PUBLICATION
Design and Biological Evaluation of Furan/Pyrrole/Thiophene-2-carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus
- Authors
- Janupally, R., Medepi, B., Brindha Devi, P., Suryadevara, P., Jeankumar, V.U., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-170214-224
- Date
- 2015
- Source
- Chemical Biology & Drug Design 86: 918-25 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- DNA gyrase, Staphylococcus aureus, biofilm, cytotoxicity
- MeSH Terms
-
- Animals
- DNA Gyrase/metabolism*
- Furans/chemistry
- Furans/pharmacology
- Furans/toxicity
- Humans
- Models, Molecular
- Pyrroles/chemistry
- Pyrroles/pharmacology
- Pyrroles/toxicity
- Staphylococcal Infections/drug therapy
- Staphylococcal Infections/microbiology
- Staphylococcus aureus/drug effects*
- Staphylococcus aureus/enzymology*
- Thiophenes/chemistry*
- Thiophenes/pharmacology*
- Thiophenes/toxicity
- Topoisomerase II Inhibitors/chemistry*
- Topoisomerase II Inhibitors/pharmacology*
- Topoisomerase II Inhibitors/toxicity
- Zebrafish
- PubMed
- 25619742 Full text @ Chem. Biol. Drug Des.
Citation
Janupally, R., Medepi, B., Brindha Devi, P., Suryadevara, P., Jeankumar, V.U., Kulkarni, P., Yogeeswari, P., Sriram, D. (2015) Design and Biological Evaluation of Furan/Pyrrole/Thiophene-2-carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus. Chemical Biology & Drug Design. 86:918-25.
Abstract
DNA topoisomerases are well-validated targets in micro-organisms. DNA gyraseB is one of the most important enzymes among them as per their clinical importance. In earlier study, a novel lead 4-((4-(furan-2-carboxamido)phenyl)amino)-4-oxobutanoic acid was identified as inhibitor against DNA gyraseB with an IC50 of 12.88 ± 1.39 μm. Subsequently, analogues of this lead were developed and evaluated through in vitro assays and in vivo studies. Among the 24 analogues, compound 22 was found to be the top hit with an improved DNA gyraseB activity of 5.35 ± 0.61 μm, and the binding affinity of this compound was further ascertained biophysically through differential scanning fluorimetry. The most potent ligand did not show any signs of cardiotoxicity in zebra fish ether-ago-go-related gene, ascertaining the safety profile of this series a breakthrough among the previously reported cardiotoxic gyraseB inhibitors.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping