Thiazole–aminopiperidine hybrid analogues: Design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors

• Published in: European journal of medicinal chemistry 2013-12, Vol.70, p.143-153
• Main Authors: Jeankumar, Variam Ullas, Renuka, Janupally, Santosh, Peddi, Soni, Vijay, Sridevi, Jonnalagadda Padma, Suryadevara, Priyanka, Yogeeswari, Perumal, Sriram, Dharmarajan
• Format: Article
• Language: English
• Subjects: Amino piperidine; Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cell Line; Cell Survival - drug effects; DNA gyrase; DNA Gyrase - metabolism; Dose-Response Relationship, Drug; Drug Design; GyrB subunit; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis - enzymology; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Structure-Activity Relationship; Thiazole; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Tuberculosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.09.025

A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM. Ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (2) was found to be the promising compound which showed activity against MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM. [Display omitted] •Identification of a novel class of mycobacterial gyraseB inhibitor.•24 novel thiazole–aminopiperidine hybrid analogues were designed via molecular hybridization and synthesized efficaciously.•Compounds demonstrated unique activity against mycobacterial GyrB ATPase site with promising in-vitro MTB activity.•The structure–activity relationship has been well rationalized by docking studies.