide (3.51 mmol, 3.00 eq.) was slowly added to the reaction mixture, which was then heated to reflux. After 18 hours, the suspension was quenched with 20 mL of distilled water. The reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 20 mL of saturated NaCl solution and dried over sodium sulfate. Excess solvent was removed in vacuo. The crude product was chromatographed (hexane / EtOAc) and then purified by HPLC. Pure desired product MF-08 (29.0 mg, 0.12 mmol, 10%) was obtained as a white solid.

[0303] TLC:R f =0.42 (hexane / EtOAc 1:5) [UV].

[0304] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 1.17 (s, 3H, H-13), 1.76 (s, 3H, H-12), 2.52 (s, 3H, H-6), 4.47 (t, 3 J=5.0Hz,2H,H-8),4.59(m, 3 J=7.3Hz,1.5Hz,4H,H-9,H-7),5.32(tt,1H,H-10),7.98(s,1H,H-4).

[0305] 13 C-NMR (100MHz, CDCl3): δ [ppm] = 14.2 (C-6), 18.1 (C-12), 25.8 (C-13), 45.4 (C-7), 65.3 (C-9),65.6(C-8),117.5(C-10),130.1(C-4),132.6(C-11),140.9(C-5),151.1(C-2).

[0306] HR-MS (ESI): m / z = calc. [M+H] + :240.1343, found: 240.1343.

[0307] Example 3 Biological Test

[0308] 3.1 Inhibition assay

[0309] The compounds of the present invention were tested against a variety of bacterial strains. Tables 2 and 3 below summarize the results and show the minimum inhibitory concentration (MIC) values ​​of the compounds against the indicated bacterial strains.

[0310] Table 2: MIC values ​​of metronidazole, Metro-P1, Metro-P2, and Metro-P3 in different bacterial strains: Helicobacter pylori (microaerophilic), Clostridium difficile (anaerobic), Escherichia coli (aerobic), and Staphylococcus aureus (aerobic). MIC determinations were taken after 3 days of incubation (for Helicobacter pylori and Clostridium difficile) and 1 day of incubation (for Escherichia coli and Staphylococcus aureus). The assays were performed in duplicate.

[0311]

[0312] In H. pylori, the determined MIC values ​​for metronidazole (12.5–50 μM) against susceptible strains fall within the literature MIC range of 10 to 50 μM (Megraud 2007; Wu et al. 2000), which is important for the accuracy and comparability of MIC values ​​obtained in this assay. The MIC values ​​for Metro-P2 (12.5–50 μM) were identical to those for metronidazole. Surprisingly, the MIC values ​​for Metro P1 (250 nM–380 nM) and Metro-P3 (190–250 nM) were up to 100-fold higher than the determined values ​​for metronidazole (12.5–50 μM). The substantial increase in antibiotic activity observed was likely due to the modification of the ether moiety with the free hydroxyl group in both probes. Therefore, several derivatives were synthesized and their antimicrobial activity against susceptible and resistant H. pylori strains was additionally evaluated.

[0313] In addition, MIC determinations were performed on susceptible and metronidazole-resistant H. pylori strains at concentrations ranging from 100 nM to 1 mM. MIC determinations were performed twice on susceptible H. pylori, and the results were read visually after 3 days of incubation with metronidazole or the corresponding probe. The resulting values ​​are summarized in Table 3.

[0314] Table 3: Measured MIC values ​​of metronidazole, Metro-P1, Metro-P2, Metro-P3, MF01 to MF09 in H. pylori (wild type, ATCC 26695) and metronidazole-resistant H. pylori strains (clinical isolates). MIC assay results were read after 3 days of incubation. MIC assays were performed over a concentration range of 950 nM to 500 μM for susceptible strains within a concentration range of 90 nM to 50 μM.

[0315]

[0316] The observed changes in the MICs of metronidazole and all tested compounds against resistant H. pylori suggest the existence of similar resistance mechanisms. However, Metro-P3, MF03, MF05, MF06, and MF08 still had an MIC value (62.5 μM) that was superior to that of metronidazole and Metro-P2 (250–500 μM) in resistant H. pylori and was close to the lower end of the MIC range for metronidazole in susceptible H. pylori strains (10–50 μM) (Megraud 2007; Wu et al. 2000).

[0317] 3.2 Target Recognition

[0318] Target identification experiments revealed that two hitherto unknown protein targets of metronidazole in H. pylori are also involved in the mechanism of action of these compounds, namely:

[0319] - Helicobacter pylori chaperone protein HpGroEL (P42383), and

[0320] - thiol peroxidase HpTpx (O25151).

[0321] MS-based binding site studies revealed that the hydroxylamine intermediate of the metronidazole probe binds to the active site cysteine ​​of these proteins, acting as a suicide inhibitor. Furthermore, HpTpx and HpGroEL (HpGroEL) can be successfully modified with metronidazole or Metro-P3 during recombinant protein expression. Figure 4 exemplarily shown for HpTpx in the figure). Further functional activity assays of the two enzymes showed reduced or complete loss of activity: ATPase activity assays showed that HpGroEL was reduced by up to 60% after modification with metronidazole or Metro-P3. Antioxidant activity assays showed that if metronidazole or Metro-P3 covalently bound to HpTpx at the active site, modification-dependent loss of activity occurred, rendering Helicobacter pylori completely unable to effectively eliminate the oxidative stress that leads to cell death. However, what is most interesting is that new compounds such as Metro-P3 are more likely to modify HpTpx than metronidazole ( Figure 6 , as shown in vitro during recombinant protein expression in E. coli and in situ during recombinant protein expression in H. pylori).

[0322] 3.3 Crystal structure analysis

[0323] Crystal structure analysis also revealed that the binding motifs of metronidazole and Metro-P3 for HpTpx are completely different, further indicating that even small changes in the structure can lead to significant changes in the binding affinity and mode of action of nitroimidazoles in H. pylori (Figure 7). Metro-P3 binds to HpTpx in its reduced state (which is the more stable and prevalent form in the cytoplasm of H. pylori). Figure 7B) and form a helical dipole to stabilize the ligand, while metronidazole binds to HpTpx shortly after the disulfide bond opens in the catalytic cycle ( Figure 7A The formation of active site disulfide bonds in HpTpx results in a constrained protein geometry (the cysteines are farther apart), which reduces the thermodynamic stability of the oxidized state of HpTpx. Due to the different binding motifs, there is also additional evidence that Metro-P3 is more favorable for inhibiting the activity of HpTpx and supports the present invention, that is, the small changes in the structure of the present invention do lead to a significant change in the mode of action compared to the current gold standard metronidazole.

[0324] In summary, HpTpx mainly promotes the enhanced activity of the novel nitroimidazole compounds of the present invention (compared with the parent compound metronidazole, its anti-Helicobacter pylori activity is enhanced by >60 times).

[0325] 3.4 Cytotoxicity

[0326] Mohindra and Rauth (1976) published the IC of metronidazole in HeLa cells after 14 days of culture without medium change. 50 The values ​​were ≥10 mM, indicating that metronidazole is a non-toxic drug to human cells. However, the incubation time in this experiment was very long, and because Metro-P1 and Metro-P3 were 100-fold more potent than metronidazole against H. pylori, it was important to understand whether the enhanced antibacterial activity was also directly related to increased cytotoxicity in human cells. Therefore, MTT assays were performed in HeLa and HepG2 cells at different concentrations of the compounds (ranging from 1 μM to 1 mM), with an incubation time of 24 hours.

[0327] Table 4: Measured IC of Nitroimidazole Compounds Following MTT Readout 50 After 24 hours of culture, the MTT assay results were read. The MTT assay was performed on two cell lines (HeLa and HepG2) in a concentration range of 10 μM to 1 mM.

[0328]

[0329]

[0330] After reading the assay results, IC values ​​could not be determined for all tested compounds in HeLa and HepG2 cell lines until the final concentration reached 1 mM, as no reduction in metabolic activity was observed. 50Only for Metro-P1, a slight decrease in metabolic activity was observed at a final concentration of 10 mM. Metro-P1 began to be cytotoxic to HeLa cells at concentrations ≥ 10 mM. However, since Metro-P1 is insoluble in higher concentrations of DMSO, the exact IC value could not be determined. 50 Table 4 summarizes the IC values ​​of the compounds. 50 value. Figure 2 Some selected examples are shown.

