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Rational Design, Synthesis, and Evaluation of Nanomolar Type II Dehydroquinase Inhibitors
Author(s) -
Payne Richard J.,
Peyrot Fabienne,
Kerbarh Olivier,
Abell Andrew D.,
Abell Chris
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700032
Subject(s) - chemistry , stereochemistry , quinic acid , enzyme , streptomyces coelicolor , in silico , rational design , mycobacterium tuberculosis , biochemistry , combinatorial chemistry , biology , tuberculosis , medicine , genetics , pathology , mutant , gene
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 were synthesised from (−)‐quinic acid using palladium‐catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants against type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis. These are among the most potent inhibitors of these enzymes reported to date.