PUBLICATION
Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors
- Authors
- Medapi, B., Renuka, J., Saxena, S., Sridevi, J.P., Medishetti, R., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-150325-5
- Date
- 2015
- Source
- Bioorganic & Medicinal Chemistry 23(9): 2062-78 (Journal)
- Registered Authors
- Medishetti, Raghavender
- Keywords
- Aminopiperidine, DNA gyrase, Quinoline, Tuberculosis
- MeSH Terms
-
- Animals
- Topoisomerase II Inhibitors/chemical synthesis
- Topoisomerase II Inhibitors/chemistry
- Topoisomerase II Inhibitors/pharmacology*
- Anti-Bacterial Agents/chemical synthesis
- Anti-Bacterial Agents/chemistry
- Anti-Bacterial Agents/pharmacology*
- Mycobacterium tuberculosis/drug effects*
- Mycobacterium tuberculosis/enzymology
- Structure-Activity Relationship
- Piperidines/chemistry
- Piperidines/pharmacology*
- Quinolines/chemistry
- Quinolines/pharmacology*
- Molecular Structure
- DNA Gyrase/metabolism*
- Microbial Sensitivity Tests
- Mycobacterium smegmatis/drug effects
- Mycobacterium smegmatis/enzymology
- Dose-Response Relationship, Drug
- Drug Design*
- Zebrafish
- PubMed
- 25801151 Full text @ Bioorg. Med. Chem.
Citation
Medapi, B., Renuka, J., Saxena, S., Sridevi, J.P., Medishetti, R., Kulkarni, P., Yogeeswari, P., Sriram, D. (2015) Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors. Bioorganic & Medicinal Chemistry. 23(9):2062-78.
Abstract
Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC50 of 0.95±0.12μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC50 of 0.62±0.16μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping