Novel pyridine carboxamide compounds with Anti-tubercular activity

Abstract

The present invention provides novel pyridine carboxamide compounds that have anti-tubercular activity. The compounds of the invention have inhibitory action against drug sensitive as well as drug resistant M. tuberculosis infection.

Description

[0001] DESCRIPTION

[0002] TITLE :NOVEL PYRIDINE CARBOXAMIDE COMPOUNDS WITH ANTI-TUBERCULAR ACTIVITY

[0003] FIELD OF THE INVENTION

[0004] The present invention is related to novel pyridine carboxamide compounds and their antimicrobial action against M. tuberculosis. The compounds of the invention are particularly effective against drug sensitive as well as drug resistant strains of M. tuberculosis.

[0005] BACKGROUND OF THE INVENTION

[0006] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis') and has been recognized as a global threat. In India, despite DOTS-Plus program’s success, TB continues to prevail. The emergence of multi-drug resistant (MDR) and extensively-drug resistant (XDR)-Mtb strains is predicted to significantly hinder DOTS-Plus success. Globally 3.7% of new TB cases and 20% of previously treated TB cases turn MDR. Of them, approximately 9% turn XDR. India accounts for one fourth of the global TB burden. According to Global TB report 2020, India has an incident rate of 2.64 million and 4.4 lakh individuals die due to TB. An estimated 1.3 lakh MDR-TB cases occur in India annually out of which 79,000 include pulmonary TB cases. This situation is further worsened due to emergence of HIV-TB nexus and failure of BCG vaccine to impart protection. The long treatment regimen of drug sensitive and in particular drug resistant tuberculosis often proves toxic in certain patient populations.

[0007] Therefore, it is highly pertinent to develop new interventions having better safety and efficacy profile to control the spread of this deadly infectious disease. New drugs as well as new regimen are required to combat the tuberculosis pandemic and the spread of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) forms of TB .

[0008] The present invention provides novel pyridine carboxamide compounds for their therapeutic activity against tuberculosis infection. These compounds inhibit growth of drug sensitive as well as drug resistant M. tuberculosis. The identified small molecule(s) did not interfere with mechanism of action or activity of first-line / second line Mtb (Mycobacterium tuberculosis) drugs that are in clinical use for this infection. Therefore, these series of compounds would be amenable to use in combination with existing tuberculosis drugs.

[0009] SUMMARY One aspect of the invention is a pyridine carboxamide compound represented by formula I, its stereoisomer, or pharmaceutically acceptable salt thereof wherein R1 is selected from group consisting of H, Ar, alkyl Ar, a cycloalkyl group, or an optionally substituted linear or branched alkyl chain of carbon length 1-8, and R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group ,and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl, carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium. The compound of claim 1 wherein the heteroaryl ring in R1 or R2 has one or more hetero atoms selected from nitrogen, oxygen or sulphur or their combination. In one aspect the optionally substituted aryl or heteroaryl ring in R2 is benzene, naphthalene, quinoline, pyridine, coumarin, benzofuranone , pyrazine, pyrimidine, furan, pyrazole, pyrrole, imidazole, furanone, thiophene, oxazole, pyrido-oxazine, pyrido pyridine, pyrido- pyrimidine, pyrido-thiazine rings, pyrrollo pyridine, indole, indazole rings.

[0010] In one aspect wherein R2 is an aryl or heteroaryl ring optionally substituted with deuterium, fluorine, chloro, bromo, methyl, isopropyl, hydroxyl, carboxyl, nitro, sulfonyl, sulfonamide, aryl or a cycloalkyl group at ortho, meta or para-position of the ring.

[0011] In one aspect the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine, coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl, carboxyl group, ester, nitro, sulfonyl group, substituted or unsubstituted amino group, halogen or deuterium at ortho, meta or para-position of the ring.

[0012] In one aspect of the invention is a compound represented by the formula (II);

[0013] Wherein n= 0-5, R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group, ester, nitro, sulfonyl group, substituted or unsubstituted amino group, halogen or deuterium.

[0014] In one aspect the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine, coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl, carboxyl group, ester, nitro, sulfonyl group, substituted or unsubstituted amino group, halogen or deuterium at ortho, meta or para-position of the ring.

[0015] In one aspect the compound is represented by the formula (III);

[0016] Wherein n= 0-5,

[0017] R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

[0018] In one aspect the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine, coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl, carboxyl group, ester, nitro, sulfonyl group, substituted or unsubstituted amino group, halogen or deuterium at ortho, meta or para-position of the ring. In one aspect the compounds represented by formula I, II and III have inhibitory effect against drug sensitive and drug resistant strains of M. tuberculosis.

[0019] One aspect of the invention is a composition comprising a compound represented by formula I. II and III and one or more of tuberculosis drugs selected from a group consisting of pyrazinamide, Rifampicin, Bedaquiline, Pretomanid, Isoniazid, Levofloxacin.

[0020] One aspect of the invention is a pharmaceutical composition comprising a compound represented by formula I, II or III or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient, or diluent.

[0021] BRIEF DESCRIPTION OF FIGURES

[0022] Figure 1: shows pyridine carboxamide compounds represented by formula I

[0023] Figure 2A: shows pyridine carboxamide compounds represented by formula II

[0024] Figure 2B: shows pyridine carboxamide compounds represented by formula III

[0025] Figure3 : shows a general procedure for the synthesis of substituted pyridine carboxylic acids.

[0026] Figure 4: shows a general procedure for the synthesis of amides

[0027] Figure 5: shows a general procedure for the synthesis of hydrazides from acids

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] In the following detailed description, a reference is made to the accompanying drawings that form a part hereof, and in which the specific embodiments that may be practiced is shown by way of illustration. These embodiments are described in sufficient detail to enable those skilled in the art to practice the embodiments and it is to be understood that other changes may be made without departing from the scope of the embodiments. The following detailed description is therefore not to be taken in a limiting sense.

[0030] Current treatment options of individuals with Drug resistant -TB (DR-TB) is complicated and often requires 18-24 months to complete. The treatment of individuals with DR-TB involves the use of drugs that are less effective, more toxic and have serious adverse effect. Individuals with DR-TB have a treatment success rate of 57% compared to 85% observed for individuals with drug-susceptible TB. The increase in incident rates of DR-TB has necessitated the need to identify scaffolds with a novel mechanism of action. The newly identified molecules should be effective against DR-TB and target a pathway that is essential, druggable and distinct from the existing TB drug targets. The embodiments of the present invention encompass novel pyridine carboxamide compounds. The pyridine carboxamide compounds inhibit growth of tuberculosis causing Mycobacterium tuberculosis.

[0031] Definitions:

[0032] As used herein, the term “MIC” or “Minimum Inhibitory Concentration” refers to minimum concentration of a drug after two-fold serially diluted concentration of the drugs that inhibits growth of more than 99.0% of a bacterial proportion of the tested M. tuberculosis within 14 to 21 days of incubation at 37°C. [1]

[0033] Multidrug-resistant TB (MDR-TB), defined as tuberculosis caused by M. tuberculosis which is resistant against the two first-line drugs rifampicin and isoniazid, has dramatically increased in recent years. [2]

[0034] As used herein, the term “drug resistant” or “multi drug resistant” strains of M. tuberculosis refers to tuberculosis strains that are not affected or inhibited by first line or second line drugs for treatment of TB, including isoniazid (INH).

[0035] Extensively drug resistant TB (XDR TB) is a rare type of MDR TB that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin) as per Centre of Disease Control and Prevention.

[0036] As used herewith, the term “pyridine carboxamide compounds” refers to compounds having pyridine carboxamide linkage formed by pyridine carboxylic acids and different amines or hydrazines or hydrazides. Pyridine ring also refers to an Azabenzene ring or an azaarene comprising a benzene core in which one -CH group is replaced by a nitrogen atom. The pyridine carboxamide compounds in this disclosure are pyridine-2-carboxamide compounds.

[0037] Pyridine-2 carboxyamide ring has a carboxyamide ring linked to the second carbon of the pyridine ring.

[0038] As used herewith, the term “TC50” was defined as the concentration that reduces the cell viability of THP-1 macrophages by 50 %.

[0039] As used herewith “known TB drugs” refer to various drugs that inhibit a wide range of cellular processes, and include Bedaquiline (BDQ), which targets ATP synthase and pretomanid (PTM), delamanid (DLM) which targets cell wall biosynthesis were identified by phenotypic screening and have been recently approved by FDA for the treatment of individuals with MDR-TB, repurposed drugs such as protein synthesis inhibitor (linezolid, LZD) or P-lactams (such as meropenem) or DNA gyrase inhibitor (moxifloxacin).

[0040] As used herein, the term “optionally substituted” refers to mono, di or multi-substituted compounds. The substituents include, without limitation, deuterium, halogen, alkyl, aryl, alkyl aryl, heteroaryl, saturated or unsaturated cycoalkyl, linear or branched alkyl chain, carboxyl, hydroxyl, alkoxy, ester, nitro, sulfonyl, amino groups. The substitutions can be attached varied positions. For Aryl or heteroaryl groups, the substituents can be attached at ortho, meta or para positions.

[0041] As used herein, the term “Pharmaceutically Acceptable Salts” refers to the salts of the compounds described in the invention with an acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases.

[0042] As used herewith, the term “halogen” includes a fluorine, a chlorine, a bromine or an iodine radical. As used herewith, the term “Pharmaceutical Compositions” refers to compositions containing the compounds of the Formulae (I), (II) or pharmaceutically acceptable salts thereof disclosed herein.

[0043] As used herewith, the term “Methods of Treatment” refers to use of the compounds of formula I or II or pharmaceutically acceptable salts thereof for use in the treatment or prevention of any of the conditions disclosed herein.

[0044] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0045] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group may be branched or unbranched. The alkyl group can also be substituted or unsubstituted.

[0046] As used herewith, the term “C(O)” or (CO) is a short hand notation for a carbonyl group, i.e., C=O. As used herewith, the term “amine” or “amino” are represented by a formula -NH2, where the hydrogen may be optionally substituted with alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0047] As used herewith, the tern “hydrazine” is represented by a formular -NH-NH2, where the hydrogen may be optionally substituted with alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0048] As used herewith, the tern “hydrazide” is represented by a formular -NH-NH(CO)-Ar, wherein Ar may be optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

[0049] As used herewith, the term “alkyl aryl”, or “Ar alkyl” refer to groups having an alkyl and aryl group bonded covalently, and the aryl group may include a heteroaryl ring.

[0050] As used herewith, the term “carboxyl” as used herein is represented by a formula — C(O)O-.

[0051] As used herewith, the term “alkoxy” is an alkyl group singularly bonded to oxygen, denoted as R-O. Examples include methoxy (CEEO-), ethoxy group (CH3CH2O-) and the like.

[0052] As used herewith ,the term “heterocycle,” as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, and the like.

[0053] As used herewith ,the term “hydroxyl” as used herein is represented by a formula — OH.

[0054] As used herewith, “the term “subject” (or “patient”) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Although the embodiments herein are described with various specific embodiments, it will be obvious for a person skilled in the art to practice the embodiments herein with modifications.

[0055] One embodiment of the invention is a compound represented by formula I, its stereoisomer, or pharmaceutically acceptable of salt thereof wherein R1 is selected from group consisting of H, Ar, alkyl Ar, a cycloalkyl group, an optionally substituted linear or branched alkyl chain of carbon length 1-8, and R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

[0056] In one embodiment, the heteroaryl ring in R1 is a monocyclic or bicyclic ring. In one embodiment the heteroaryl ring has hetero atoms selected from Nitrogen, Oxygen or Sulphur.

[0057] In one embodiment, the alkyl group of carbon chain 1-8 in R1 is optionally substituted with a group selected from hydroxyl, alkoxy, substituted or unsubstituted amino, fluorine, chlorine, bromine, deuterium, phenyl or heteroaryl ring.

[0058] In one embodiment, the branched or linear cyclo-alkyl chain in R1 is optionally substituted with groups selected from alkoxy, substituted or unsubstituted amino, fluorine, chlorine, deuterium, phenyl or hetero aryl ring.

[0059] In one embodiment, the aryl or heteroaryl ring in R1 is optionally substituted with a deuterium, halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfone, sulfonamide or a cycloalkyl group.

[0060] In one embodiment , the position of R1 comprised in the compound represented by formula I is meta position to nitrogen of pyridine.

[0061] In one embodiment, the alkyl Ar group in R1 is C1-C6, linear or branched alkyl group. In one embodiment, the alkyl Ar group in R2 is C1-C6, linear or branched alkyl group.

[0062] In one embodiment ,the heteroaryl ring in R1 or R2 has hetero atoms selected from Nitrogen, Oxygen or Sulphur.

[0063] In one embodiment, the heteroaryl ring in R2 is monocyclic or bicyclic ring. In one embodiment the heteroaryl ring in R2 has hetero atoms selected from Nitrogen, Oxygen or Sulphur. In one embodiment, the alkyl group of carbon chain 1-8 in R2 is optionally substituted with a group selected from hydroxyl, substituted or unsubstituted amino, Fluorine, chlorine, bromine, deuterium, phenyl or heteroaryl ring. In one embodiment, the branched or linear cyclo-alkyl chain in R2 is optionally substituted with groups selected from hydroxyl, substituted or unsubstituted amino, fluorine, chlorine, deuterium, phenyl or heteroaryl ring.

[0064] In one embodiment, the optionally substituted aryl or heteroaryl ring in R2 is benzene, naphthalene, quinoline, pyridine, coumarin, benzofuranone, pyrazine, pyrimidine, furan, pyrazole, pyrrole, imidazole, furanone, thiophene, oxazole, pyrido-oxazine, pyrido pyridine, pyrido-pyrimidine, pyrido-thiazine rings, pyrrollo pyridine, indole, indazole rings.

[0065] In one embodiment ,the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine , coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.In one embodiment the substituents are attached to ortho, para or meta positions of the aryl or heteroaryl ring in R2.

[0066] In one embodiment, the aryl or heteroaryl ring in R2 is optionally substituted with a halogen, alkyl, alkoxy , hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0067] In one embodiment, the fused or unfused, aliphatic heterocyclic, saturated or unsaturated, monocyclic or bicyclic rings in R2 is optionally substituted with a halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0068] In one embodiment, the fused or unfused , monocyclic or heterocyclic , saturated or unsaturated, monocyclic or bicyclic ring in R2 has one or more heteroatoms selected from Nitrogen, Sulphur or Oxygen. In one embodiment, the nitrogen atoms are coupled to protecting groups. In one embodiment the protecting group is a Boc group (tert-butyloxy carbonyl).

[0069] In one embodiment the compounds of formula I are N-(4-fluorophenyl)-5-pentylpicolinamide, 5- pentyl-N-(pyridin-2-yl)picolinamide, N'-isonicotinoyl-5-pentylpicolinohydrazide , 5-butyl-N'- isonicotinoylpicolinohydr azide.

[0070] One embodiment of the invention is a pyridine carboxamide compound represented by the formula

[0071] II Wherein n= 0-5,

[0072] R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

[0073] In one embodiment, the optionally substituted aryl or heteroaryl ring in R2 is benzene, naphthalene, quinoline, pyridine, coumarin, benzofuranonepyrazine, pyrimidine, furan, pyrazole, pyrrole, imidazole, furanone, thiophene, oxazole, pyrido-oxazine, pyrido pyridine, pyrido-pyrimidine, pyrido-thiazine rings, pyrrollo pyridine, indole, indazole rings.

[0074] In one embodiment ,the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine , coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group Substituted or unsubstituted amino group, halogen or deuterium.In one embodiment the substituents are attached to ortho, para or meta positions of the aryl or heteroaryl ring in R2.

[0075] In one embodiment, the aryl or heteroaryl ring in R2 is optionally substituted with a halogen, alkyl, alkoxy , hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0076] In one embodiment, the fused or unfused, aliphatic heterocyclic, saturated or unsaturated, monocyclic or bicyclic rings in R2 is optionally substituted with a halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0077] In one embodiment, the fused or unfused , monocyclic or heterocyclic , saturated or unsaturated, monocyclic or bicyclic ring in R2 has one or more heteroatoms selected from Nitrogen, Sulphur or Oxygen. In one embodiment, the nitrogen atoms are coupled to protecting groups. In one embodiment the protecting group is a Boc group (tert-butyloxy carbonyl).

[0078] In one embodiment the compounds of formula I are N-(4-methyl-2-oxo-2H-chromen-7-yl)-5- pentylpicolinamide, 4-(5-butylpicolinamido)-2-hydroxybenzoic acid,5-butyl-N'-(2- methylisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(3- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 2-hydroxy-4-(5- pentylpicolinamido)benzoic acid One embodiment of the invention is a pyridine carboxamide compound represented by the formula

[0079] III

[0080] Wherein n= 0-5,

[0081] R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

[0082] In one embodiment, the optionally substituted aryl or heteroaryl ring in R2 is benzene, naphthalene, quinoline, pyridine, coumarin, benzofuranonepyrazine, pyrimidine, furan, pyrazole, pyrrole, imidazole, furanone, thiophene, oxazole, pyrido-oxazine, pyrido pyridine, pyrido-pyrimidine, pyrido-thiazine rings, pyrrollo pyridine, indole, indazole rings.

[0083] In one embodiment ,the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine , coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group Substituted or unsubstituted amino group, halogen or deuterium.In one embodiment the substituents are attached to ortho, para or meta positions of the aryl or heteroaryl ring in R2.

[0084] In one embodiment, the aryl or heteroaryl ring in R2 is optionally substituted with a halogen, alkyl, alkoxy , hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0085] In one embodiment, the fused or unfused, aliphatic heterocyclic, saturated or unsaturated, monocyclic or bicyclic rings in R2 is optionally substituted with a halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfone or a cycloalkyl group.

[0086] One embodiment is the compound represented by formula II wherein n=3, and R2 is 4-pyridine. In one embodiment the compound represented by formula II is N'-isonicotinoyl-5- pentylpicolinohydrazide. In one embodiment the compound represented by formula II is N-(4- fluorophenyl)-5-pentylpicolinamide (Compound 30).

[0087] One embodiment of the invention is a salt of the compound represented by formula I or II or III wherein the salt is a hydrochloric acid (HC1), acetic acid, or oxalic acid salt. In one embodiment the salt is a HCL salt.

[0088] In one embodiment, the R2 in pyridine carboxamide compounds of the invention represented by formula I comprises of cyclic and acyclic amine

[0089] In one embodiment, the R2 in pyridine carboxamide compounds of the invention represented by formula I is an aromatic or heteroaryl amine group optionally substituted with a deuterium, halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfonyl, sulfonamide, or a cycloalkyl group. In one embodiment, the sulfonamide group is further attached to a 5 or 6 membered aryl, or a heteroaryl ring.

[0090] In one embodiment, the R2 in pyridine carboxamide compounds of the invention represented by formula I comprises of aromatic or heteroaryl amides.

[0091] In one embodiment, the aryl or heteroaryl ring in R2 is substituted with 5 or 6 membered aryl or heteroaryl rings, aliphatic heterocyclic rings, fused saturated or unsaturated bicyclic rings that are optionally substituted with a halogen, alkyl, hydroxyl, carboxyl, nitro, sulfonyl, sulfonamide, or a cycloalkyl group. In one embodiment, the cycloalkyl group is a cyclopropyl group. In one embodiment, the sulfonamide group is further attached to a 5 or 6 membered aryl, or a heteroaryl ring. In one embodiment, the aryl ring is a benzene. In one embodiment, the aryl ring is a pyridine or pyrimidine.

[0092] In one embodiment, the fused or unfused , aliphatic heterocyclic , saturated or unsaturated, monocyclic or bicyclic ring in R2 is coupled to a 5 or 6 membered aryl or heteroaryl group that are optionally substituted with a halogen, alkyl, alkoxy, hydroxyl, carboxyl, nitro, sulfonyl, sulfonamide or a cycloalkyl group. In one embodiment, the coupling is done by sulfonamide, or carbonyl groups.

[0093] In one embodiment of the invention, R1 is an alkyl group with carbon chain of 5. In one embodiment of the invention, R1 is a pentyl group.

[0094] In one embodiment the R2 is Ar. In one embodiment the Ar is a 6-membered aryl ring. In one embodiment the aryl ring is substituted with a halogen. In one embodiment the halogen is fluorine. In one embodiment the compound represented by formula I is 5-butyl-N-(4- fluorophenyl)picolinamide, 5 -butyl-N-(pyridin-2-yl)picolinamide, 5 -butyl-N-(4- nitrophenyl)picolinamide, 5 -ethyl-N-(4-fluorophenyl)picolinamide, 5 -butyl-N- hydroxypicolinamide, 5-ethyl-N-(pyridin-2-yl)picolinamide, 5-butyl-N-hydroxypicolinamide, 5- ethyl-N-(pyridin-2-yl)picolinamide, 5-butyl-N-(3,4-difluorophenyl)picolinamide, 5-butyl-N-(3- chloro-4-fluorophenyl)picolinamide , 5-butyl-N-(p-tolyl)picolinamide, 5-butyl-N-(4- chlorophenyl)picolinamide, N-(4-fluorophenyl)-5-hexanoylpicolinamide, N-(4-fluorophenyl)-5- propylpicolinamide, N,5-bis(4-fluorophenyl)picolinamide, 5-(4-fluorophenyl)-N-(pyridin-2- yl)picolinamide, N-(pyridin-2-yl)picolinamide, 5-hexanoyl-N-(pyridin-2-yl)picolinamide, 5- butylpicolinohydrazide, 5-(4-fluorophenyl)-N-(4-nitrophenyl)picolinamide, 5-butyl-N- methylpicolinamide, N-(4-fluorophenyl)-5-pentylpicolinamide, 5-pentyl-N-(pyridin-2- yl)picolinamide, N-(4-nitrophenyl)-5-pentylpicolinamide, N'-isonicotinoyl-5- pentylpicolinohydrazide, 5-butyl-N'-isonicotinoylpicolinohydrazide, N'-isonicotinoyl-5- pentylpicolinohydrazide hydrogen chloride, 5-butyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-cyclopentyl-N-(4-fluorophenyl)picolinamide, N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-phenylpicolinohydrazide, N'-isonicotinoyl-5-propylpicolinohydrazide hydrogen chloride, 5-pentyl-N'-phenylpicolinohydrazide, 5-butyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, 5-isopentyl-N-(pyridin-2-yl)picolinamide, N-(lH-indol-4-yl)-5- pentylpicolinamide, 5-butyl-N-(lH-indol-4-yl)picolinamide, 5-(sec-butyl)-N-(pyridin-2- yl)picolinamide hydrogen chloride, 5-pentylpicolinohydrazide, 4-butyl-N-(pyridin-2- yl)picolinamide hydrogen chloride, 5-isopentyl-N-(pyridin-2-yl)picolinamide, N-(4-(N-(4- methylpyrimidin-2-yl)sulfamoyl)phenyl)-5-pentylpicolinamide, l-cyclopropyl-6-fluoro-4-oxo-7-(4- (5-pentylpicolinoyl)piperazin-l-yl)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, 5-pentyl-N-(3- sulfamoylphenyl)picolinamide, 5 -pentyl-N-(4-(N -phenylsulf amoyl)phenyl)picolinamide, 5 -butyl-N - (4-(N-phenylsulfamoyl)phenyl)picolinamide, 4-(5-butylpicolinamido)-2-hydroxybenzoic acid, 2- hydroxy-4-(5-pentylpicolinamido)benzoic acid, 2-hydroxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 3 ,3-dimethyl-7 -oxo-6-(5 -pentylpicolinamido)-4-thia- 1 - azabicyclo[3.2.0]heptane-2-carboxylic acid, 2-chloro-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 2-hydroxy-5-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 2- hydroxy-4-(5-pentylpicolinamido)benzoate hydrogen chloride, 2-methyl-4-(5- pentylpicolinamido)benzoic acid hydrogen chloride, 2-fluoro-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 5-(5-butylpicolinamido)-2-hydroxybenzoic acid hydrogen chloride, 5-pentyl-N- (4-sulfamoylphenyl)picolinamide hydrogen chloride, methyl 2-methoxy-4-(5- pentylpicolinamido)benzoate hydrogen chloride, N-(l-oxo-l,3-dihydroisobenzofuran-5-yl)-5- pentylpicolinamide hydrogen chloride, 2-methoxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 4-(5-butylpicolinamido)-2-hydroxybenzoate hydrogen chloride, 4-(5- butylpicolinamido)-2-methylbenzoic acid hydrogen chloride, 4-(5-butylpicolinamido)-2- fluorobenzoic acid hydrogen chloride, 4-(2-(5-butylpicolinoyl)hydrazineyl)benzoic acid hydrogen chloride, N-(4-(hydrazineylsulfonyl)phenyl)-5-pentylpicolinamide hydrogen chloride, (R)-5-butyl- N-(3-oxoisoxazolidin-4-yl)picolinamide, (R)-N-(3-oxoisoxazolidin-4-yl)-5-pentylpicolinamide, 5- ethyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-hexyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-picolinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-nicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'- (thiophene-2-carbonyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(furan-2- carbonyl)picolinohydrazide hydrogen chloride, N'-(5-butylpicolinoyl)quinoline-2-carbohydrazide hydrogen chloride, N'-isonicotinoyl-5-methylpicolinohydrazide hydrogen chloride, 5-butyl-N'- (thiophene-3-carbonyl)picolinohydrazide hydrogen chloride, N'-(5-butylpicolinoyl)quinoline-4- carbohydrazide, N'-(5-butylpicolinoyl)-lH-indole-2-carbohydrazide hydrogen chloride, N-(5- bromopyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, N-(4-methoxyphenyl)-5- pentylpicolinamide hydrogen chloride, (3,4-dihydroquinolin-l(2H)-yl)(5-pentylpyridin-2- yl)methanone hydrogen chloride, N-(3-chloro-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-fluorophenyl)-N-methyl-5-pentylpicolinamide hydrogen chloride, N-(4- isopropylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-chlorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(3,4-dichlorophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(p-tolyl)picolinamide hydrogen chloride, 5-pentyl-N-(pyridin-4- yl)picolinamide hydrogen chloride, N-(3-chloro-4-fluorophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-bromophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3,4-difluorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(2-morpholinophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(3-(trifluoromethoxy)phenyl)picolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethyl)phenyl)picolinamide hydrogen chloride, N-(4-bromophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, N-(lH-indol-4- yl)picolinamide hydrogen chloride, N-(4-chloro-3-(trifluoromethyl)phenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyrimidin-2-yl)picolinamide hydrogen chloride, N-(4- chloropyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, N-(5-nitropyridin-2-yl)-5- pentylpicolinamide hydrogen chloride, N-(lH-indol-4-yl)-5-propylpicolinamide hydrogen chloride, N-(3-amino-2-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-amino-4- methylphenyl)-5-pentylpicolinamide hydrogen chloride, 4-pentyl-N-(pyridin-2-yl)picolinamide hydrogen chloride, N'-isonicotinoyl-4-pentylpicolinohydrazide hydrogen chloride, 6-butyl-N- (pyridin-2-yl)picolinamide hydrogen chloride, 3-butyl-N-(pyridin-2-yl)picolinamide hydrogen chloride, 6-pentyl-N-(pyridin-2-yl)picolinamide hydrogen chloride, 3-pentyl-N-(pyridin-2- yl)picolinamide hydrogen chloride, 6-bromo-N-(pyridin-2-yl)picolinamide, N'-isonicotinoyl-3- pentylpicolinohydrazide hydrogen chloride, 6-butyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-6-pentylpicolinohydrazide hydrogen chloride, N-(4-(benzo[d]thiazol-2- yl)phenyl)-5-pentylpicolinamide, N-(4-methyl-2-oxo-2H-chromen-7-yl)-5-pentylpicolinamide, N- (4-(benzo[d]thiazol-2-yl)phenyl)picolinamide, N-(4-methyl-2-oxo-2H-chromen-7-yl)picolinamide, N'-(2-bromoisonicotinoyl)-5-butylpicolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methoxyisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(3- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methylisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, N-(4-(benzo[d]thiazol-2-yl)phenyl)-5- methylpicolinamide, N-(4-bromopyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, 5-ethyl-N- (4-methyl-2-oxo-2H-chromen-7-yl)picolinamide, N-(6-bromobenzo[d]thiazol-2-yl)-5- pentylpicolinamide, N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-ethylpicolinamide, 5-pentyl-N-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)picolinamide, N-(5-bromobenzo[d]thiazol-2- yl)-5-pentylpicolinamide, N'-(5-butylpicolinoyl)pyrazine-2-carbohydrazide, N-(1H- benzo[d]imidazol-2-yl)-5-pentylpicolinamide, 5-pentyl-N-(4-(trifluoromethyl)phenyl)picolinamide, N-(2-chloro-4-(trifluoromethyl)phenyl)-5-pentylpicolinamide, methyl 2-(5- pentylpicolinamido)isonicotinate, methyl 2-(5-pentylpicolinamido)thiophene-3-carboxylate, N-(2- chloro-4-nitrophenyl)-5-pentylpicolinamide

[0095] In one embodiment the compound represented by formula I is the compound is 5-butyl-N-(4- fluorophenyl)picolinamide, 5 -butyl-N-(pyridin-2-yl)picolinamide, 5 -butyl-N-(4- nitrophenyl)picolinamide, 5 -butyl-N-(3 ,4-difluorophenyl)picolinamide, 5 -butyl-N-(3 -chloro-4- fluoropheny l)picolinamide, 5-butyl-N-(p -toly l)picolinamide, 5 -buty 1-N- (4 - chlorophenyl)picolinamide , N-(4-fluorophenyl)-5-hexanoylpicolinamide, 5-hexanoyl-N-(pyridin-2- yl)picolinamide, N-(4-fluorophenyl)-5-pentylpicolinamide, 5-pentyl-N-(pyridin-2-yl)picolinamide, N'-isonicotinoyl-5-pentylpicolinohydrazide, 5-butyl-N'-isonicotinoylpicolinohydrazide, N'- isonicotinoyl-5-pentylpicolinohydrazide hydrogen chloride, 5-butyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-5-propylpicolinohydrazide hydrogen chloride, 5-pentyl-N'-phenylpicolinohydrazide, N-(lH-indol-4-yl)-5-pentylpicolinamide, 4-(5-butylpicolinamido)-2-hydroxybenzoic acid, 2-hydroxy-4-(5-pentylpicolinamido)benzoic acid, 2-hydroxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 2-methoxy-4-(5- pentylpicolinamido)benzoate hydrogen chloride, N-(l-oxo-l,3-dihydroisobenzofuran-5-yl)-5- pentylpicolinamide hydrogen chloride, 5-ethyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-hexyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, N-(5-bromopyridin-2-yl)-5- pentylpicolinamide hydrogen chloride, N-(4-methoxyphenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-chloro-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4- isopropylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-chlorophenyl)-5- pentylpicolinamide hydrogen chloride, 5-pentyl-N-(p-tolyl)picolinamide hydrogen chloride, 5- pentyl-N-(pyridin-4-yl)picolinamide hydrogen chloride, N-(3-chloro-4-fluorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(3-bromophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3,4-difluorophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethoxy)phenyl)picolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethyl)phenyl)picolinamide hydrogen chloride, N-(4-bromophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, 5-pentyl-N- (pyrimidin-2-yl)picolinamide hydrogen chloride, 5-pentyl-N-(lH-pyrazol-3-yl)picolinamide hydrogen chloride, N-(3-amino-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N'- isonicotinoyl-4-pentylpicolinohydrazide hydrogen chloride, 6-butyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-6-pentylpicolinohydrazide hydrogen chloride, N-(4-methyl-2-oxo-2H-chromen-7-yl)-5-pentylpicolinamide, 5-butyl-N'-(2- methoxyisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(3- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methylisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-pentyl-N-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)picolinamide.

[0096] In one embodiment the compounds of formula I are represented by the following formula ;

[0097] In one embodiment of the invention, the compounds represented by formula I, II or III have inhibitory effect against M. tuberculosis strains in vitro.

[0098] In one embodiment of the invention, the compounds represented by formula I, II or III have inhibitory effect against M. tuberculosis strains in vivo. In one embodiment the pyridine carboxamide compounds represented by formula I, II or III inhibit M. tuberculosis growth in macrophages In one embodiment the M.tuberculosis strain is M. bovis BCG. In one embodiment the M.tuberculosis strains includes drug sensitive and drug resistant clinical strains of M.tuberculosis.

[0099] In one embodiment, the MIC for the compound 30 (N-(4-fluorophenyl)-5-pentylpicolinamide) for a drug susceptible strain of M.tuberculosis is <1.5 uM. In one embodiment, the MIC for compound 30 for a MDR strain of M.tuberculosis is <1.5 uM. In one embodiment, the MIC of compound 30 for a XDR strain of M.tuberculosis is <1.5 uM

[0100] In one embodiment, the novel pyridine carboxamide compounds of the invention do not interfere with the effect of other important tuberculosis drugs when dosed in combination. In one embodiment, the pyridine carboxamide compounds of formula I, II or III have a synergistic effect when dosed along with known Tuberculosis drugs. In one embodiment, the known Tuberculosis drugs include Rifampicin, Bedaquiline, Pretomanid, Isoniazid, pyrazinamide, Levofloxacin. In one embodiment, the novel pyridine carboxamide compounds of the invention represented by formula I, II and III have a synergistic effect when dosed along with known Tuberculosis drugs. In one embodiment, the known Tuberculosis drugs include Rifampicin, Bedaquiline, Pretomanid, Isoniazid, pyrazinamide, Levofloxacin.

[0101] One embodiment of the invention is a composition comprising compounds represented by formula I and tuberculosis drugs selected from Rifampicin, Bedaquiline, Pretomanid, Isoniazid, and Levofloxacin. One embodiment of the invention is a composition comprising compounds represented by formula II and known tuberculosis drugs selected from Rifampicin, Bedaquiline, Pretomanid, Isoniazid and Levofloxacin. One embodiment of the invention is a composition comprising compounds represented by formula III and tuberculosis drugs selected from Rifampicin, Bedaquiline, Pretomanid, Isoniazid and Levofloxacin. In one embodiment the tuberculosis drugs is Isoniazid. One embodiment of the invention is a use of the compound represented by formula I for treating infection caused by M. tuberculosis strains in a subject.

[0102] One embodiment of the invention is a pharmaceutical composition comprising a compound represented by formula I, II or III or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient, or diluent.

[0103] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such as specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modifications. However, all such modifications are deemed to be within the scope of the claims.

[0104] EXAMPLES

[0105] Materials and methods

[0106] Chemicals and Reagents. Primary antibodies like rabbit anti-(P-actin, ATG 3, ATG 7 and LC3) and HRP-linked secondary antibodies (anti-rabbit) were purchased from Cell signaling Technology (MA, USA). Phorbol 12-myristate 13-acetate (PMA), bafilomycin Al (Baf-Al), wortmannin, monodansyl cadaverine (MDC), 4’,6-diamidino-2-phenylindole (DAPI), bicinchoninic acid (BCA) protein estimation kit, fluoromountaqueous medium, protease inhibitor cocktail (100 x), and anti-p62 antibody were procured from Millipore Sigma (St. Louis, MO, USA). Cytiva (MA, USA) provided the ECL western blotting detection reagents. Mycobacterial culture media like Middlebrook 7H9 broth and 7H11 agar was purchased from Becton dickinson (MD, USA). All other general chemicals not mentioned were procured from either HiMedia laboratory (Mumbai, India) or Merck. All reagents for chemical synthesis, silica and analytical thin layer chromatography (TLC) were purchased from Sigma- Aldrich, Avra Pvt Ltd., Spectrochem and Merck, unless otherwise mentioned.

[0107] Bacterial culture conditions. Mycobacterial strains were cultured in MB7H9 broth supplemented with glycerol, tween-80, and albumin-dextrose-saline (ADS) at 37 °C with shaking (200 rpm). For bacterial enumeration, 10-fold serial dilutions were prepared and plated on MB7H11 agar plates supplemented with oleic-album-dextrose-saline (GADS) and 0.5% glycerol at 37 °C for 3-4 weeks. Intracellular activity assays in macrophages. Human monocyte cell-line THP-1 was cultured in Roswell Park Memorial Institute (RPMI) 1640 medium. The monocytes were differentiated into macrophages by overlaying cells with RPMI medium with 20 ng / ml of PMA for 24 h. Cell viability assays were performed in flat bottom 96 well plates using WST-1 cell proliferation assay as per the manufacturer’s recommendations. For infection studies, THP-1 cells were infected with various strains at a multiplicity of infection, 1:10 for 4 h followed by treatment with 200 pg / ml of amikacin for 2 h to remove extracellular bacteria. If required, macrophages were washed and treated with 200 nM wortmannin for 2 h before treating with drugs for autophagy and CFU experiments. For CFU enumeration, macrophages were lysed in lx PBST (lx PBS with 0.1% Triton X-100) at designated time points and 10.0-fold serial dilutions were plated on MB7H11 at 37 °C for 3-4 weeks.

[0108] Example 1: In vitro MIC determination, drug combination and killing kinetic assays.

[0109] For MIC determination assays against M. tuberculosis H37RV, the compounds were diluted in MB7H9 medium and screened for antimycobacterial activity at 10 pM concentration. All reaction plates included INH as a positive control. MIC value against various strains was determined using microdilution method. For MIC determination experiments, two-fold serial dilutions of various compound were prepared in 96 well clear ‘U’ bottom plates. Subsequently, early logarithmic cultures (OD600nm ~ 0.2-0.3) was diluted 1:1000 and equal volume of diluted cultures were added to 96 well plates and incubated at 37 °C for 14 days. All assay plates included no drug, medium only controls, and positive controls such as INH. The MIC value is defined as the lowest concentration at which no visible growth was seen relative to the untreated bacterial only control. Checkerboard assays were performed against M. tuberculosis H37RV to determine the activity of the identified compounds in combination with known drugs RIF, INH, levofloxacin (LEVO), BDQ, PTM. The fractional inhibitory concentration (FIC) and fractional inhibitory concentration index (FICI) were calculated for various drug-combinations. For killing kinetics experiment, early log phase cultures (ODeoonm 0.2-0.3) of M. tuberculosis were exposed to 50x MIC concentration of drugs for either 4 or 7 days and CFU enumeration was performed as described above.

[0110] Table 1: Anti-tubercular activity of pyridine carboxamide compounds (1-136).

[0111] Some pyridine carboxamide based compounds of formula I, II or III are listed as representative examples of compounds encompassed by the present invention

[0112]

[0113] Table 2: Biological data pertaining to activity of the some compounds encompassed by the invention mentioned herewith;

[0114] Example 2: In vivo Inhibition of M. tuberculosis by Compound 30 (N-(4-fluorophenyl)-5- pentylpicolinamide)

[0115] The ability of compound 30 to inhibit the growth of M. tuberculosis in vivo was determined. The compound 30 was well tolerated at a dose of 50 mg / kg in our dose-tolerance studies. The drug was administered for 7 consecutive days and animals were observed for 10 days. There were no behavioral change or signs of adverse effects such as weight loss, hair loss or change in feed intake upon administration of compound 30. The lead compound 30 was found to have a significant plasma exposure (eAUCso-no value = ~ 157 pM), when dosed orally to mice at 50 mg / kg. Therefore, in vivo efficacy experiments were performed at an oral dose of 50 mg / kg in a chronic infection model of Balb / c mice. A daily administration of INH for 4 weeks led to 12.5-fold reduction in lung bacillary loads relative to untreated animals (****P<0.0001'). In comparison, 5.0-fold reduction was noticed in the lungs of animals treated with compound 30. The bacillary loads in lungs of vehicle control group and mice treated with INH or compound 30 were logio 5.84, logio 4.75 and logio 5.13, respectively. In agreement, treatment of M. tuberculosis infected animals with INH or compound 30 reduced the splenic bacillary loads by 33.0- and 4.5-folds, respectively. The bacillary loads in spleens of vehicle control group and mice treated with INH or compound 30 were logio 4.56, logio 3.02 and logio 3.99, respectively.

[0116] It was observed that compound 30 inhibited M. tuberculosis growth in a bacteriostatic manner in liquid cultures. In THP-1 macrophages, compound 30 inhibited the growth of intracellular M. tuberculosis in a bactericidal manner.

[0117] Example 3: Interaction of Compound 30 (N-(4-fluorophenyl)-5-pentylpicolinamide) with existing TB drugs

[0118] The antimycobacterial activity of compound 30 was measured either alone or in combination with INH or RIF or LEVO or BDQ or PTM in checkerboard assays. In this analysis, compound 30 showed an indifferent effect with anti-TB drugs with the FIC value in the range of 0.625-2.0 as mentioned in below Table 3. Compound 30 did not interfere with the activity of any of the tested Mtb drug. This highlights the potential of co-dosing of compound 30 for TB along with the existing drugs. It was observed that compound 30 also inhibited the growth of various drug-resistant clinical strains. The MIC value of compound 30 against drug-resistant clinical strains was in the range of 0.78 - 1.56 pM.

[0119] Table 3

[0120] Example 4: General procedure for the synthesis of the compounds disclosed in this invention.

[0121] The various pyridine carboxamides were synthesized from corresponding pyridine carboxylic acids and amines exploiting acid amine coupling methods. To enable the synthesis of various substituted pyridine carboxamides, corresponding substituted pyridine carboxylic acids / esters were also synthesized, A brief on this synthetic chemistry procedure is provided below.

[0122] General procedure for the synthesis of substituted pyridine carboxylic acids

[0123] The general procedure is shown in Fig 3

[0124] Scheme. Reaction conditions: (a) thionyl chloride, methanol, reflux, 16 h. (b) dry THF, RMgX, ZnCh, Pd (PPh)4, -10 °C, 16 h. (c) methanol: THF (1:1), IN NaOH, rt, 16 h.

[0125] Step (a):-

[0126] Thionyl chloride (5.0 eq.) was added to a stirred solution of carboxylic acid (1.0 eq.) in MeOH (1 ml / mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature and subsequently refluxed for 16 h. The progress of the chemical reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the excess solvent was removed under reduced pressure. The reaction mixture was treated with a saturated solution of aqNaHCOs and extracted using ethyl acetate (EtOAc). The organic layer was washed with water brine solution and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure.

[0127] Step (b):-

[0128] To a stirred solution of corresponding Grignard reagent (RMgX) (2.2 eq., 2M solution in THF) in dry THF (1 ml / mmol), ZnCh (2.1 eq., IM solution in diethyl ether,) was added at 0 °C under a N2 atmosphere and stirred at room temperature for 15 mins. This was followed by the addition of tetrakis(triphenylphosphine)palladium (0.02 eq.) and methyl ester of carboxylic acid (1.0 eq) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction was quenched with IN aqHCl and extracted using ethyl acetate (EtOAc). The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield a crude compound that was further purified by column chromatography using 60:120 silica gel.

[0129] Step (c):- To a stirred solution of substituted picolinate (1.0 eq.) in MeOH: THF (1:1) (1 ml / mmol), IN NaOH (4.0 eq.) was added at room temperature and allowed to stir for 16 h. TLC was used to monitor the progress of the chemical reaction. After completion, the reaction mixture was concentrated under reduced pressure, acidified using IN aqHCl and extraction was performed with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain desired compound.

[0130] The above mentioned procedure was used to synthesize all substituted pyridine carboxylic acids without any modifications.

[0131] Example 5: A general procedure for the synthesis of pyridine amides

[0132] For the synthesis of the pyridine carboxamides, different acid amine coupling reaction conditions were exploited as mentioned below.

[0133] The general procedure is shown in Fig 4

[0134] Scheme. Reaction conditions:

[0135] (d) DMF, EDC.HC1, HOBt, NMP, room temperature, 24 h.

[0136] (d’) DIPEA, HATU, DMF, 0 °C - rt, 16 h.

[0137] (d”) SOC12, DMF, DCM, 0 °C - rt,5 h, TEA, DCM, 24 h.

[0138] Procedure (d): -

[0139] To a stirred mixture of carboxylic acid (1.0 eq.) in DMF (1 ml / mmol), EDC.HC1 (1.5 eq.), hydroxyl benzotriazole (HOBt) (1.5 eq.) and N-methyl pyrrolidine (NMP) (3.0 eq.) were added under N2 atmosphere. Then reaction mixture was stirred for 30 min. and then amine (1.2 eq.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 h. The progress of reaction was monitored using TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using 60:120 silica gel.

[0140] Procedure (d’): -

[0141] To a stirred mixture of carboxylic acid (1.0 eq.) in DMF (1 ml / mmol), were added DIPEA (3.0 eq.), and HATU (1.5 eq.) under N2 atmosphere at 0°C. The reaction mixture was stirred for 30 min. Then amine (1.2 eq.) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The progress of reaction was monitored using TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using 60: 120 silica gel.

[0142] Procedure (d”): -

[0143] To a stirred mixture of carboxylic acid (1.0 eq.) in DCM (1 ml / mmol), were added SOCh (5.0 eq) and cat. Amount of DMF under N2 atmosphere at 0 °C. Then reaction mixture was stirred at room temperature for 5 h. The progress of reaction was monitored was TLC. Then excess of SOCI2 was removed by high vacuum. The crude was diluted with DCM and TEA was added to it followed by addition of amine. The reaction mixture was stirred at room temperature for 24 h. The progress of reaction was monitored using TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using 60:120 silica gel.

[0144] Example 6: A general procedure for the synthesis of hydrazides from acids

[0145] Scheme. Reaction conditions: (e) thionyl chloride, methanol, reflux, 16 h. (f) hydrazine hydrate, methanol, reflux, 16 h. (g) N-hydroxy succinamide, DCC, 1,4-dioxane, rt, 16 h, DMF, rt, 24 h.

[0146] The general procedure is shown in Fig 5

[0147] Procedure (e):-

[0148] Thionyl chloride (5.0 eq.) was added to a stirred solution of carboxylic acid (1.0 eq.) in MeOH (1 ml / mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature and subsequently refluxed for 16 h. The progress of the chemical reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the excess solvent was removed under reduced pressure. The reaction mixture was treated with a saturated solution of aqNaHCOs and extracted using ethyl acetate (EtOAc). The organic layer was washed with water brine solution and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure.

[0149] Procedure (f):-To a stirred solution of methyl ester of carboxylic acid (1.0 eq.) in MeOH (1 ml / mmol), was added hydrazine hydrate (5.0 eq.) at 0 °C under nitrogen atmosphere. The reaction was refluxed for 16 h. The progress of the chemical reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the excess solvent was removed under reduced pressure. The crude was purified by column chromatography using 60:120 silica gel. Procedure (g):-To a stirred solution of 5-butyl picolinic acid (1.0 eq.) in 1,4-dioxane (1 ml / mmol), were added N-hydroxy succinamide (1.5 eq.) and DCC (1.5 eq.) under N2 atmosphere at 0 °C. Then reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered with the help of Buchner funnel. The filtrate was concentrated under reduced pressure. Then the crude was diluted with DMF (1 ml / mmol) and other reactant (1.0 eq.) was added to reaction mixture. The reaction mixture was stirred at room temperature for 24 h. The progress of the chemical reaction was monitored by thin layer chromatography (TLC). After completion reaction was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography using 60:120 silica gel.

[0150] References

[0151] 1. Nicolas Schonfeld, Thorsten Bergmann, Silvan Vesenbeckh, Harald Mauch, Gudrun Bettermann, Torsten T. Bauer, and Holger Riissmann, Minimal inhibitory concentrations of first-line drugs of multidrug-resistant tuberculosis isolates. Lung India. 2012 Oct-Dec; 29(4): 309-312.

[0152] 2. H. M. Adnan Hameed et al.. Molecular Targets Related Drug Resistance Mechanisms in MDR-,XDR-, and TDR-Mycobacterium tuberculosis Strains. Front. Cell. Infect. Microbiol., 10 April 2018, Sec. Molecular Bacterial Pathogenesis, Volume 8 - 2018

[0153] 3. Padam Singh, Arun Kumar, Pankaj Sharma, Saurabh Chugh, Ashish Kumar, Nidhi Sharma, Sonu Gupta, Manisha Singh, Saqib Kidwai, Jishnu Sankar, Neha Taneja, Yashwant Kumar, Rohan Dhiman, Dinesh Mahajan ,Ramandeep Singh, Identification and optimization of pyridine carboxamide-based scaffold as a drug lead for Mycobacterium tuberculosis Antimicrob Agents Chemother, 2024 Feb 7;68(2):e0076623.

Claims

CLAIMS1.A pyridine carboxamide compound represented by formula I, its stereoisomer, or pharmaceutically acceptable salt thereofwherein R1 is selected from group consisting of H, Ar, alkyl Ar, a cycloalkyl group, or an optionally substituted linear or branched alkyl chain of carbon length 1-8, and R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group ,and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group, ester, nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

2. The compound of claim 1 wherein the heteroaryl ring in R2 has one or more hetero atoms selected from Nitrogen, Oxygen or Sulphur.

3. The compound of claim 1 wherein R1 is optionally substituted linear alkyl chain of carbon length 1-8.4.The compound of claim 1 wherein the optionally substituted aryl or heteroaryl ring in R2 is benzene, naphthalene, quinoline, pyridine, coumarin, benzofuranone , pyrazine, pyrimidine, furan, pyrazole, pyrrole, imidazole, furanone, thiophene, oxazole, pyrido-oxazine, pyrido pyridine, pyrido- pyrimidine, pyrido-thiazine rings, pyrrollo pyridine, indole, indazole rings.

5. The compound of claim 1 wherein R2 is an aryl or heteroaryl ring optionally substituted with deuterium, fluorine, chloro, bromo, methyl, isopropyl, hydroxyl, carboxyl, nitro, sulfonyl, sulfonamide, aryl or a cycloalkyl group at ortho, meta or para-position of the ring.

5. The compound of claim 1 wherein the optionally substituted aryl or heteroaryl ring in R2 is benzene, quinoline, pyridine, pyrimidine , coumarin, benzofuranone and the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro,sulfonyl group substituted or unsubstituted amino group, halogen or deuterium at ortho, meta or paraposition of the ring.6.The compound of claim 1 represented by formula I wherein the compound is 5-butyl-N-(4- fluorophenyl)picolinamide, 5 -butyl-N-(pyridin-2-yl)picolinamide, 5 -butyl-N-(4- nitrophenyl)picolinamide, 5 -ethyl-N-(4-fluorophenyl)picolinamide, 5 -butyl-N- hydroxypicolinamide, 5-ethyl-N-(pyridin-2-yl)picolinamide, 5-butyl-N-hydroxypicolinamide, 5- ethyl-N-(pyridin-2-yl)picolinamide, 5 -btyl-N-(3 ,4-difluorophenyl)picolinamide, 5 -butyl-N-(3 - chloro-4-fluorophenyl)picolinamide , 5-butyl-N-(p-tolyl)picolinamide, 5-butyl-N-(4- chlorophenyl)picolinamide, N-(4-fluorophenyl)-5-hexanoylpicolinamide, N-(4-fluorophenyl)-5- propylpicolinamide, N,5-bis(4-fluorophenyl)picolinamide, 5-(4-fluorophenyl)-N-(pyridin-2- yl)picolinamide, N-(pyridin-2-yl)picolinamide, 5-hexanoyl-N-(pyridin-2-yl)picolinamide, 5- butylpicolinohydrazide, 5-(4-fluorophenyl)-N-(4-nitrophenyl)picolinamide, 5-butyl-N- methylpicolinamide, N-(4-fluorophenyl)-5-pentylpicolinamide, 5-pentyl-N-(pyridin-2- yl)picolinamide, N-(4-nitrophenyl)-5-pentylpicolinamide, N'-isonicotinoyl-5- pentylpicolinohydrazide, 5-butyl-N'-isonicotinoylpicolinohydrazide, N'-isonicotinoyl-5- pentylpicolinohydrazide hydrogen chloride, 5-butyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-cyclopentyl-N-(4-fluorophenyl)picolinamide, N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-phenylpicolinohydrazide, N'-isonicotinoyl-5-propylpicolinohydrazide hydrogen chloride, 5-pentyl-N'-phenylpicolinohydrazide, 5-butyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, 5-isopentyl-N-(pyridin-2-yl)picolinamide, N-(lH-indol-4-yl)-5- pentylpicolinamide, 5-butyl-N-(lH-indol-4-yl)picolinamide, 5-(sec-butyl)-N-(pyridin-2- yl)picolinamide hydrogen chloride, 5-pentylpicolinohydrazide, 4-butyl-N-(pyridin-2- yl)picolinamide hydrogen chloride, 5-isopentyl-N-(pyridin-2-yl)picolinamide, N-(4-(N-(4- methylpyrimidin-2-yl)sulfamoyl)phenyl)-5-pentylpicolinamide, l-cyclopropyl-6-fluoro-4-oxo-7-(4- (5-pentylpicolinoyl)piperazin-l-yl)-l,2,3,4-tetrahydroquinoline-3-carboxylic acid, 5-pentyl-N-(3- sulfamoylphenyl)picolinamide, 5 -pentyl-N-(4-(N -phenylsulf amoyl)phenyl)picolinamide, 5 -butyl-N - (4-(N-phenylsulfamoyl)phenyl)picolinamide, 4-(5-butylpicolinamido)-2-hydroxybenzoic acid, 2- hydroxy-4-(5-pentylpicolinamido)benzoic acid, 2-hydroxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 3 ,3-dimethyl-7 -oxo-6-(5 -pentylpicolinamido)-4-thia- 1 - azabicyclo[3.2.0]heptane-2-carboxylic acid, 2-chloro-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 2-hydroxy-5-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 2- hydroxy-4-(5-pentylpicolinamido)benzoate hydrogen chloride, 2-methyl-4-(5- pentylpicolinamido)benzoic acid hydrogen chloride, 2-fluoro-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, 5-(5-butylpicolinamido)-2-hydroxybenzoic acid hydrogen chloride, 5-pentyl-N-(4-sulfamoylphenyl)picolinamide hydrogen chloride, methyl 2-methoxy-4-(5- pentylpicolinamido)benzoate hydrogen chloride, N-(l-oxo-l,3-dihydroisobenzofuran-5-yl)-5- pentylpicolinamide hydrogen chloride, 2-methoxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 4-(5-butylpicolinamido)-2-hydroxybenzoate hydrogen chloride, 4-(5- butylpicolinamido)-2-methylbenzoic acid hydrogen chloride, 4-(5-butylpicolinamido)-2- fluorobenzoic acid hydrogen chloride, 4-(2-(5-butylpicolinoyl)hydrazineyl)benzoic acid hydrogen chloride, N-(4-(hydrazineylsulfonyl)phenyl)-5-pentylpicolinamide hydrogen chloride, (R)-5-butyl- N-(3-oxoisoxazolidin-4-yl)picolinamide, (R)-N-(3-oxoisoxazolidin-4-yl)-5-pentylpicolinamide, 5- ethyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-hexyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-picolinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'-nicotinoylpicolinohydrazide hydrogen chloride, 5-butyl-N'- (thiophene-2-carbonyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(furan-2- carbonyl)picolinohydrazide hydrogen chloride, N'-(5-butylpicolinoyl)quinoline-2-carbohydrazide hydrogen chloride, N'-isonicotinoyl-5-methylpicolinohydrazide hydrogen chloride, 5-butyl-N'- (thiophene-3-carbonyl)picolinohydrazide hydrogen chloride, N'-(5-butylpicolinoyl)quinoline-4- carbohydrazide, N'-(5-butylpicolinoyl)-lH-indole-2-carbohydrazide hydrogen chloride, N-(5- bromopyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, N-(4-methoxyphenyl)-5- pentylpicolinamide hydrogen chloride, (3,4-dihydroquinolin-l(2H)-yl)(5-pentylpyridin-2- yl)methanone hydrogen chloride, N-(3-chloro-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-fluorophenyl)-N-methyl-5-pentylpicolinamide hydrogen chloride, N-(4- isopropylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-chlorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(3,4-dichlorophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(p-tolyl)picolinamide hydrogen chloride, 5-pentyl-N-(pyridin-4- yl)picolinamide hydrogen chloride, N-(3-chloro-4-fluorophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-bromophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3,4-difluorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(2-morpholinophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(3-(trifluoromethoxy)phenyl)picolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethyl)phenyl)picolinamide hydrogen chloride, N-(4-bromophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, N-(lH-indol-4- yl)picolinamide hydrogen chloride, N-(4-chloro-3-(trifluoromethyl)phenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyrimidin-2-yl)picolinamide hydrogen chloride, N-(4- chloropyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, N-(5-nitropyridin-2-yl)-5- pentylpicolinamide hydrogen chloride, N-(lH-indol-4-yl)-5-propylpicolinamide hydrogen chloride, N-(3-amino-2-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-amino-4- methylphenyl)-5-pentylpicolinamide hydrogen chloride, 4-pentyl-N-(pyridin-2-yl)picolinamidehydrogen chloride, N'-isonicotinoyl-4-pentylpicolinohydrazide hydrogen chloride, 6-butyl-N- (pyridin-2-yl)picolinamide hydrogen chloride, 3-butyl-N-(pyridin-2-yl)picolinamide hydrogen chloride, 6-pentyl-N-(pyridin-2-yl)picolinamide hydrogen chloride, 3-pentyl-N-(pyridin-2- yl)picolinamide hydrogen chloride, 6-bromo-N-(pyridin-2-yl)picolinamide, N'-isonicotinoyl-3- pentylpicolinohydrazide hydrogen chloride, 6-butyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-6-pentylpicolinohydrazide hydrogen chloride, N-(4-(benzo[d]thiazol-2- yl)phenyl)-5-pentylpicolinamide, N-(4-methyl-2-oxo-2H-chromen-7-yl)-5-pentylpicolinamide, N- (4-(benzo[d]thiazol-2-yl)phenyl)picolinamide, N-(4-methyl-2-oxo-2H-chromen-7-yl)picolinamide, N'-(2-bromoisonicotinoyl)-5-butylpicolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methoxyisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(3- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methylisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, N-(4-(benzo[d]thiazol-2-yl)phenyl)-5- methylpicolinamide, N-(4-bromopyridin-2-yl)-5-pentylpicolinamide hydrogen chloride, 5-ethyl-N- (4-methyl-2-oxo-2H-chromen-7-yl)picolinamide, N-(6-bromobenzo[d]thiazol-2-yl)-5- pentylpicolinamide, N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-ethylpicolinamide, 5-pentyl-N-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)picolinamide, N-(5-bromobenzo[d]thiazol-2- yl)-5-pentylpicolinamide, N'-(5-butylpicolinoyl)pyrazine-2-carbohydrazide, N-(1H- benzo[d]imidazol-2-yl)-5-pentylpicolinamide, 5-pentyl-N-(4-(trifluoromethyl)phenyl)picolinamide, N-(2-chloro-4-(trifluoromethyl)phenyl)-5-pentylpicolinamide, methyl 2-(5- pentylpicolinamido)isonicotinate, methyl 2-(5-pentylpicolinamido)thiophene-3-carboxylate, N-(2- chloro-4-nitrophenyl)-5-pentylpicolinamide, 5 -pentyl-N-( 1 H-pyrazol-3 -yl)picolinamide hydrogen chloride, N'-(2-aminoisonicotinoyl)-5-butylpicolinohydrazide7.The compound of claim 1 represented by formula I wherein the compound is 5-butyl-N-(4- fluorophenyl)picolinamide, 5 -butyl-N-(pyridin-2-yl)picolinamide, 5 -butyl-N-(4- nitrophenyl)picolinamide, 5 -butyl-N-(3 ,4-difluorophenyl)picolinamide, 5 -butyl-N-(3 -chloro-4- fluoropheny l)picolinamide, 5-butyl-N-(p -toly l)picolinamide, 5 -buty 1-N- (4 - chlorophenyl)picolinamide , N-(4-fluorophenyl)-5-hexanoylpicolinamide, 5-hexanoyl-N-(pyridin-2- yl)picolinamide, N-(4-fluorophenyl)-5-pentylpicolinamide, 5-pentyl-N-(pyridin-2-yl)picolinamide, N'-isonicotinoyl-5-pentylpicolinohydrazide, 5-butyl-N'-isonicotinoylpicolinohydrazide, N'- isonicotinoyl-5-pentylpicolinohydrazide hydrogen chloride, 5-butyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-5-propylpicolinohydrazide hydrogen chloride, 5-pentyl-N'-phenylpicolinohydrazide, N-(lH-indol-4-yl)-5-pentylpicolinamide, 4-(5-butylpicolinamido)-2-hydroxybenzoic acid, 2-hydroxy-4-(5-pentylpicolinamido)benzoic acid,2-hydroxy-4-(5-pentylpicolinamido)benzoic acid hydrogen chloride, methyl 2-methoxy-4-(5- pentylpicolinamido)benzoate hydrogen chloride, N-(l-oxo-l,3-dihydroisobenzofuran-5-yl)-5- pentylpicolinamide hydrogen chloride, 5-ethyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, 5-hexyl-N'-isonicotinoylpicolinohydrazide hydrogen chloride, N-(5-bromopyridin-2-yl)-5- pentylpicolinamide hydrogen chloride, N-(4-methoxyphenyl)-5-pentylpicolinamide hydrogen chloride, N-(3-chloro-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4- isopropylphenyl)-5-pentylpicolinamide hydrogen chloride, N-(4-chlorophenyl)-5- pentylpicolinamide hydrogen chloride, 5-pentyl-N-(p-tolyl)picolinamide hydrogen chloride, 5- pentyl-N-(pyridin-4-yl)picolinamide hydrogen chloride, N-(3-chloro-4-fluorophenyl)-5- pentylpicolinamide hydrogen chloride, N-(3-bromophenyl)-5-pentylpicolinamide hydrogen chloride, N-(3,4-difluorophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethoxy)phenyl)picolinamide hydrogen chloride, 5-pentyl-N-(3- (trifluoromethyl)phenyl)picolinamide hydrogen chloride, N-(4-bromophenyl)-5-pentylpicolinamide hydrogen chloride, 5-pentyl-N-(pyridin-3-yl)picolinamide hydrogen chloride, 5-pentyl-N- (pyrimidin-2-yl)picolinamide hydrogen chloride, 5-pentyl-N-(lH-pyrazol-3-yl)picolinamide hydrogen chloride, N-(3-amino-4-methylphenyl)-5-pentylpicolinamide hydrogen chloride, N'- isonicotinoyl-4-pentylpicolinohydrazide hydrogen chloride, 6-butyl-N'- isonicotinoylpicolinohydrazide hydrogen chloride, N'-isonicotinoyl-6-pentylpicolinohydrazide hydrogen chloride, N-(4-methyl-2-oxo-2H-chromen-7-yl)-5-pentylpicolinamide, 5-butyl-N'-(2- methoxyisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(3- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- methylisonicotinoyl)picolinohydrazide hydrogen chloride, 5-butyl-N'-(2- fluoroisonicotinoyl)picolinohydrazide hydrogen chloride, 5-pentyl-N-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)picolinamide.

8. The compound of claim 1 represented by the formula (II);Wherein n= 0-5,R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , andwherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl , carboxyl group , ester , nitro, sulfonyl group substituted or unsubstituted amino group, halogen or deuterium.

9. The compound of claim 1 represented by the formula (III);Wherein n= 0-5,R2 is selected from the group consisting of H, Ar, alkyl Ar, NHAr, NH-CO-Ar, optionally substituted alkyl group of carbon chain 1-8 and wherein the carbon chain is linear or branched optionally substituted cyclo-alkyl group , and wherein Ar in R2 group is an optionally substituted and / or fused aryl or heteroaryl ring wherein the optional substituents are branched or unbranched aliphatic chain, alkoxy group, hydroxyl, carboxyl group, ester, nitro, sulfonyl group, substituted or unsubstituted amino group, halogen or deuterium. lO.The compound of claim 1 represented by the following formula;11.The compounds of claim 1 wherein the compounds represented by formula I, have inhibitory effect against drug sensitive and drug resistant strains of M. tuberculosis.12.A composition comprising a compound represented by formula I, formula II or formula III and one or more of tuberculosis drugs selected from a group consisting of pyrazinamide, Rifampicin, Bedaquiline, Pretomanid, Isoniazid, and Levofloxacin.

13. A pharmaceutical composition comprising a compound represented by a formula I, II or III or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, excipient, or diluent.

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