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(1H-indol-1-yl)acetic acid
-
(2,3-dihydrocyclopenta[b]indol-4(1H)-yl)acetic acid
-
(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetic acid
32.8% inhibition at 0.010 mM
(3-sulfanyl-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid
-
(3-[[(2-fluorophenyl)methyl]sulfanyl]-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid
-
(3-[[2-oxo-2-(2,4,6-trimethylanilino)ethyl]sulfanyl]-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid
-
(4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indol-5-yl)acetic acid
-
(6H-indolo[2,3-b]quinoxalin-6-yl)acetic acid
-
(7H-indolo[2',3':5,6][1,2,4]triazino[2,3-a]benzimidazol-7-yl)acetic acid
-
(8-methyl-3-[[2-oxo-2-(propylamino)ethyl]sulfanyl]-5H-[1,2,4]triazino[5,6-b]indol-5-yl)acetic acid
-
1-(2-(bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine
i.e. GBR13069. 0.08 mM, 61% inhibition
1-(2-diphenylmethoxyethyl)-4-(3-phenyl-2-propenyl)-piperazine
GBR12783, i.e. 0.08 mM, 59% inhibition
1-(4-nitrobenzyl)-3-(4-(2-morpholinoethyl) piperazin-1-yl)quinoxalin-2(1H)-one
23% inhibition
1-(4-nitrobenzyl)-3-(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl) quinoxalin-2(1H)-one
43% inhibition
1-(4-nitrobenzyl)-3-(4-(4-methoxyphenyl) piperazin-1-yl)quinoxalin-2(1H)-one
26% inhibition
1-(4-nitrobenzyl)-3-(4-(pyrazin-2-yl) piperazin-1-yl)quinoxalin-2(1H)-one
24% inhibition
1-(4-nitrobenzyl)-3-styrylquinoxalin-2(1H)-one
30% inhibition
12-ketochenodeoxycholic acid
-
inhibition of the ADH from Lactobacillus brevis by bile acids, acetone prevents partially
2,3-dimethylsuccinic acid
2,4-dimethylglutaric acid
-
-
2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione
-
2-(2-oxo-3-phenethylquinoxalin-1(2H)-yl) acetic acid
-
2-(2-oxo-3-styrylquinoxalin-1(2H)-yl) acetic acid
-
2-(3,7-bis(4-fluorophenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
41.0% inhibition at 0.010 mM
2-(3-(2,4-difluorophenylamino)-6-nitro-2-oxoquinoxalin-1(2H)-yl) acetic acid
-
2-(3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
36.6% inhibition at 0.010 mM
2-(3-(3-(tert-butylamino)-3-oxoprop-1-en-1-yl)-2-oxoquinoxalin-1(2H)-yl) acetic acid
-
2-(3-(3-indolyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
32.3% inhibition at 0.010 mM
2-(3-(4-(4-methoxyphenyl) piperazin-1-yl)-2-oxoquinoxalin-1(2H)-yl) acetic acid
-
2-(3-(4-bromothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid
12.8% inhibition at 0.010 mM
2-(3-(4-chlorothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid
42.4% inhibition at 0.010 mM
2-(3-(4-fluorophenethyl)-2-oxoquinoxalin-1(2H)-yl) acetic acid
-
2-(3-(4-fluorophenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
31.8% inhibition at 0.010 mM
2-(3-(4-fluorostyryl)-2-oxoquinoxalin-1(2H)-yl) acetic acid
-
2-(3-(4-fluorostyryl)-6-nitro-2-oxoquinoxalin-1(2H)-yl)acetic acid
-
2-(3-(4-hydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
34.6% inhibition at 0.010 mM
2-(3-phenoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid
6.6% inhibition at 0.010 mM
2-(3-phenyl-2-oxoquinoxalin-1(2H)-yl)acetic acid
25.4% inhibition at 0.010 mM
2-(3-thiophenoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid
32.2% inhibition at 0.010 mM
2-(6-bromo-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
38.1% inhibition at 0.010 mM
2-(6-bromo-3-(4-bromothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
8.7% inhibition at 0.010 mM
2-(6-chloro-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
46.5% inhibition at 0.010 mM
2-(6-chloro-3-(4-fluorostyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
-
2-(6-fluoro-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
42.5% inhibition at 0.010 mM
2-(7-(4-fluorobenzyl)-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
11.6% inhibition at 0.010 mM
2-(7-bromo-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
35.9% inhibition at 0.010 mM
2-(7-bromo-3-(3-indolyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
17.5% inhibition at 0.010 mM
2-(7-bromo-3-(4-bromothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
24.0% inhibition at 0.010 mM
2-(7-bromo-3-(4-chlorothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
10.2% inhibition at 0.010 mM
2-(7-chloro-2-oxo-3-styrylquinoxalin-1(2H)-yl) acetic acid
-
2-(7-chloro-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
44.5% inhibition at 0.010 mM
2-(7-chloro-3-(2-benzothiophene)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
53.3% inhibition at 0.010 mM
2-(7-chloro-3-(4-bromothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
14.1% inhibition at 0.010 mM
2-(7-chloro-3-(4-chlorothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
17.3% inhibition at 0.010 mM
2-(7-chloro-3-(4-fluorophenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
23.6% inhibition at 0.010 mM
2-(7-fluoro-3-(2,4-dihydroxyphenyl)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
46.2% inhibition at 0.010 mM
2-(7-fluoro-3-(4-bromothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
45.5% inhibition at 0.010 mM
2-(7-fluoro-3-(4-chlorothiophenoxy)-2-oxoquinoxalin-1(2H)-yl)-acetic acid
29.5% inhibition at 0.010 mM
2-(7-fluoro-3-(4-fluorophenyl)-2-oxoquinoxalin-1(2H)-yl)acetic acid
35.8% inhibition at 0.010 mM
20alpha-hydroxysteroid dehydrogenase
competitive inhibition, the inhibitor forms a 10fold stronger binding interaction with the catalytic residue (Tyr55), non-conserved hydrogen bonding interaction with His222, and additional van der Waals contacts with the non-conserved C-terminal residues Leu306, Leu308 and Phe311 that contribute to the inhibitor's selectivity advantage for 20alpha-hydroxysteroid dehydrogenase over 3,5-dichlorosalicylic acid
-
3,3'-tetramethylenglutaric acid
3,3-dimethylglutaric acid
-
-
3,5-dichlorosalicylic acid
mixed type of competitive and non-competitive patterns with respect to the substrate. The inhibitor forms a network of hydrogen bonds with the active site residues Trp22, Tyr50, His113, Trp114 and Arg312. Is a less potent inhibitor of ALR1 (256fold) when compared to 20alpha-hydroxysteroid dehydrogenase
3-(1H-indol-1-yl)propanoic acid
-
3-(4-fluorostyryl)-1-(4-nitrobenzyl) quinoxalin-2(1H)-one
24% inhibition
3-(benzo[b] thiophen-3-yl)-1-(4-nitrobenzyl)quinoxalin-2(1H)-one
32% inhibition
3-[3-[(diethylamino)methyl]-1H-indol-1-yl]propanoic acid
-
4-carboxybenzaldehyde
-
uncompetitive substrate inhibition
4-chloromercuribenzoate
-
1 mM, complete inactivation
5,5'-dithiobis-(2-nitrobenzoate)
-
-
AL-1576
0.5 microM, (10 x KI), 13fold higher affinity for aldehyde reductase than for aldose reductase; 0.5 microM, (10 x KI), 13fold higher affinity for aldehyde reductase than for aldose reductase, reversible
Al3+
1 mM, 14.7% of initial activity
ascorbic acid
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 24%
ATP-ribose
-
competitive inhibition
beta-mercaptoethanol
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 25%
Cd2+
1 mM, complete inhibition
cholic acid
-
inhibition of the ADH from Lactobacillus brevis by bile acids, acetone prevents partially
D-glucuronate
-
high concentrations, inhibition in a non-competitive manner
diethyldicarbonate
-
kidney aldehyde reductase
diethyldithiocarbamate
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 50%, 0.25 mM inhibits by 39%
dipyridyl
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 54%, 0.25 mM inhibits by 41%
Dithionite
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 75%, 0.25 mM inhibits by 92%
dithiothreitol
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 24%
Dodecanol
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 46%, 0.25 mM inhibits by 45%
flunarizine
0.08 mM, 54% inhibition
glycerol
-
non-competitive inhibitor with D-glyceraldehyde as substrate
K+
1 mM, 82.3% of initial activity
L-Gulonic acid
-
product inhibition
lidorestat
binding mode, overview
N-(tert-butyl)-3-(4-(4-nitrobenzyl)-3-oxo-3, 4-dihydroquinoxalin-2-yl) acryl amide
36% inhibition
NaN3
1 mM, complete loss of activity
Phenylmethylsulfonylfluoride
-
lower molecular weight form
phenylpyruvic acid
-
low-molecular weight aldehyde reductase, noncompetitively inhibition
SDS
1 mM,0% of initial activity
[(5H-[1,2,4]triazino[5,6-b]indol-3-yl)sulfanyl]acetic acid
-
[2-oxo-3-(2-phenylethyl)quinoxalin-1(2H)-yl]acetic acid
22.0% inhibition at 0.010 mM
[2-oxo-3-[(Z)-2-phenylethenyl]quinoxalin-1(2H)-yl]acetic acid
32.0% inhibition at 0.010 mM
[3-(2,2-dimethylpropanoyl)-1H-indol-1-yl]acetic acid
-
[3-[(diethylamino)methyl]-1H-indol-1-yl]acetic acid
-
[3-[(dimethylamino)methyl]-2-methyl-1H-indol-1-yl]acetic acid
-
[3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
32.6% inhibition at 0.010 mM
[3-[(E)-2-(4-hydroxyphenyl)ethenyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
42.4% inhibition at 0.010 mM
[3-[(E)-2-(4-methoxyphenyl)ethenyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
21.8% inhibition at 0.010 mM
[3-[(morpholin-4-yl)methyl]-1H-indol-1-yl]acetic acid
-
[3-[(propan-2-yl)sulfanyl]-5H-[1,2,4]triazino[5,6-b]indol-5-yl]acetic acid
-
[3-[(pyrrolidin-1-yl)methyl]-1H-indol-1-yl]acetic acid
-
[3-[2-(4-hydroxyphenyl)ethyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
12.2% inhibition at 0.010 mM
[5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
crystallization data. The rotameric state of the conserved residue Trp220 in aldehyde reductase ALR1, i.e Trp 219 in aldose reductase ALR2, is important in forming a pi-stacking interaction with the inhibitor in aldose reductase and contributes to the difference in the binding of the inhibitor to the enzymes; i.e. CMD, a potent inhibitor of ALR2, but not for ALR1. For binding to ALR1, the partially disordered inhibitor forms a tight network of hydrogen bonds with the active site residues Tyr50 and His113 and NADPH, structure molecular modelling, overview. The non-conserved C-terminal residue Leu300 in ALR2, which is Pro301 in ALR1, contributes to inhibitor selectivity
[5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid
i.e. HMD, modelling of inhibitor-enzyme active site complex
[7-fluoro-3-[(E)-2-(4-hydroxyphenyl)ethenyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
36.2% inhibition at 0.010 mM
[7-fluoro-3-[2-(4-hydroxyphenyl)ethyl]-2-oxoquinoxalin-1(2H)-yl]acetic acid
23.0% inhibition at 0.010 mM
1,10-phenanthroline
-
in 250 mM glycine-NaOH buffer (pH 9.0), purified water and 20 mM heptanal, at 5 mM inhibits by 16% and at 10 mM inhibits by 68% in the presence of 10 mM NADH, at 5 mM inhibits by 25% and at 10 mM inhibits by 63% in the presence of 10 mM NADPH
2,3-dimethylsuccinic acid
-
-
2,3-dimethylsuccinic acid
-
-
3,3'-tetramethylenglutaric acid
-
-
3,3'-tetramethylenglutaric acid
-
AR1 and AR3
3,3'-tetramethylenglutaric acid
-
-
3,3'-tetramethylenglutaric acid
-
3,3'-tetramethylenglutaric acid
-
-
acetone
-
at high concentrations of e.g. 3.4 M
acetone
-
at high concentrations of e.g. 3.4 M
AL1576
-
-
Alconil
-
-
Alrestatin
-
-
benzodiazepine
-
-
Ca2+
-
26% inhibition
Ca2+
1 mM, 0% of initial activity
chlorpromazine
-
-
chlorpromazine
-
isozyme AR3
Cibacron blue F3GA
-
dead-end inhibitor
Co2+
-
91% inhibition
Co2+
1 mM, 68.7% of initial activity
Cu2+
1 mM, 14.0% of initial activity
Cu2+
1 mM, complete loss of activity
Cu2+
1 mM, complete inhibition
Diphenic acid
-
-
EDTA
-
0.5 mM, about 15% residual activity
EDTA
Marinobacter nauticus VT8
-
in 100 mM MES buffer (pH 6.5) with 200 mM NADPH, 0.25 mM decanal, and 125 microg of FALDR fusion protein. 1 mM inhibits by 19%
EDTA
0.1 mM, 38% residual activity. Activity is completely restored by the addition of 1 mM Co2+ and to 37% by addition of Ni2+, respectively
EDTA
-
lower molecular weight form
EDTA
1 mM, slightly decreased the enzyme activity
EDTA
5 mM, 80% of initial activity
epalrestat
-
-
epalrestat
73.6% inhibition at 0.010 mM
Fe2+
1 mM, 10-20% decrease in activity
Fe2+
10 mM, 74% of initial activity
fidarestat
-
interaction with the residues Tyr50, His113, Trp114 and Pro301
fidarestat
-
van der Waals contacts, with residues His110, Tyr48, and Trp111
FK366
-
-
Hg2+
-
100% inhibition
Hg2+
1 mM, complete inhibition
iodoacetamide
-
-
iodoacetic acid
1 mM, 72.6% residual activity
Li2SO4
-
aldehyde reductase I inhibited by 86%, aldehyde reductase II is not affected
Li2SO4
-
0.4 mM completely inhibits aldehyde reductase II
Li2SO4
-
both aldehyde reductase I and II are susceptible to inhibition
Mg2+
1 mM, 0.3% of initial activity
Mg2+
10 mM, 78% of initial activity
Mn2+
-
29% inhibition
Mn2+
1 mM, 23.4% of initial activity
N-ethylmaleimide
-
-
NaCl
-
aldehyde reductase I and II
NADP+
-
product inhibition
NADP+
-
competitive inhibition
NADPH
-
product inhibition
NADPH
strong inhibition at high NADPH concentrations, assay below 0.8 mM
NADPH
-
competitive inhibitor for reductase I
Ni2+
-
84% inhibition
Ni2+
1 mM, 18.2% of initial activity
Ni2+
1 mM, 10-20% decrease in activity
p-chloromercuribenzoate
-
-
p-chloromercuribenzoate
-
-
p-hydroxymercuribenzoate
-
-
p-hydroxymercuribenzoate
-
in 250 mM glycine-NaOH buffer (pH 9.0), purified water and 20 mM heptanal, at 10 mM inhibits by 100% in the presence of 10 mM NADH, at 10 mM inhibits by 95% and at 15 mM inhibits by 100% in the presence of 10 mM NADPH
p-mercuribenzoate
-
-
p-mercuribenzoate
-
aldehyde reductase I is more sensitive than aldehyde reductase II
p-mercuribenzoate
-
above 1 mM
Phenobarbital
-
-
ponalrestat
-
-
pyrazole
-
-
pyridine 3-aldehyde
-
-
quercetin
-
-
Sodium barbitone
-
-
sodium phenobarbital
-
-
sodium phenobarbital
-
aldehyde reductase II activity diminished by 84%
sodium valproate
-
-
sodium valproate
-
liver ALR1
sorbinil
-
-
Tolrestat
-
-
Zn2+
-
100% inhibition
Zn2+
1 mM, 14.1% of initial activity
Zn2+
1 mM, complete inhibition
Zn2+
10 mM, 79% of initial activity
zopolrestat
-
-
additional information
structure-activity relationships study of quinoxalinone derivatives as aldose reductase inhibitors. Among them, N1-acetate derivatives have significant activity, molecular modeling and docking, overview. Both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors
-
additional information
design and synthesis of inhibitors based on quinoxalinones, overview. Phenolic structure is installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications, radical scavenging activity using the model reaction with the stable free radicals of 2,2-diphenyl-1-picrylhydrazyl
-
additional information
identification of aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold, the compouds have also lower inhibitory potency against aldehyde reductase, structure-activity relationships, overview
-
additional information
-
enzyme active site interactions with the 3-carboxymethoxy-4-methoxy-phenyl moiety of the inhibitor, binding structure, overview
-
additional information
enzyme active site interactions with the 3-carboxymethoxy-4-methoxy-phenyl moiety of the inhibitor, binding structure, overview
-
additional information
-
not inhibitory: EDTA (5 mM), MgCl2 (10 mM), CaCl2 (1O mM), CuCl2 (1 mM) and ZnCl2 (1 mM)
-