[0331] 3.5 Plasma stability

[0332] In addition, compounds Metro-P1, Metro-P2, Metro-P3, MF01 to MF09 were tested for in vitro plasma stability over a period of 28 hours in mouse serum. All tested compounds showed very good stability and half-lives could not be determined. For example, after 28 hours, 75% of Metro-P1, 99% of Metro-P2, 82% of Metro-P3, 66% of MF01, 81% of MF03 and 87% of MF07 were still present in the sample and not degraded (see Figure 3 ).

[0333] Table 5. Summary of all in vitro data. Metronidazole was the starting material for the synthesis of compounds Metro-P1, Metro-P2, MF01, MF03, MF05, MF07, and MF09. Dimetridazole-OH was the starting material for the synthesis of compounds Metro-P3, MF02, MF04, MF06, and MF08. Both are included for reference.

[0334]

[0335]

[0336] 3.6 ADME (Absorption, Distribution, Metabolism, and Excretion Studies)

[0337] Six potential drug candidates (Metro-P1, Metro-P3, MF-01, MF-02, MF-03, and MF-07) were characterized for absorption, distribution, metabolism, and excretion (ADME) properties to provide further safety considerations for the nitroimidazole compounds of the present invention. Four of the six compounds met the required ADME thresholds, indicating that the compounds of the present invention have significant potential for further drug development (Table 6).

[0338] Table 6 Overview of ADME and protein plasma binding data: Six drug candidates (Metro-P1, Metro-P3, MF01, MF02, MF03, MF07) were subjected to in vitro testing of ADME properties and protein plasma binding to human or mouse plasma.

[0339]

[0340] 3.7 Pharmacological Data

[0341] Further pharmacokinetic data were obtained. Figure 8 The results of pharmacokinetic experiments in mice for four compounds are shown. Depending on the type of infection, different concentrations are required in plasma, urine, and feces. Ideal PK data for Metro-P3 for treating gastrointestinal infections can be observed: low concentrations of Metro-P3 in plasma and urine, and high and sustained concentrations in feces, result in a prolonged residence time of the compound in the gastrointestinal tract, thus providing better conditions for treating Helicobacter pylori in the human stomach. However, compounds MF-01 and MF-03 exhibit higher plasma and urine concentrations without rapid clearance. Therefore, the compounds of this invention can be fine-tuned to different treatments and infection types.

[0342] The features disclosed in the preceding description, the claims and / or the drawings, either alone or in any combination thereof, may be material for realizing the invention in various forms.

[0343] References Ang CW, Jarrad AM, Cooper MA, Blaskovich MA, Journal of Medicinal Chemistry2017, 60, 7636-7657.

[0344] Bandow JE, H,Leichert LIO,Labischinski H,Hecker M,AntimicrobialAgents and Chemotherapy 2003,47,948-955.

[0345] Boucher HW,Talbot GH,Bradley JS,Edwards JE,Gilbert D,Rice LB,ScheldM,Spellberg B,Bartlett J,Clin.Infect.Dis.2009,48,1-12.

[0346] Davies J, Davies D, Microbiology and Molecular Biology Reviews 2010, 74, 417 - 433.

[0347] Foroumadi A et al. Arch. Pharm. Res. 2004, 27(5), 502 - 506.

[0348] Jamshidi H et al. Chem. Biol. Drug Des. 2022, 100, 935 - 946.

[0349] Lehours P, Yilmaz, O., Helicobacter 2007, 12, 1 - 3.

[0350] Li Z - Z et al. Eur J Med Chem. 2019, 179, 723 - 735.

[0351] S, Edlund C, Nord CE, Clinical infectious diseases 2010, 50, S16 - S23. Megraud F, Gut 2004, 53, 1374 - 1384.

[0352] [[ID=,19]]Megraud F, Gut 2007, 56, 1502 - 1502.

[0353] Mohindra JK, Rauth AM, Cancer Res., 1976, 36, 930 - 936.

[0354] Perez - Perez GI, Rothenbacher D, Brenner H, Helicobacter 2004, 9, 1 - 6.

[0355] Vakil N, Megraud F, Gastroenterology 2007, 133, 9,85 - 1001.

[0356] Wu H, Shi XD, Wang HT, Liu JX, J. Antimicrob. Chemother., 2000, 46, 121 - 123. Zagari RM, Rabitti S, Eusebi LH, Bazzoli F, Eur J Clin Invest. 2018, 48, e12857.

Claims

1. A compound of formula I, II or III or a pharmaceutically acceptable salt thereof for use in treating a non-viral infection or a disease caused by a non-viral infection: in, R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group, R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group, For R 2 , the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl may be optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 is hydrogen or C1-C6 alkyl, The conditions for compounds of formula II or III are: When R 1 When it is methyl, then R 2 is not ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2, NH(CH3)2 or NH(CH2-CH3)2, When R 1 When it is CF3, then R 2 C1-C4 alkyl not substituted by halogen, When R 1 When is isopropyl, then R 2 C1-C4 alkyl which is not substituted by halogen; The conditions for compounds of formula III are: R 1 and R 2 Not all methyl.

2. The compound for use according to claim 1, wherein R 1 is methyl, and the compound has Formula Ia or IIa or IIIa:

3. The compound for use according to claim 1 or 2, wherein R 2 is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl or n-hexyl; or R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl; or R 2 It is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl, 1-butynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl or 2-propynyl.

4. The compound for use according to any one of claims 1 to 3, wherein R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group substituted by: Halogen, or OR 3 , where R 3 is hydrogen or methyl, or SR 3 , where R 3 is hydrogen or methyl.

5. The compound for use according to any one of claims 1 to 4, wherein the compound has formula Ia And R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or 1-butyne; or R 2 is a C1-C6 alkyl group, preferably a methyl group; or wherein the compound has the formula IIa And R 2 is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl or 1-butyne; or R 2 is a C1-C6 alkyl group, preferably a C1-C4 alkyl group, more preferably a methyl group or an ethyl group; R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl or dimethylallyl; or wherein the compound has the formula IIIa And R 2 It is a C3-C6 alkynyl group, preferably a C3-C4 alkynyl group, more preferably a propargyl group or 1-butyne.

6. The compound for use according to any one of claims 1 to 5, selected from Preferably selected from:

7. The compound for use according to any one of claims 1 to 6, wherein the non-viral infection is an infection by protozoa, anaerobic bacteria or microaerophilic bacteria, Preferably, the infection is caused by Helicobacter pylori, Clostridium difficile, Trichomonas vaginalis, Giardia lamblia (Giardia lamblia), Entamoeba histolytica, Fusobacterium nucleatum or Gardnerella vaginalis, And / or wherein the infection is with a strain of Helicobacter pylori that is resistant to metronidazole.

8. A compound of formula III or a pharmaceutically acceptable salt thereof: in, R 1 is a C1-C6 alkyl group or a C1-C6 haloalkyl group, and R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl is optionally substituted by halogen, OR 3 or SR 3 Substituted, where R 3 is hydrogen or C1-C6 alkyl, The conditions are: R 1 and R 2 Not all methyl, When R 1 When it is methyl, then R 2 is not ethyl or C1-C4 alkyl substituted by halogen, OH, OMe, NH2 or NH(CH3)2, When R 1 When it is CF3, then R 2 C1-C4 alkyl not substituted by halogen, When R 1 When is isopropyl, then R 2 C1-C4 alkyl which is not substituted by halogen.

9. The compound according to claim 8, wherein R 1 is methyl, and the compound has the formula IIIa:

10. The compound according to claim 8 or 9, wherein R 2 is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl or n-hexyl; or R 2 is C2-C6 alkenyl, preferably C2-C5 alkenyl, more preferably allyl, vinyl, dimethylallyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl or 4-pentenyl; or R 2 It is C3-C6 alkynyl, preferably C3-C4 alkynyl, more preferably propargyl, 1-butynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl or 2-propynyl.

11. A compound according to any one of claims 8 to 10, wherein R 2 is a C1-C6 alkyl, C2-C6 alkenyl or C3-C6 alkynyl group, which is substituted by: Halogen, or OR 3 , where R 3 is hydrogen or methyl, or SR 3 , where R 3 is hydrogen or methyl.

12. The compound according to any one of claims 8 to 11, wherein the compound has formula IIIa And R 2 It is a C3-C6 alkynyl group, preferably a C3-C4 alkynyl group, more preferably a propargyl group or 1-butyne.

13. The compound according to any one of claims 8 to 12, which is:

14. A pharmaceutical composition comprising: (i) at least one compound according to any one of claims 8 to 13, (ii) optional pharmaceutically acceptable excipients and / or carriers.

15. A compound according to any one of claims 8 to 13 for use in medicine.

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