Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors

Karyakulam Andrews Bobesh; Janupally Renuka; Rudraraju Reshma Srilakshmi; Swapna Yellanki; Pushkar Kulkarni; Perumal Yogeeswari; Dharmarajan Sriram

doi:10.1016/j.bmc.2015.11.039

Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors

Bioorg Med Chem. 2016 Jan 1;24(1):42-52. doi: 10.1016/j.bmc.2015.11.039. Epub 2015 Nov 28.

Authors

Karyakulam Andrews Bobesh¹, Janupally Renuka¹, Rudraraju Reshma Srilakshmi¹, Swapna Yellanki², Pushkar Kulkarni², Perumal Yogeeswari¹, Dharmarajan Sriram³

Affiliations

¹ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
² Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Zephase Therapeutics (an Incubated Company at the Dr Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
³ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.

PMID: 26678175
DOI: 10.1016/j.bmc.2015.11.039

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(1H)-one, by following a multistep protocol. Among them compound 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-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±0.22μM, with a good MTB MIC of 3.45μM. These kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines.

Keywords: 1,5-Naphthyridin-2(1H)-one; DNA gyrase; Topoisomerase; Tuberculosis; zERG toxicity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / pharmacology*
Antitubercular Agents / toxicity
Atrioventricular Block / drug therapy
Cardiotoxicity / drug therapy*
DNA Gyrase / metabolism
Enzyme Assays
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Heart Rate / drug effects
Mycobacterium tuberculosis / enzymology*
Naphthyridines / chemical synthesis
Naphthyridines / pharmacology*
Naphthyridines / toxicity
Novobiocin / pharmacology
Piperazines / chemical synthesis
Piperazines / pharmacology*
Piperazines / toxicity
Terfenadine / pharmacology
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / pharmacology*
Topoisomerase II Inhibitors / toxicity
Zebrafish
Zebrafish Proteins / antagonists & inhibitors

Substances

4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-nitrophenyl)piperazine-1-carboxamide
Antitubercular Agents
Erg protein, zebrafish
Ether-A-Go-Go Potassium Channels
KCNH1 protein, human
Naphthyridines
Piperazines
Topoisomerase II Inhibitors
Zebrafish Proteins
Novobiocin
Terfenadine
DNA Gyrase