1.3.1.118 (1H-indol-5-yl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone 0.015 mM, 74% inhibition 228019 1.3.1.118 (4-(9H-fluoren-9-yl) piperazin-1-yl)-(4-methylbenzyl)-methanone 0.015 mM, 99% inhibition 228009 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (2,5-difluorophenyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228056 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (2-fluorophenyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228055 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (3-fluorophenyl)methanone uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA 228054 1.3.1.118 (4-(9H-Fluoren-9-yl)piperazin-1-yl) (3-tolyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228053 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (4-chlorophenyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228051 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (4-fluorophenyl)methanone uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA 228052 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (4-methoxyphenyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228049 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (4-tolyl)methanone uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA 228050 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl) (phenyl)methanone uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA 228048 1.3.1.118 (4-(9H-fluoren-9-yl)piperazin-1-yl)(indolin-5-yl)methanone i.e. Genz10850 228113 1.3.1.118 (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(1H-indole-5-carbonyl)-methanone 0.015 mM, 84% inhibition 228012 1.3.1.118 (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(4-methylbenzyl)-methanone 0.015 mM, 83% inhibition 228013 1.3.1.118 (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-benzyl-methanone 0.015 mM, 81% inhibition 228014 1.3.1.118 (4-benzylpiperidin-1-yl)(4-methylphenyl)methanone - 228115 1.3.1.118 (4-benzylpiperidin-1-yl)(p-tolyl)methanone - 228117 1.3.1.118 (4-methylphenyl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone 0.015 mM, 77% inhibition 228017 1.3.1.118 1-(2-furoyl)-4-[3-(2-ethylphenoxy)benzyl]piperazine 39.5% residual activity at 0.05 mM 260939 1.3.1.118 1-(2-furoyl)-4-[3-(2-methylphenoxy)benzyl]piperazine 41.2% residual activity at 0.05 mM 260940 1.3.1.118 1-(2-furoyl)-4-[3-(phenoxy)benzyl]piperazine KES4, potent inhibitor, 68% residual activity at 0.05 mM 262369 1.3.1.118 1-(2-furoyl)-4-[3-[2-(sec-butyl)phenoxy]benzyl]piperazine 48.8% residual activity at 0.05 mM 260941 1.3.1.118 1-(2-furoyl)-4-[3-[2-(tert-butyl)phenoxy]benzyl]piperazine 66.5% residual activity at 0.05 mM 260942 1.3.1.118 1-(2-furoyl)-4-[3-[3-(tert-butyl)phenoxy]benzyl]piperazine 63.9% residual activity at 0.05 mM 260943 1.3.1.118 1-(2-furoyl)-4-[3-[3-(trifluoromethyl)phenoxy]benzyl]piperazine 45.4% residual activity at 0.05 mM 260944 1.3.1.118 1-(2-furoyl)-4-[3-[4-(methoxycarbonylmethyl)phenoxy]benzyl]piperazine 83.4% residual activity at 0.05 mM 260945 1.3.1.118 1-cyclohexyl-N-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide - 68364 1.3.1.118 1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide - 68366 1.3.1.118 1-cyclohexyl-N-(5'-hydroxy-[1,1':4',1''-terphenyl]-2'-yl)-5-oxopyrrolidine-3-carboxamide - 228116 1.3.1.118 2-(2-bromophenoxy)-5-hexylphenol - 228088 1.3.1.118 2-(2-chloro-4-fluorophenyl)-N-(4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)phenyl)acetamide - 228045 1.3.1.118 2-(2-chlorophenoxy)-5-hexylphenol - 228087 1.3.1.118 2-(2-chlorophenoxy)-5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]phenol - 228094 1.3.1.118 2-(2-fluorophenoxy)-5-hexylphenol - 228086 1.3.1.118 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide - 228075 1.3.1.118 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide - 228082 1.3.1.118 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide - 228071 1.3.1.118 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide - 228065 1.3.1.118 2-(2-methylphenoxy)-5-[[4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl]phenol - 228093 1.3.1.118 2-(4-hexyl-2-hydroxyphenoxy)benzonitrile - 228089 1.3.1.118 2-(4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide - 228063 1.3.1.118 2-(4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide - 228057 1.3.1.118 2-(4-[[4-(2-bromoethyl)-1H-1,2,3-triazol-1-yl]methyl]-2-hydroxyphenoxy)benzonitrile - 228097 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide - 228068 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide - 228076 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide - 228083 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide - 228070 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide - 228072 1.3.1.118 2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide - 228066 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide - 228060 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide - 228074 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide - 228081 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide - 228062 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide - 228064 1.3.1.118 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide - 228058 1.3.1.118 2-(ethanesulfonyl)-6-[2-[(E)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol - 228107 1.3.1.118 2-(ethanesulfonyl)-7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol diazaborine, in vitro bactericidal activity against replicating bacteria active against several drug-resistant clinical isolates. AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. It shows good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibits dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection. AN12855 is a promising candidate for the development of new antitubercular agents 228102 1.3.1.118 2-(o-tolyloxy)-5-hexylphenol i.e. PT70, slow, tight binding inhibitor. It binds preferentially to the enzyme/NAD+x01complex and has a residence time of 24 min on the target, which is 14000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 A crystal structure of the ternary complex between InhA, NAD+, and PT70 reveals the molecular details of enzyme inhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket 41134 1.3.1.118 2-hexadecynoyl-CoA - 228108 1.3.1.118 2-octadecynoyl-CoA - 228109 1.3.1.118 2-[2-hydroxy-4-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]phenoxy]benzonitrile - 228096 1.3.1.118 2-[4-[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile - 228100 1.3.1.118 2-[4-[(4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile - 228101 1.3.1.118 2-[4-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile - 228095 1.3.1.118 2-[4-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile - 228098 1.3.1.118 4-(trifluoromethyl)-2-(4,5-dihydro-4-(2,4-dinitrophenyl)pyrazol-1-yl)pyrimidine i.e. Genz8575 228114 1.3.1.118 4-[[1-hydroxy-2-(methanesulfonyl)-1,2-dihydro-2,3,1-benzodiazaborinin-7-yl]oxy]benzonitrile - 228105 1.3.1.118 5-butyl-2-phenoxyphenol - 217530 1.3.1.118 5-ethyl-2-phenoxyphenol - 37709 1.3.1.118 5-hexyl-2-(2-methylphenoxy)phenol - 228085 1.3.1.118 5-hexyl-2-phenoxyphenol - 228111 1.3.1.118 5-octyl-2-phenoxyphenol - 217531 1.3.1.118 5-pentyl-2-phenoxyphenol - 89642 1.3.1.118 5-tetradecyl-2-phenoxyphenol - 228112 1.3.1.118 5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol - 228091 1.3.1.118 5-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol - 228099 1.3.1.118 5-[2-[(E)-(hydroxyimino)methyl]phenoxy]-2,1-benzoxaborol-1(3H)-ol - 228104 1.3.1.118 5-[[4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl]methyl]-2-(2-methylphenoxy)phenol - 228092 1.3.1.118 6-[4-(trifluoromethyl)phenoxy]-2,1-benzoxaborol-1(3H)-ol - 228103 1.3.1.118 7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2-(methanesulfonyl)-2,3,1-benzodiazaborinin-1(2H)-ol - 228106 1.3.1.118 9H-fluoren-9-yl-piperazine - 262368 1.3.1.118 Ethionamide the indirect inhibitor forms a covalent adduct with the cofactor 2142 1.3.1.118 Ethionamide the prodrug requires activation by EthA, a flavin-dependent monooxygenase. According to the crystal structure of InhA with bound ethionamide-NAD adduct, the ethyl-isonicotinic-acyl moiety is located in a hydrophobic pocket formed by the rearrangement of the side chain of Phe149, and an aromatic ringstacking interaction with the pyridine ring 2142 1.3.1.118 Genz10850 - 151189 1.3.1.118 GENZ8575 - 228047 1.3.1.118 isoniazid - 851 1.3.1.118 isoniazid fast and efficient inhibition of InhA in the presence of NADH and INH using MnIII-pyrophosphate as nonenzymatic reagent. This chemical oxidant might be a useful tool for further mechanistic studies of isoniazid activation in attempts to establish the exact structures of isoniazid reactive species and InhA inhibitor complex(es). 851 1.3.1.118 isoniazid the indirect inhibitor forms a covalent adduct with the cofactor, leading compound for antitubercular drug therapy 851 1.3.1.118 isoniazid a pro-drug, which is oxidatively activated in vivo by the katG-encoded mycobacterial catalase peroxidase to generate an isonicotinoyl radical. This highly reactive species then reacts nonenzymatically with the cellular pyridine nucleotide coenzymes, NAD+ and NADP+, to generate 12 isonicotinoyl-NAD(P)+ adducts. Of these, the acyclic 4S isomer of isoniazid-NAD+ and the acyclic 4R isomer of isoniazid-NADP+ inhibit the inhA-encoded enoyl-ACP reductase 851 1.3.1.118 isoniazid inhibits through the formation of an INH-NAD adduct which is a slow-onset inhibitor of InhA 851 1.3.1.118 isoniazid prodrug which is biologically activated by the Mycobacterium tuberculosis catalase-peroxidase KatG enzyme. The activation reaction promotes the formation of an isonicotinyl-NAD adduct which inhibits the InhA enzyme, resulting in reduction of mycolic acid biosynthesis 851 1.3.1.118 isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis 851 1.3.1.118 isoniazid as a pro-drug, isoniazid requires activation by KatG, a catalase-peroxidase enzyme with dual activities of catalase and peroxidase oxidizing isoniazid to an acyl radical binding to position 4 of nicotinamide adenine dinucleotide (NAD) to form an active isoniazid-NAD adduct. Addition of the isonicotinoyl radical to position 4 of the nicotinamide ring can result in two stereoisomersi n which only 4(S) isomers of isoniazid-NAD adduct possess potent activity 851 1.3.1.118 isoniazid inhibits InhA via formation of a covalent adduct with NAD+. KatG, the mycobacterial catalase-peroxidase, is essential for isoniazid activation. While cross-linking studies indicate that enzyme inhibition causes dissociation of the InhA tetramer into dimers, analytical ultracentrifugation and size exclusion chromatography reveal that ligand binding causes a conformational change in the protein that prevents cross-linking across one of the dimer-dimer interfaces in the InhA tetramer 851 1.3.1.118 isoniazid-coenzyme adduct inhibition by several types of isoniazid-coenzyme adducts coexisting in solution is discussed in relation with the structure of the coenzyme, the stereochemistry of the adducts, and their existence as both open and cyclic forms 228003 1.3.1.118 isoniazid-NAD+ - 170971 1.3.1.118 isoniazid-NADP competitive 228084 1.3.1.118 additional information SAR studies on novel inhibitor scaffolds. Inhibitor scaffolds include the diaryl ethers, pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles, arylamides, fatty acids, and imidazopiperidines, all of which form ternary complexes with InhA and the NAD cofactor, as well as isoniazid and the diazaborines which covalently modify the cofactor. Analysis of the structural data has enabled the development of a common binding mode for the ternary complex inhibitors, which includes a hydrogen bond network, a large hydrophobic pocket and a third size-limited binding area comprised of both polar and non-polar groups. A critical factor in InhA inhibition involves ordering of the substrate binding loop, located close to the active site, and a direct link is proposed between loop ordering and slow onset enzyme inhibition. Slow onset inhibitors have long residence times on the enzyme target, a property that is of critical importance for in vivo activity 2 1.3.1.118 additional information overview of 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors 2 1.3.1.118 additional information twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives are synthesized and evaluated for their in vitro Mycobacterium tuberculosis InhA inhibition. Compounds are evaluated for their in vitro activity against drug sensitive and resistant Mycobacterium tuberculosis strains and cytotoxicity against RAW 264.7 cell line. Compounds are docked at the active site of InhA to understand their binding mode and differential scanning fluorimetry is performed to ascertain their protein interaction and stability 2 1.3.1.118 additional information a series of piperazine derivatives is synthesized and screened as MtInhA inhibitors, which results in the identification of compounds with IC50 values in the submicromolar range 2 1.3.1.118 additional information the heterologous enzyme is ectopically expressed in a yeast mutant strain from which the native gene encoding the corresponding mitochondrial FASII enzyme is missing.Using an appropriate fungal mitochondrial leader sequence, the mycobacterial protein is directed to the mitochondria, where it can rescue the respiratory growth phenotype of the mutant. The rationale behind the assay is that added antimycolates are foreseen to inhibit the mycobacterial enzyme, thereby recreating the respiratory deficiency of the original mutant, discernible as poor colony formation and growth on glycerol medium 2 1.3.1.118 N-((4-bromo-1-ethyl-1H-pyrazol-5-yl)methyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide - 228033 1.3.1.118 N-(2,3-dichlorophenyl)-4-(1H-pyrrol-1-yl)benzamide anti-tuberculosis activity 228005 1.3.1.118 N-(2-aminophenyl)-4-(1H-pyrrol-1-yl)benzamide anti-tuberculosis activity 228007 1.3.1.118 N-(2-bromobenzyl)-4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzamide - 230278 1.3.1.118 N-(2-chloro-4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228021 1.3.1.118 N-(2-chloro-4-fluorobenzyl)-4-((4-methylthiazol-2-yl)methyl)-benzamide - 228041 1.3.1.118 N-(2-chloro-5-(2-phenylacetamido)benzyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide - 228036 1.3.1.118 N-(2-chloro-5-(3-phenylureido)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228035 1.3.1.118 N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide - 228067 1.3.1.118 N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide - 228059 1.3.1.118 N-(2-chloro-5-aminobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228034 1.3.1.118 N-(2-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228023 1.3.1.118 N-(2-nitrobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228025 1.3.1.118 N-(2-nitrophenyl)-4-(1H-pyrrol-1-yl)benzamide anti-tuberculosis activity 228008 1.3.1.118 N-(2-trifluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-benzamide - 228022 1.3.1.118 N-(3-bromobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228026 1.3.1.118 N-(3-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228027 1.3.1.118 N-(3-fluorophenyl)-4-(1H-pyrrol-1-yl)benzamide anti-tuberculosis activity 228006 1.3.1.118 N-(3-methanesulfonybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)benzamide - 228029 1.3.1.118 N-(3-propan-2-yloxybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228024 1.3.1.118 N-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)benzamide anti-tuberculosis activity 228004 1.3.1.118 N-(4-fluoro-2-(trifluoromethyl)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228030 1.3.1.118 N-(4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228031 1.3.1.118 N-(5-nitrothiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide - 228073 1.3.1.118 N-(6-nitrobenzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide - 228080 1.3.1.118 N-(benzo[d]thiazol-2-yl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide - 228078 1.3.1.118 N-(benzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide - 228077 1.3.1.118 N-(benzo[d]thiazol-2-yl)-2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide - 228079 1.3.1.118 N-(benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide - 228028 1.3.1.118 N-(furan-2-yl-methyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide - 228061 1.3.1.118 N-(furan-2-ylmethyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide - 228069 1.3.1.118 N-([1,1'-biphenyl]-4-yl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide - 228118 1.3.1.118 N-[(1-[[3-hydroxy-4-(2-methylphenoxy)phenyl]methyl]-1H-1,2,3-triazol-4-yl)methyl]cyclopropanecarboxamide - 228090 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide - 228042 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(3-methyl-1H-pyrazol-1-yl)methyl]benzamide - 228037 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)-oxy]benzamide - 228039 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)methyl]benzamide - 228044 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)sulfanyl]benzamide - 228040 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[(dimethyl-1,3-thiazol-2-yl)methyl]benzamide - 228043 1.3.1.118 N-[(2-chloro-4-fluorophenyl)methyl]-4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzamide - 228038 1.3.1.118 N-[(4-fluorophenyl)methyl]-4-[[2-methyl-5-(2,2,2-trifluoroethyl)furan-3-yl]methyl]benzamide - 228032 1.3.1.118 NAD+ linear competitive inhibitor versus NADH 7 1.3.1.118 pentacyano(isoniazid)ferrate(II) the inorganic complex inhibits both wild-type and isoniazid-resistant Ile21Val mutants of InhA and this inactivation did not require activation by KatG. Molecular dynamics simulations show that the interaction of pentacyano(isoniazid)ferrate(II) with InhA leads to macromolecular instabilities reflected in the long time necessary for simulation convergence. These instabilities are mainly due to perturbation of the substrate binding loop, particularly the partial denaturation of helices alpha6 and alpha7 174596 1.3.1.118 prothionamide the prodrug requires activation by EthA, a flavin-dependent monooxygenase. According to the crystal structure of InhA with bound prothionamide-NAD adduct, the propyl-isonicotinic-acyl moiety is located in a hydrophobic pocket formed by the rearrangement of the side chain of Phe149, and an aromatic ringstacking interaction with the pyridine ring 228110 1.3.1.118 triclosan demonstration of triclosan inhibition of InhA in yeast represents a meaningful variation in studying this effect in mycobacteria, because it occurrs without the potentially confusing aspects of perturbing protein-protein interactions which are presumed vital to mycobacterial FASII, inactivating other important enzymes or eliciting a dedicated transcriptional response in Mycobacterium tuberculosis 744 1.3.1.118 triclosan uncompetitive inhibitor 744 1.3.1.118 triclosan - 744 1.3.1.118 Trp-Tyr-Trp structure-based computer modelling approach to design a tripeptide inhibitor. Docking studies indicate that the designed peptide has potency 100 times higher than the best known inhibitor. The results suggest that the designed inhibitor is a suitable lead compound for the development of novel anti-TB drugs 228046 1.3.1.118 [4-(9H-fluoren-9-yl) piperazin-1-yl]-benzyl-methanone 0.015 mM, 97% inhibition 228010 1.3.1.118 [4-(9H-fluoren-9-yl)piperazin-1-yl](1H-indol-5-yl)methanone 0.015 mM, 94% inhibition 228011 1.3.1.118 [4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone 0.015 mM, 67% inhibition 228020 1.3.1.118 [4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](4-methylphenyl)methanone 0.015 mM, 74% inhibition 228018 1.3.1.118 [4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone 0.015 mM, 81% inhibition 228016 1.3.1.118 [4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](phenyl)methanone 0.015 mM, 81% inhibition 228015