Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: Hit to lead optimization of a novel class of thiazole inhibitors. Issue 3 (1st February 2015)

• Record Type: Journal Article
• Authors: Jeankumar, Variam Ullas; Kotagiri, Sonali; Janupally, Renuka; Suryadevara, Priyanka; Sridevi, Jonnalagadda Padma; Medishetti, Raghavender; Kulkarni, Pushkar; Yogeeswari, Perumal; Sriram, Dharmarajan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 3(2015)
• Page Start: 588
• Page End: 601
• Publication Date: 2015-02-01
• Subjects: Mycobacterium tuberculosis -- Gyrase ATPase domain -- Medium throughput screening -- hERG -- Tuberculosis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2014.12.001
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 μM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents.