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

• DOI: 10.1016/j.ejmech.2015.03.014
• Publication Date: 2015-03-07T05:32:36Z
• Authors: Wei Lu; Irshad Ahmed Baig; Hui-Jie Sun; Chang-Jun Cui; Rui Guo; In-Pil Jung; Di Wang; Mei Dong; Moon-Young Yoon; Jian-Guo Wang
• Keywords: Models, Molecular; 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; 3002 Drug Discovery; Antitubercular Agents; Acetohydroxyacid synthase; Microbial Sensitivity Tests; Mycobacterium tuberculosis; 540; Crystallography, X-Ray; Benzoates; Drug-resistant pathogen; 3. Good health; Quinazolinone benzoates; Acetolactate Synthase; Structure-Activity Relationship; 03 medical and health sciences; 3004 Pharmacology; Enzyme Inhibitors; Antitubercular activity; 1605 Organic Chemistry; Quinazolinones

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.