PUBLICATION
Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors
- Authors
- Jeankumar, V.U., Kotagiri, S., Janupally, R., Suryadevara, P., Sridevi, J.P., Medishetti, R., Kulkarni, P., Yogeeswari, P., Sriram, D.
- ID
- ZDB-PUB-170214-242
- Date
- 2015
- Source
- Bioorganic & Medicinal Chemistry 23: 588-601 (Journal)
- Registered Authors
- Kulkarni, Pushkar
- Keywords
- Gyrase ATPase domain, Medium throughput screening, Mycobacterium tuberculosis, Tuberculosis, hERG
- MeSH Terms
-
- Adenosine Triphosphatases/antagonists & inhibitors*
- Adenosine Triphosphatases/chemistry
- Adenosine Triphosphatases/metabolism
- Animals
- Antitubercular Agents/chemistry
- Antitubercular Agents/pharmacology*
- DNA Gyrase/chemistry*
- DNA Gyrase/metabolism
- Drug Design
- Drug Discovery
- Humans
- Models, Molecular
- Mycobacterium smegmatis/drug effects
- Mycobacterium smegmatis/enzymology
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Structure-Activity Relationship
- Thiazoles/chemistry
- Thiazoles/pharmacology*
- Topoisomerase II Inhibitors/chemistry
- Topoisomerase II Inhibitors/pharmacology*
- Zebrafish
- PubMed
- 25541204 Full text @ Bioorg. Med. Chem.
Citation
Jeankumar, V.U., Kotagiri, S., Janupally, R., Suryadevara, P., Sridevi, J.P., Medishetti, R., Kulkarni, P., Yogeeswari, P., Sriram, D. (2015) Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors. Bioorganic & Medicinal Chemistry. 23:588-601.
Abstract
Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 μM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping