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Nanomolar competitive inhibitors of Mycobacterium tuberculosis and Streptomyces coelicolor type II dehydroquinase

Lookup NU author(s): Dr Heather Lamb, Professor Alastair Hawkins


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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 common vinyl triflate intermediate. These studies showed that para-nitrophenyl derivative is almost 20-fold more potent as 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, 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 Ki 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 μM), 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 π-stacking interaction between the aromatic rings and Tyr 28, a residue that has been identified as essential for enzyme activity. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

Publication metadata

Author(s): Prazeres VFV, Sanchez-Sixto C, Castedo L, Lamb H, Hawkins AR, Riboldi-Tunnicliffe A, Coggins JR, Lapthorn AJ, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: ChemMedChem

Year: 2007

Volume: 2

Issue: 2

Pages: 194-207

ISSN (print): 1860-7179

ISSN (electronic): 1860-7187

Publisher: Wiley - VCH Verlag GmbH & Co. KGaA


DOI: 10.1002/cmdc.200600208

PubMed id: 17245805


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