title: Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR- and XDR-MTB.
abstract: A high-throughput screening effort on 45,000 compounds resulted in the discovery of a disubstituted oxazole as a new structural class inhibitor of Mycobacterium tuberculosis (Mtb). In order to improve the activity and investigate the SAR of this scaffold, a series of disubstituted azole analogues have been designed and synthesized. The newly synthesized compounds 1a-y were evaluated for their in vitro anti-TB activity versus replicating, multi- and extensive drug resistant Mtb strains. All the compounds, except 1o, 1p and 1q, showed potent anti-TB activity with MIC of 1-64 mg/L. The test of broad spectrum panel revealed that this series are specific to Mtb. The cytotoxicity assessment indicated that the compounds were not cytotoxic against HEK 293 cells. The compounds could have a novel mechanism to anti-Mtb as they can inhibit drug sensitive and drug resistant Mtb.
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Nana
authors.initials: N
authors.lastname: Gao
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Ningyu
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Institute of Material Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Xiannongtan No 1, Beijing 100050, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China.
authors.forename: Xuefu
authors.initials: X
authors.lastname: You
authors.affiliation: Beijing Tuberculosis and Thoracic Tumor Research Institute, Beimachang No 97, Beijing 101149, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Chinese Center for Disease Control and Prevention, Changbai Road No 155, Beijing 102206, PR China.
authors.forename: Kanglin
authors.initials: K
authors.lastname: Wan
authors.affiliation: Institute of Material Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Xiannongtan No 1, Beijing 100050, PR China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China. Electronic address: imbjiangv@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tiantanxili No 1, Beijing 100050, PR China. Electronic address: sisyimb@hotmail.com.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004146:Dioxanes / Q000138:chemical synthesis / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy*; D057809:HEK293 Cells; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000609109:2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)(1-((2-(4-fluorophenyl)-oxazol-4-yl)methyl)piperidin-4-yl)methanone; D000995:Antitubercular Agents; D004146:Dioxanes; D010080:Oxazoles
keywords: Antituberculosis; Disubstituted oxazole; MDR-MTB; XDR-MTB