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

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. IC50 = 6.50 μM MTB-AHAS. MIC = 2.5 mg/L for MDR and XDR MTB. [Display omitted] •We synthesized 24 quinazolinone benzoate compounds as novel inhibitors of Mycobacterium tuberculosis acetohydroxyacid synthase.•Five compounds exhibit significant inhibition on both MTB-AHAS and various strains of MTB.•Selected compound 5h shows desirable intracellular anti-MTB activity against MDR or XDR strains.