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

Lu, Wei, Baig, Irshad Ahmed, Sun, Hui-Jei, Cui, Chang-Jun, Guo, Rui, Jung, In-Pil, Wang, Di, Dong, Mei, Yoon, Moon-Young and Wang, Jian-Guo (2015) Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase. European Journal of Medicinal Chemistry, 94 298-305. doi:10.1016/j.ejmech.2015.03.014


Author Lu, Wei
Baig, Irshad Ahmed
Sun, Hui-Jei
Cui, Chang-Jun
Guo, Rui
Jung, In-Pil
Wang, Di
Dong, Mei
Yoon, Moon-Young
Wang, Jian-Guo
Title Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1768-3254
0223-5234
Publication date 2015-04-13
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2015.03.014
Open Access Status
Volume 94
Start page 298
End page 305
Total pages 8
Place of publication Issy les Moulineaux, France
Publisher Elsevier Masson
Language eng
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 μM–12.08 μM. 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.
Keyword Acetohydroxyacid synthase
Mycobacterium tuberculosis
Quinazolinone benzoates
Antitubercular activity
Drug-resistant pathogen
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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