Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors. Issue 1 (1st January 2016)

• Record Type: Journal Article
• Authors: Bobesh, Karyakulam Andrews; Renuka, Janupally; Srilakshmi, Rudraraju Reshma; Yellanki, Swapna; Kulkarni, Pushkar; Yogeeswari, Perumal; Sriram, Dharmarajan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 1(2016)
• Page Start: 42
• Page End: 52
• Publication Date: 2016-01-01
• Subjects: DNA gyrase -- Topoisomerase -- Tuberculosis -- 1, 5-Naphthyridin-2(1H)-one -- zERG toxicity; 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.2015.11.039
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: This kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines. Abstract: Recently numerous non-fluoroquinolone-based bacterial type II topoisomerase inhibitors from both the GyrA and GyrB classes have been reported as antibacterial agents. Inhibitors of the GyrA class include aminopiperidine-based novel bacterial type II topoisomerase inhibitors (NBTIs). However, inhibition of the cardiac ion channel remains a serious liability for the aminopiperidine based NBTIs. In this paper we replaced central aminopiperidine linker with piperazine moiety and tested for its biological activity. We developed a series of twenty four compounds with a piperazine linker 1-(2-(piperazin-1-yl)ethyl)-1, 5-naphthyridin-2(1 H )-one, by following a multistep protocol. Among them compound 4-(2-(7-methoxy-2-oxo-1, 5-naphthyridin-1(2 H )-yl)ethyl)- N -(4-nitrophenyl)piperazine-1-carboxamide (11 ) was the most promising inhibitor with Mycobacterium tuberculosis (MTB) DNA gyrase enzyme supercoiling IC50 of 0.29 ± 0.22 μM, with a good MTB MIC of 3.45 μM. These kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines.