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Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase

Title
Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase
Author
윤문영
Keywords
Acetohydroxyacid synthase; Mycobacterium tuberculosis; Quinazolinone benzoates; Antitubercular activity; Drug-resistant pathogen
Issue Date
2015-04
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 94, Page. 298-305
Abstract
Acetohydroxyacid synthase (AHAS) catalyzes the first essential biosynthetic step of branched-chain amino acids and is a biologically safe target against Mycobacterium tuberculosis (MTB). In our previous research, we used virtual screening to identify some novel AHAS inhibitors as potent antituberculosis agents. In this study, we synthesized twenty-four additional quinazolinone benzoates and explored their antitubercular activity. Five of these compounds displayed significant MTB-AHAS inhibition and their IC50 values were determined to be in the range of 6.50 mu M-12.08 mu M. Importantly, these compounds also exhibited strong in vitro activity (MICs in the range of 2.5-10 mg/L) and intracellular activity against clinically isolated extensively drug-resistant strains of M. tuberculosis. Taken together, these results indicated that the quinazolinone benzoate compounds should be regarded as promising lead compounds for the development of potent antituberculosis drugs with a novel mode of action. (C) 2015 Elsevier Masson SAS. All rights reserved.
URI
http://www.sciencedirect.com/science/article/pii/S0223523415001816http://hdl.handle.net/20.500.11754/23882
ISSN
0223-5234; 1768-3254
DOI
10.1016/j.ejmech.2015.03.014
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > CHEMISTRY(화학과) > Articles
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