title: Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis.
abstract: A series of biheterocyclic (1H-indole, benzofuran, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidin-5(4H)-one, imidazo[2,1-b]thiazole and pyrazolo[5,1-b]thiazole) derivatives were synthesized and evaluated for their anti-tubercular activities. The imidazo[2,1-b]thiazoles 9a-c and pyrazolo[5,1-b]thiazoles 10a-c exhibited promising anti-tubercular activity in varying degrees. Especially, the 2,6-dimethylpyrazolo[5,1-b]thiazole 10a exhibited strong suppressing function against H37Ra strain with MIC value of 0.03μg/mL. Compound 10a also displayed good pharmacokinetic profiles with oral bioavailability (F) of 41.7% and a half-life of 13.4h. Furthermore, 10a significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential for development of anti-tubercular drugs.
authors.affiliation: School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China. Electronic address: luxy2016@jnu.edu.cn.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China; University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China.
authors.forename: Minke
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Guangzhou Eggbio Co., Ltd., 3 Ju Quan Road, Science Park, Guangzhou 510663, China.
authors.forename: Xiantao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, #190, Kai Yuan Avenue, Guangzhou 510530, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents
keywords: Anti-tubercular agent; Imidazo[21-b]thiazole; Pyrazolo[51-b]thiazole; Scaffold hopping