PUBLICATION
Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors
- Authors
- Bobesh, K.A., Renuka, J., Srilakshmi, R.R., Yellanki, S., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-170214-63
- Date
- 2016
- Source
- Bioorganic & Medicinal Chemistry 24: 42-52 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- 1,5-Naphthyridin-2(1H)-one, DNA gyrase, Topoisomerase, Tuberculosis, zERG toxicity
- 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
- PubMed
- 26678175 Full text @ Bioorg. Med. Chem.
Citation
Bobesh, K.A., Renuka, J., Srilakshmi, R.R., Yellanki, S., Kulkarni, P., Yogeeswari, P., Sriram, D. (2016) Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors. Bioorganic & Medicinal Chemistry. 24:42-52.
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping