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Information on EC 1.3.1.118 - meromycolic acid enoyl-[acyl-carrier-protein] reductase
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1.3.1.118 meromycolic acid enoyl-[acyl-carrier-protein] reductaseIUBMB Comments
InhA is a component of the fatty acid synthase (FAS) II system of Mycobacterium tuberculosis, catalysing an enoyl-[acyl-carrier-protein] reductase step. The enzyme acts on very long and unsaturated fatty acids that form the meromycolic component of mycolic acids. It extends FASI-derived C20 fatty acids to form C60 to C90 mycolic acids. The enzyme, which forms a homotetramer, is the target of the preferred antitubercular drug isoniazid.
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Word Map
- 1.3.1.118
- tuberculosis
- mycobacterium
- isoniazid
- ethionamide
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antituberculous
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isonicotinic
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drug-targeted
- pharmacology
- fas-ii
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antitubercular
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
inha protein, enoyl-acp reductase inha, 2-trans-enoyl-acyl carrier protein reductase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
2-trans-enoyl-ACP reductase
2-trans-enoyl-acyl carrier protein reductase
enoyl acyl carrier protein reductase
enoyl acyl carrier protein reductase InhA
enoyl-ACP reductase
enoyl-ACP reductase InhA
enoyl-acyl carrier protein reductase
FAS-II enoyl reductase
InhA
InhA Protein
MtInhA
InhA
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InhA
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a meromycolyl-[acyl-carrier protein] + NAD+ = a trans-DELTA2-meromycolyl-[acyl-carrier protein] + NADH + H+
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
meromycolyl-[acyl-carrier protein]:NAD+ oxidoreductase
InhA is a component of the fatty acid synthase (FAS) II system of Mycobacterium tuberculosis, catalysing an enoyl-[acyl-carrier-protein] reductase step. The enzyme acts on very long and unsaturated fatty acids that form the meromycolic component of mycolic acids. It extends FASI-derived C20 fatty acids to form C60 to C90 mycolic acids. The enzyme, which forms a homotetramer, is the target of the preferred antitubercular drug isoniazid.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
trans-2-octenoyl-[acyl-carrier protein] + NADH + H+
octanoyl-[acyl-carrier protein] + NAD+
trans-2-decenoyl-CoA + NADH + H+
decanoyl-CoA + NAD+
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?
trans-2-decenoyl-CoA + NADH + H+
decanoyl-CoA + NAD+
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?
trans-2-decenoyl-CoA + NADH + H+
decanoyl-CoA + NAD+
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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pre-steady state kinetics and equilibrium data of 2-trans-dodecenoyl-CoA substrate binding to InhA. The results indicate both positive homotropic cooperativity upon substrate binding to InhA, and a bimolecular association process followed by a slow isomerization of the enzyme-substrate binary complex
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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?
trans-2-dodecenoyl-CoA + NADH + H+
dodecanoyl-CoA + NAD+
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?
trans-2-hexadecenoyl-CoA + NADH + H+
hexadecanoyl-CoA + NAD+
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?
trans-2-hexadecenoyl-CoA + NADH + H+
hexadecanoyl-CoA + NAD+
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?
trans-2-octenoyl-CoA + NADH + H+
octanoyl-CoA + NAD+
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?
trans-2-octenoyl-CoA + NADH + H+
octanoyl-CoA + NAD+
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?
trans-2-octenoyl-[acyl-carrier protein] + NADH + H+
octanoyl-[acyl-carrier protein] + NAD+
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?
trans-2-octenoyl-[acyl-carrier protein] + NADH + H+
octanoyl-[acyl-carrier protein] + NAD+
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?
additional information
?
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no activity with crotonoyl-CoA. The enzyme preferentially reduces long-chain 2-trans-enoyl-ACP substrates (12-24 carbons). The two substrates bind to InhA via a sequential kinetic mechanism, with the preferred ordered addition of NADH and the enoyl substrate. The chemical mechanism involves stereospecific hydride transfer of the 4S hydrogen of NADH to the C3 position of the 2-trans-enoyl substrate, followed by protonation at C2 of an enzymestabilized enolate intermediate
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additional information
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no activity with crotonoyl-CoA. The enzyme preferentially reduces long-chain 2-trans-enoyl-ACP substrates (12-24 carbons). The two substrates bind to InhA via a sequential kinetic mechanism, with the preferred ordered addition of NADH and the enoyl substrate. The chemical mechanism involves stereospecific hydride transfer of the 4S hydrogen of NADH to the C3 position of the 2-trans-enoyl substrate, followed by protonation at C2 of an enzymestabilized enolate intermediate
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?
additional information
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no activity with crotonoyl-CoA. The enzyme preferentially reduces long-chain 2-trans-enoyl-ACP substrates (12-24 carbons). The two substrates bind to InhA via a sequential kinetic mechanism, with the preferred ordered addition of NADH and the enoyl substrate. The chemical mechanism involves stereospecific hydride transfer of the 4S hydrogen of NADH to the C3 position of the 2-trans-enoyl substrate, followed by protonation at C2 of an enzymestabilized enolate intermediate
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?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADH
although very flexible, in the wild-type enzyme/NADH complex, the NADH molecule keeps its extended conformation firmly bound to the binding site of the enzyme
NADH
while NADH binding to wild-type InhA is hyperbolic, the InhA mutants bind the cofactor with positive cooperativity, suggesting that the mutations permit access to a second conformational state of the protein
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1H-indol-5-yl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone
0.015 mM, 74% inhibition
(4-(9H-fluoren-9-yl) piperazin-1-yl)-(4-methylbenzyl)-methanone
0.015 mM, 99% inhibition
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2,5-difluorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (2-fluorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (3-fluorophenyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-Fluoren-9-yl)piperazin-1-yl) (3-tolyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-chlorophenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-fluorophenyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-methoxyphenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (4-tolyl)methanone
uncompetitive versus NADH, competitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl) (phenyl)methanone
uncompetitive versus NADH, noncompetitive versus trans-2-dodecenoyl-CoA
(4-(9H-fluoren-9-yl)piperazin-1-yl)(indolin-5-yl)methanone
i.e. Genz10850
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(1H-indole-5-carbonyl)-methanone
0.015 mM, 84% inhibition
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-(4-methylbenzyl)-methanone
0.015 mM, 83% inhibition
(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-benzyl-methanone
0.015 mM, 81% inhibition
(4-methylphenyl)[4-[(4-methylphenyl)(phenyl)methyl]piperazin-1-yl]methanone
0.015 mM, 77% inhibition
1-(2-furoyl)-4-[3-(2-ethylphenoxy)benzyl]piperazine
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39.5% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-(2-methylphenoxy)benzyl]piperazine
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41.2% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-(phenoxy)benzyl]piperazine
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KES4, potent inhibitor, 68% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-[2-(sec-butyl)phenoxy]benzyl]piperazine
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48.8% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-[2-(tert-butyl)phenoxy]benzyl]piperazine
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66.5% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-[3-(tert-butyl)phenoxy]benzyl]piperazine
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63.9% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-[3-(trifluoromethyl)phenoxy]benzyl]piperazine
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45.4% residual activity at 0.05 mM
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1-(2-furoyl)-4-[3-[4-(methoxycarbonylmethyl)phenoxy]benzyl]piperazine
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83.4% residual activity at 0.05 mM
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1-cyclohexyl-N-(2,5-dimethylphenyl)-5-oxopyrrolidine-3-carboxamide
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1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide
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1-cyclohexyl-N-(5'-hydroxy-[1,1':4',1''-terphenyl]-2'-yl)-5-oxopyrrolidine-3-carboxamide
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2-(2-chloro-4-fluorophenyl)-N-(4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)phenyl)acetamide
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2-(2-chlorophenoxy)-5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]phenol
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2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
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2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
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2-(2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
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2-(2-methylphenoxy)-5-[[4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl]phenol
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2-(4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
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2-(4-[[4-(2-bromoethyl)-1H-1,2,3-triazol-1-yl]methyl]-2-hydroxyphenoxy)benzonitrile
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
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2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-phenylacetamide
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2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(2-chloro-5-(trifluoromethyl)phenyl)acetamide
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2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(5-nitrothiazol-2-yl)acetamide
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2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide
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2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(furan-2-ylmethyl)acetamide
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2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N-(thiophen-2-ylmethyl)acetamide
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2-(ethanesulfonyl)-6-[2-[(E)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2,3,1-benzodiazaborinin-1(2H)-ol
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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
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
2-[2-hydroxy-4-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]phenoxy]benzonitrile
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2-[4-[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
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2-[4-[(4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
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2-[4-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
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2-[4-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
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4-(trifluoromethyl)-2-(4,5-dihydro-4-(2,4-dinitrophenyl)pyrazol-1-yl)pyrimidine
i.e. Genz8575
4-[[1-hydroxy-2-(methanesulfonyl)-1,2-dihydro-2,3,1-benzodiazaborinin-7-yl]oxy]benzonitrile
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5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol
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5-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol
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5-[2-[(E)-(hydroxyimino)methyl]phenoxy]-2,1-benzoxaborol-1(3H)-ol
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5-[[4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl]methyl]-2-(2-methylphenoxy)phenol
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7-[2-[(Z)-(hydroxyimino)methyl]-4-(trifluoromethyl)phenoxy]-2-(methanesulfonyl)-2,3,1-benzodiazaborinin-1(2H)-ol
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isoniazid-coenzyme adduct
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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
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N-((4-bromo-1-ethyl-1H-pyrazol-5-yl)methyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
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N-(2,3-dichlorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-aminophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-bromobenzyl)-4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]benzamide
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N-(2-chloro-4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(2-chloro-4-fluorobenzyl)-4-((4-methylthiazol-2-yl)methyl)-benzamide
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N-(2-chloro-5-(2-phenylacetamido)benzyl)-4-((3,5-dimethyl-1Hpyrazol-1-yl)methyl)benzamide
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N-(2-chloro-5-(3-phenylureido)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
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N-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
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N-(2-chloro-5-aminobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(2-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(2-nitrobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(2-nitrophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(2-trifluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-benzamide
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N-(3-bromobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(3-chlorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(3-fluorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(3-methanesulfonybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)-methyl)benzamide
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N-(3-propan-2-yloxybenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(4-chlorophenyl)-4-(1H-pyrrol-1-yl)benzamide
anti-tuberculosis activity
N-(4-fluoro-2-(trifluoromethyl)benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(4-fluorobenzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(5-nitrothiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
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N-(6-nitrobenzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
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N-(benzo[d]thiazol-2-yl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
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N-(benzo[d]thiazol-2-yl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
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N-(benzo[d]thiazol-2-yl)-2-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
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N-(benzyl)-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamide
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N-(furan-2-yl-methyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide
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N-(furan-2-ylmethyl)-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide
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N-([1,1'-biphenyl]-4-yl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide
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N-[(1-[[3-hydroxy-4-(2-methylphenoxy)phenyl]methyl]-1H-1,2,3-triazol-4-yl)methyl]cyclopropanecarboxamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(3-methyl-1H-pyrazol-1-yl)methyl]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)-oxy]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)methyl]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(6-methylpyridin-2-yl)sulfanyl]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[(dimethyl-1,3-thiazol-2-yl)methyl]benzamide
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N-[(2-chloro-4-fluorophenyl)methyl]-4-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzamide
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N-[(4-fluorophenyl)methyl]-4-[[2-methyl-5-(2,2,2-trifluoroethyl)furan-3-yl]methyl]benzamide
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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
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
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
[4-(9H-fluoren-9-yl) piperazin-1-yl]-benzyl-methanone
0.015 mM, 97% inhibition
[4-(9H-fluoren-9-yl)piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 94% inhibition
[4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 67% inhibition
[4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl](4-methylphenyl)methanone
0.015 mM, 74% inhibition
[4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](1H-indol-5-yl)methanone
0.015 mM, 81% inhibition
[4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl](phenyl)methanone
0.015 mM, 81% inhibition
Ethionamide
the indirect inhibitor forms a covalent adduct with the cofactor
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
isoniazid
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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).
isoniazid
the indirect inhibitor forms a covalent adduct with the cofactor, leading compound for antitubercular drug therapy
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
isoniazid
inhibits through the formation of an INH-NAD adduct which is a slow-onset inhibitor of InhA
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
isoniazid
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acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis
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
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
triclosan
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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
additional information
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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
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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
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additional information
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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
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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
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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
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additional information
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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
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Tuberculosis
A Structural and Energetic Model for the Slow-Onset Inhibition of the Mycobacterium tuberculosis Enoyl-ACP Reductase InhA.
Tuberculosis
Acetylation of Isoniazid Is a Novel Mechanism of Isoniazid Resistance in Mycobacterium tuberculosis.
Tuberculosis
Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis.
Tuberculosis
Computational approach identifies protein off-targets for Isoniazid-NAD adduct: hypothesizing a possible drug resistance mechanism in Mycobacterium tuberculosis.
Tuberculosis
Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis.
Tuberculosis
Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate.
Tuberculosis
Determination of the primary target for isoniazid in mycobacterial mycolic acid biosynthesis with Mycobacterium aurum A+.
Tuberculosis
Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis.
Tuberculosis
InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II.
Tuberculosis
Mn(III) pyrophosphate as an efficient tool for studying the mode of action of isoniazid on the InhA protein of Mycobacterium tuberculosis.
Tuberculosis
Multidimensional infrared spectroscopy reveals the vibrational and solvation dynamics of isoniazid.
Tuberculosis
Rational Modulation of the Induced-Fit Conformational Change for Slow-Onset Inhibition in Mycobacterium tuberculosis InhA.
Tuberculosis
The activity of Levisticum officinale W.D.J. Koch essential oil against multidrug-resistant Mycobacterium tuberclosis.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0015
trans-2-hexadecenoyl-CoA
pH 6.8, 25°C, wild-type enzyme
0.0045
NADH
pH 6.8, 25°C, cosubstrate: trans-2-hexadecenoyl-CoA, wild-type enzyme
0.0058
NADH
pH 6.8, 25°C, cosubstrate: trans-2-dodecenoyl-CoA, wild-type enzyme
0.0076
NADH
pH 6.8, 25°C, cosubstrate: trans-2-octenoyl-CoA, wild-type enzyme
0.0081
NADH
pH 6.8, 25°C, cosubstrate: trans-2-octenoyl-[acyl-carrier protein], wild-type enzyme
0.0373
NADH
pH 6.8, 25°C, cosubstrate: trans-2-octenoyl-[acyl-carrier protein], mutant enzyme S94A
0.065
NADH
pH 6.8, 25°C, cosubstrate: trans-2-octenoyl-CoA, mutant enzyme S94A
0.0196
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266D
0.0203
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266E
0.0409
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, wild-type enzyme
0.048
trans-2-dodecenoyl-CoA
pH 6.8, 25°C, wild-type enzyme
0.0523
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266A
0.688
trans-2-octenoyl-CoA
pH 6.8, 25°C, mutant enzyme S94A
0.002
trans-2-octenoyl-[acyl-carrier protein]
pH 6.8, 25°C, wild-type enzyme
-
0.0027
trans-2-octenoyl-[acyl-carrier protein]
pH 6.8, 25°C, mutant enzyme S94A
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.46
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266D
2.49
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266E
7.12
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266A
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
74.49
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266D
122.7
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266E
130.6
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, wild-type enzyme
136.13
trans-2-dodecenoyl-CoA
pH 7.5, 25°C, mutant enzyme T266A
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.016
2-(2-chlorophenoxy)-5-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]phenol
pH 6.8, 23°C
0.006
2-(2-methylphenoxy)-5-[[4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl]methyl]phenol
pH 6.8, 23°C
0.0071
2-(4-[[4-(2-bromoethyl)-1H-1,2,3-triazol-1-yl]methyl]-2-hydroxyphenoxy)benzonitrile
pH 6.8, 23°C
0.028
2-[2-hydroxy-4-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]phenoxy]benzonitrile
pH 6.8, 23°C
0.0063
2-[4-[(4-cyclohexyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
pH 6.8, 23°C
0.083
2-[4-[(4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
pH 6.8, 23°C
0.099
2-[4-[(4-cyclopropyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
pH 6.8, 23°C
0.05
2-[4-[(4-ethyl-1H-1,2,3-triazol-1-yl)methyl]-2-hydroxyphenoxy]benzonitrile
pH 6.8, 23°C
0.0000094
5-hexyl-2-phenoxyphenol
pH and temperature not specified in the publication
0.0000011
5-octyl-2-phenoxyphenol
pH and temperature not specified in the publication
0.0000118
5-pentyl-2-phenoxyphenol
pH and temperature not specified in the publication
0.00003
5-tetradecyl-2-phenoxyphenol
pH and temperature not specified in the publication