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Structure-based design, synthesis, and biological evaluation of inhibitors of Mycobacterium tuberculosis type II dehydroquinase

Lookup NU author(s): Professor Alastair Hawkins


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The syntheses by Suzuki cross-coupling of 12 5-aryl analogues of the known inhibitor (LR,3/2,4R)-1,3,4-trihydroxycyclohex-5-en-1-carboxylic acid are reported. These compounds were found to be reversible competitive inhibitors against Mycobacterium tuberculosis type II dehydroquinase, the third enzyme of the shikimic acid pathway. The most potent inhibitor, the 3-nitrophenyl derivative, has a Ki of 54 nM, over 180 times more potent than the reported inhibitor (LR,3/2,4R)-5-fluoro-1,3,4-trihydroxycyclohex-5-en-1- carboxylic acid and more than 700 times lower than the KM of the substrate, making it the most potent known inhibitor against any type II dehydroquinase. Docking studies using GOLD (version 2.2) indicated a key electrostatic binding interaction between the aromatic rings and Arg19, a residue that has been identified as essential for enzyme activity. © 2005 American Chemical Society.

Publication metadata

Author(s): Sanchez-Sixto C, Prazeres VFV, Castedo L, Lamb H, Hawkins AR, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2005

Volume: 48

Issue: 15

Pages: 4871-4881

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm0501836

PubMed id: 16033267


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