Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 94, Issue -, Pages 298-305Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.03.014
Keywords
Acetohydroxyacid synthase; Mycobacterium tuberculosis; Quinazolinone benzoates; Antitubercular activity; Drug-resistant pathogen
Categories
Funding
- National Natural Science Foundation of China [81271777, 21272128]
- National Basic Research Program of China [2013CB734004]
- Tianjin Natural Science Foundation [12JCZDJC25700]
- China Scholarship Council [201406205003]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2012R1A1A2008516]
- National Research Foundation of Korea [2012R1A1A2008516] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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