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(1R,4R,5R)-1,4,5-trihydroxy-3-(phenylethynyl)cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-1,4,5-trihydroxy-3-(pyridin-3-ylethynyl)cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-1,4,5-trihydroxy-3-(quinolin-3-ylethynyl)cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-1,4,5-trihydroxy-3-(thiophen-2-ylethynyl)cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-1,4,5-trihydroxy-3-[(3-nitrophenyl)ethynyl]cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-1,4,5-trihydroxy-3-[[3-(trifluoromethyl)phenyl]ethynyl]cyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-3-(1,3-benzothiazol-2-ylethynyl)-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
(1R,4R,5R)-3-[(4-fluorophenyl)ethynyl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
(1R,4S,5R)-3,3-difluoro-1,4,5-trihydroxycyclohexane-1-carboxylic acid
inhibitor is selective for the type II dehydroquinase over the type I dehydroquinase
(1R,4S,5R)-3-fluoro-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid
inhibitor is selective for the type II dehydroquinase over the type I dehydroquinase
(1R,4R,5R)-1,4,5-trihydroxy-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(thiophen-2-ylmethyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
-
(1R,4R,5R)-3-(2-carboxy-vinyl)-1,4,5-trihydroxy-cyclohex-2-enecarboxylic acid
-
-
(1R,4R,5R)-3-(tert-butylcarbamoyl)-1,4,5-trihydroxycyclohex-2-enecarboxylic acid
-
-
(1R,4R,5R)-3-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1R,4R,5R)-3-[1-(furan-2-ylmethyl)-1H-1,2,3-triazol-4-yl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
competitive inhibitor
(1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid
-
-
(1S,3R,4R)-1,3,4-trihydroxy-5-methylenecyclohexanecarboxylic acid
-
-
(1S,3R,4R)-1,3,4-trihydroxycyclohexanecarboxylic acid
-
-
(1S,3R,4R,5E)-1,3,4-trihydroxy-5-(methylimino)cyclohexanecarboxylic acid
-
-
(3R,5R,6R)-3,5,6-trihydroxycyclohex-1-ene-1,3-dicarboxylic acid
-
-
(3R,5R,6R)-3-carbamoyl-3,5,6-trihydroxycyclohex-1-enecarboxylic acid
-
-
(4R,6R,7S)-2-(1-cyclopropylethyl)-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-2-ethenyl-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-2-ethyl-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-2-[(1E)-2-cyclopropylprop-1-en-1-yl]-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-2-(prop-2-en-1-yl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-2-(propan-2-yl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-2-methyl-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-2-[(1Z)-prop-1-en-1-yl]-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
(4R,6R,7S)-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
-
-
1,3,4-trihydroxy-5-hydroxyiminocyclohexanecarboxylic acid
-
-
1,3,4-trihydroxy-5-oxocyclohexanecarboxylic acid
-
-
1,3,4-trihydroxycyclohexanecarboxylic acid
-
-
1,4,5-trihydroxycyclohex-2-enecarboxylic acid
-
-
2,3-anhydroquinic acid
-
-
3-hydroxy-cyclohex-1-ene-1,3-dicarboxylic acid
-
-
3-[4-[(3R,5R,6R)-3-carboxy-3,5,6-trihydroxycyclohex-1-en-1-yl]-1H-1,2,3-triazol-1-yl]benzoic acid
-
competitive inhibitor
4-hydroxy-2-hydroxymethyl-4-methyl-pent-2-enedioic acid
-
-
4-hydroxy-4-methyl-pent-2-enedioic acid
-
-
Cl-
-
no significant effect
additional information
development of a range of ene-yne-based inhibitors, active site docking study using enzyme structure PDB ID 1GU1, overview
-
additional information
-
nanomolar competitive inhibitors
-
additional information
-
the in silico design, synthesis, and biological evaluation of ten potent type II dehydroquinase inhibitors are described. These compounds contain an anhydroquinate core, incorporated as a mimic of the enolate reaction intermediate. This substructure is attached by a variety of linking units to a terminal phenyl group that binds in an adjacent pocket. Inhibitors are synthesised from (-)-quinic acid using palladium-catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants
-
additional information
-
inhibitor design and synthesis, binding structure and inhibition mechanism, overview
-
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0.7
(1R,4S,5R)-3,3-difluoro-1,4,5-trihydroxycyclohexane-1-carboxylic acid
-
0.015
(1R,4S,5R)-3-fluoro-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid
-
0.0000057
(1R,4R,5R)-1,4,5-trihydroxy-3-(1-phenyl-1H-1,2,3-triazol-4-yl)cyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.000048
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(2-hydroxyphenyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.000078
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.0000057
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.000073
(1R,4R,5R)-1,4,5-trihydroxy-3-[1-(thiophen-2-ylmethyl)-1H-1,2,3-triazol-4-yl]cyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.03
(1R,4R,5R)-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
-
0.025
(1R,4R,5R)-3-(2-carboxy-vinyl)-1,4,5-trihydroxy-cyclohex-2-enecarboxylic acid
-
pH 7.0
0.029
(1R,4R,5R)-3-(tert-butylcarbamoyl)-1,4,5-trihydroxycyclohex-2-enecarboxylic acid
-
pH 7.0
0.000029
(1R,4R,5R)-3-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.000217
(1R,4R,5R)-3-[1-(furan-2-ylmethyl)-1H-1,2,3-triazol-4-yl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
-
pH 7.5, 25°C
0.5
(1S,3R,4R)-1,3,4-trihydroxy-5-methylenecyclohexanecarboxylic acid
-
-
0.6
(1S,3R,4R)-1,3,4-trihydroxycyclohexanecarboxylic acid
-
-
2.5
(1S,3R,4R,5E)-1,3,4-trihydroxy-5-(methylimino)cyclohexanecarboxylic acid
-
-
0.000032
(3R,5R,6R)-3,5,6-trihydroxycyclohex-1-ene-1,3-dicarboxylic acid
-
pH 7.0
0.00024
(3R,5R,6R)-3-carbamoyl-3,5,6-trihydroxycyclohex-1-enecarboxylic acid
-
pH 7.0
0.76
3-hydroxy-cyclohex-1-ene-1,3-dicarboxylic acid
-
pH 7.0
0.00172
3-[4-[(3R,5R,6R)-3-carboxy-3,5,6-trihydroxycyclohex-1-en-1-yl]-1H-1,2,3-triazol-1-yl]benzoic acid
-
pH 7.5, 25°C
1
4-hydroxy-2-hydroxymethyl-4-methyl-pent-2-enedioic acid
-
pH 7.0
0.47
4-hydroxy-4-methyl-pent-2-enedioic acid
-
pH 7.0
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0.000028
(1R,4R,5R)-1,4,5-trihydroxy-3-(phenylethynyl)cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.000171
(1R,4R,5R)-1,4,5-trihydroxy-3-(pyridin-3-ylethynyl)cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.000168
(1R,4R,5R)-1,4,5-trihydroxy-3-(quinolin-3-ylethynyl)cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.0000071
(1R,4R,5R)-1,4,5-trihydroxy-3-(thiophen-2-ylethynyl)cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.0000022
(1R,4R,5R)-1,4,5-trihydroxy-3-[(3-nitrophenyl)ethynyl]cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.0000069
(1R,4R,5R)-1,4,5-trihydroxy-3-[[3-(trifluoromethyl)phenyl]ethynyl]cyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.0000075
(1R,4R,5R)-3-(1,3-benzothiazol-2-ylethynyl)-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.000012
(1R,4R,5R)-3-[(4-fluorophenyl)ethynyl]-1,4,5-trihydroxycyclohex-2-ene-1-carboxylic acid
Streptomyces coelicolor
pH 7.5, 25°C
0.00000084
(4R,6R,7S)-2-(1-cyclopropylethyl)-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.00081
(4R,6R,7S)-2-ethenyl-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.00032
(4R,6R,7S)-2-ethyl-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.0000011
(4R,6R,7S)-2-[(1E)-2-cyclopropylprop-1-en-1-yl]-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.000022
(4R,6R,7S)-4,6,7-trihydroxy-2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.0018
(4R,6R,7S)-4,6,7-trihydroxy-2-(prop-2-en-1-yl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.0019
(4R,6R,7S)-4,6,7-trihydroxy-2-(propan-2-yl)-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.00315
(4R,6R,7S)-4,6,7-trihydroxy-2-methyl-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.000093
(4R,6R,7S)-4,6,7-trihydroxy-2-[(1Z)-prop-1-en-1-yl]-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
0.0097
(4R,6R,7S)-4,6,7-trihydroxy-4,5,6,7-tetrahydro-1-benzothiophene-4-carboxylic acid
Streptomyces coelicolor
-
pH 7.5, 25°C
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White, P.J.; Young, J.; Hunter, I.S.; Nimmo, H.G.; Coggins, J.R.
The purification and characterization of 3-dehydroquinase from Streptomyces coelicolor
Biochem. J.
265
735-738
1990
Streptomyces coelicolor
brenda
Frederickson, M.; Parker, E.J.; Hawkins, A.R.; Coggins, J.R.; Abell, C.
Selective inhibition of type II dehydroquinases
J. Org. Chem.
64
2612-2613
1999
Aspergillus nidulans, Mycobacterium tuberculosis, Salmonella enterica subsp. enterica serovar Typhi, Streptomyces coelicolor
brenda
Gourley, D.G.; Shrive, A.K.; Polikarpov, I.; Krell, T.; Coggins, J.R.; Hawkins, A.R.; Isaacs, N.W.; Sawyer, L.
The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction
Nat. Struct. Biol.
6
521-525
1999
Helicobacter pylori, Mycobacterium tuberculosis (P9WPX7), Mycobacterium tuberculosis H37Rv (P9WPX7), Salmonella enterica subsp. enterica serovar Typhi, Streptomyces coelicolor
brenda
Price, N.C.; Boam, D.J.; Kelly, S.M.; Duncan, D.; Krell, T.; Gourley, D.G.; Coggins, J.R.; Virden, R.; Hawkins, A.R.
The folding and assembly of the dodecameric type II dehydroquinases
Biochem. J.
338
195-202
1999
Mycobacterium tuberculosis, Streptomyces coelicolor
-
brenda
Evans, L.D.B.; Roszak, A.W.; Noble, L.J.; Robinson, D.A.; Chalk, P.A.; Matthews, J.L.; Coggins, J.R.; Price, N.C.; Lapthorn, A.J.
Specificity of substrate recognition by type II dehydroquinases as revealed by binding of polyanions
FEBS Lett.
530
24-30
2002
Streptomyces coelicolor, Mycobacterium tuberculosis (P9WPX7), Mycobacterium tuberculosis H37Rv (P9WPX7)
brenda
Toscano, M.D.; Frederickson, M.; Evans, D.P.; Coggins, J.R.; Abell, C.; Gonzalez-Bello, C.
Design, synthesis and evaluation of bifunctional inhibitors of type II dehydroquinase
Org. Biomol. Chem.
1
2075-2083
2003
Streptomyces coelicolor
brenda
Roszak, A.W.; Robinson, D.A.; Krell, T.; Hunter, I.S.; Fredrickson, M.; Abell, C.; Coggins, J.R.; Lapthorn, A.J.
The structure and mechanism of the type II dehydroquinase from Streptomyces coelicolor
Structure
10
493-503
2002
Streptomyces coelicolor (P15474), Streptomyces coelicolor
brenda
Le Sann, C.; Gower, M.A.; Abell, A.D.
Inhibitors of types I and II dehydroquinase
Mini Rev. Med. Chem.
4
747-756
2004
Aspergillus nidulans, Mycobacterium tuberculosis, Salmonella enterica subsp. enterica serovar Typhimurium, Streptomyces coelicolor
brenda
Frederickson, M.; Roszak, A.W.; Coggins, J.R.; Lapthorn, A.J.; Abell, C.
(1R,4S,5R)-3-Fluoro-1,4,5-trihydroxy-2-cyclohexene-1-carboxylic acid: the fluoro analogue of the enolate intermediate in the reaction catalyzed by type II dehydroquinases
Org. Biomol. Chem.
2
1592-1596
2004
Salmonella enterica subsp. enterica serovar Typhi, Streptomyces coelicolor (P15474), Mycobacterium tuberculosis (P9WPX7), Mycobacterium tuberculosis H37Rv (P9WPX7)
brenda
Stewart, K.A.; Robinson, D.A.; Lapthorn, A.J.
Type II dehydroquinase: molecular replacement with many copies
Acta Crystallogr. Sect. D
64
108-118
2008
Helicobacter pylori, Streptomyces coelicolor (P15474)
brenda
Toscano, M.D.; Payne, R.J.; Chiba, A.; Kerbarh, O.; Abell, C.
Nanomolar inhibition of type II dehydroquinase based on the enolate reaction mechanism
ChemMedChem
2
101-112
2007
Mycobacterium tuberculosis, Salmonella enterica subsp. enterica serovar Typhi, Streptomyces coelicolor
brenda
Payne, R.J.; Peyrot, F.; Kerbarh, O.; Abell, A.D.; Abell, C.
Rational design, synthesis, and evaluation of nanomolar type II dehydroquinase inhibitors
ChemMedChem
2
1015-1029
2007
Mycobacterium tuberculosis, Streptomyces coelicolor
brenda
Prazeres, V.F.; Sanchez-Sixto, C.; Castedo, L.; Lamb, H.; Hawkins, A.R.; Riboldi-Tunnicliffe, A.; Coggins, J.R.; Lapthorn, A.J.; Gonzalez-Bello, C.
Nanomolar competitive inhibitors of Mycobacterium tuberculosis and Streptomyces coelicolor type II dehydroquinase
ChemMedChem
2
194-207
2007
Mycobacterium tuberculosis, Streptomyces coelicolor
brenda
Blomberg, L.; Mangold, M.; Mitchell, J.; Blumberger, J.
Theoretical study of the reaction mechanism of Streptomyces coelicolor type II dehydroquinase
J. Chem. Theory Comput.
5
1284-1294
2009
Streptomyces coelicolor (P15474), Streptomyces coelicolor
brenda
Tran, A.; Cergol, K.; West, N.; Randall, E.; Britton, W.; Bokhari, S.; Ibrahim, M.; Lapthorn, A.; Payne, R.
Synthesis and evaluation of potent ene-yne inhibitors of type II dehydroquinases as tuberculosis drug leads
ChemMedChem
6
262-265
2011
Mycobacterium tuberculosis, Streptomyces coelicolor (P15474), Helicobacter pylori (Q48255)
brenda
Paz, S.; Tizon, L.; Otero, J.; Llamas-Saiz, A.; Fox, G.; Van Raaij, M.; Lamb, H.; Hawkins, A.; Lapthorn, A.; Castedo, L.; Gonzalez-Bello, C.
Tetrahydrobenzothiophene derivatives: conformationally restricted inhibitors of type II dehydroquinase
ChemMedChem
6
266-272
2011
Helicobacter pylori, Mycobacterium tuberculosis, Streptomyces coelicolor
brenda
Tran, A.; Cergol, K.; Britton, W.; Imran Bokhari, S.; Ibrahim, M.; Lapthorn, A.; Payne, R.
Rapid assembly of potent type II dehydroquinase inhibitors via 'click' chemistry
MedChemComm
1
271-275
2010
Helicobacter pylori, Mycobacterium tuberculosis, Streptomyces coelicolor
-
brenda