title: Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors.
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.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
authors.forename: Karyakulam Andrews
authors.initials: KA
authors.lastname: Bobesh
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
authors.forename: Rudraraju Reshma
authors.initials: RR
authors.lastname: Srilakshmi
authors.affiliation: 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.
authors.forename: Swapna
authors.initials: S
authors.lastname: Yellanki
authors.affiliation: 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.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D054537:Atrioventricular Block / Q000188:drug therapy; D066126:Cardiotoxicity / Q000188:drug therapy*; D027081:DNA Gyrase / Q000378:metabolism; D057075:Enzyme Assays; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006339:Heart Rate / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009287:Naphthyridines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D009675:Novobiocin / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D016593:Terfenadine / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors
chemical_list: C000609802:4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-nitrophenyl)piperazine-1-carboxamide; D000995:Antitubercular Agents; C527141:Erg protein, zebrafish; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D009287:Naphthyridines; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; D029961:Zebrafish Proteins; D009675:Novobiocin; D016593:Terfenadine; D027081:DNA Gyrase
keywords: 1,5-Naphthyridin-2(1H)-one; DNA gyrase; Topoisomerase; Tuberculosis; zERG toxicity