title: Synthesis, crystal structure and biological evaluation of substituted quinazolinone benzoates as novel antituberculosis agents targeting acetohydroxyacid synthase.
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.
authors.affiliation: State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul, South Korea.
authors.forename: Irshad Ahmed
authors.initials: IA
authors.lastname: Baig
authors.affiliation: Department of Clinical Laboratory, 309 Hospital of Chinese People's Liberation Army, Beijing, China; College of Lab Medicine, He Bei North University, Hebei, China.
authors.forename: Hui-Jie
authors.initials: HJ
authors.lastname: Sun
authors.affiliation: State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China.
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Cui
authors.affiliation: State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul, South Korea.
authors.forename: In-Pil
authors.initials: IP
authors.lastname: Jung
authors.affiliation: Department of Clinical Laboratory, 309 Hospital of Chinese People's Liberation Army, Beijing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, 309 Hospital of Chinese People's Liberation Army, Beijing, China. Electronic address: dongmei0659@sina.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Chemistry, Institute of Natural Sciences, Hanyang University, Seoul, South Korea. Electronic address: myyoon@hanyang.ac.kr.
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Yoon
authors.affiliation: State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, China; School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, Brisbane, QLD, Australia. Electronic address: nkwjg@nankai.edu.cn.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001565:Benzoates; D004791:Enzyme Inhibitors; D052999:Quinazolinones; D000095:Acetolactate Synthase
keywords: Acetohydroxyacid synthase; Antitubercular activity; Drug-resistant pathogen; Mycobacterium tuberculosis; Quinazolinone benzoates