Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis

Janupally Renuka; Kummetha Indrasena Reddy; Konduri Srihari; Variam Ullas Jeankumar; Morla Shravan; Jonnalagadda Padma Sridevi; Perumal Yogeeswari; Kondra Sudhakar Babu; Dharmarajan Sriram

doi:10.1016/j.bmc.2014.06.041

Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis

Bioorg Med Chem. 2014 Sep 1;22(17):4924-34. doi: 10.1016/j.bmc.2014.06.041. Epub 2014 Jun 27.

Authors

Janupally Renuka¹, Kummetha Indrasena Reddy², Konduri Srihari², Variam Ullas Jeankumar¹, Morla Shravan¹, Jonnalagadda Padma Sridevi¹, Perumal Yogeeswari¹, Kondra Sudhakar Babu², Dharmarajan Sriram³

Affiliations

¹ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, RangaReddy Dist, Hyderabad 500078, India.
² Department of Chemistry, Sri Krishnadevaraya University, Anantapur 515055, India.
³ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawaharnagar, Shameerpet, RangaReddy Dist, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.

PMID: 25129171
DOI: 10.1016/j.bmc.2014.06.041

Abstract

DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well-established and validated target for the development of novel therapeutics. By adapting the medium throughput screening approach, we present the discovery and optimization of ethyl 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyraseB inhibitors, selected from Birla Institute of Technology and Science (BITS) database chemical library of about 3000 molecules. These compounds were tested for their biological activity; the compound 22 emerged as the most active potent lead with an IC50 of 3.2±0.15μM against Mycobacterium smegmatis DNA gyraseB enzyme and 0.81±0.24μM in MTB supercoiling activity. Subsequently, the binding of the most active compound to the DNA gyraseB enzyme and its thermal stability was further characterized using differential scanning fluorimetry method.

Keywords: Antibacterial activity; Cytotoxicity; DNA gyraseB; Tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Benzofurans / chemical synthesis
Benzofurans / chemistry
Benzofurans / pharmacology*
Cell Line
DNA Gyrase / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology*
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

Antitubercular Agents
Benzofurans
Topoisomerase II Inhibitors
DNA Gyrase