Nanomolar competitive inhibitors of Mycobacterium tuberculosis and Streptomyces coelicolor type II dehydroquinase.
Isomeric nitrophenyl and heterocyclic analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid have been synthesized and tested as inhibitors of M. tuberculosis and S. coelicolor type II dehydroquinase, the third enzyme of the shikimic acid pathway. The target compounds were synthesized by a combination of Suzuki and Sonogashira cross-coupling and copper(I)-catalyzed 2,3-dipolar cycloaddition reactions from a common vinyl triflate intermediate. These studies showed that a para-nitrophenyl derivative is almost 20-fold more potent as a competitive inhibitor against the S. coelicolor enzyme than that of M. tuberculosis. The opposite results were obtained with the meta isomer. Five of the bicyclic analogues reported herein proved to be potent competitive inhibitors of S. coelicolor dehydroquinase, with inhibition constants in the low nanomolar range (4-30 nM). These derivatives are also competitive inhibitors of the M. tuberculosis enzyme, but with lower affinities. The most potent inhibitor against the S. coelicolor enzyme, a 6-benzothiophenyl derivative, has a K(i) value of 4 nM-over 2000-fold more potent than the best previously known inhibitor, (1R,4R,5R)-1,5-dihydroxy-4-(2-nitrophenyl)cyclohex-2-en-1-carboxylic acid (8 microM), making it the most potent known inhibitor against any dehydroquinase. The binding modes of the analogues in the active site of the S. coelicolor enzyme (GOLD 3.0.1), suggest a key pi-stacking interaction between the aromatic rings and Tyr 28, a residue that has been identified as essential for enzyme activity.
Prazeres
Verónica F V
VF
Laboratorio de Química Orgánica, CSIC and Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, Avenida de las Ciencias s/n, 15782 Santiago de Compostela, Spain.
Sánchez-Sixto
Cristina
C
Castedo
Luis
L
Lamb
Heather
H
Hawkins
Alastair R
AR
Riboldi-Tunnicliffe
Alan
A
Coggins
John R
JR
Lapthorn
Adrian J
AJ
González-Bello
Concepción
C
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D002384:Catalysis; D018360:Crystallography, X-Ray; D003511:Cyclohexanols / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008956:Models, Chemical; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D012765:Shikimic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D048372:Streptomyces coelicolor / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
C480611:1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid; D000995:Antitubercular Agents; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D012765:Shikimic Acid; D014443:Tyrosine; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase