An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition

Bioorg Med Chem. 2014 Dec 1;22(23):6552-6563. doi: 10.1016/j.bmc.2014.10.016.

Abstract

A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand-protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 °C in differential scanning fluorimetric evaluations

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*
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Cell Line
  • DNA Gyrase / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Macrophages / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis*
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • 4-(benzo(d)isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide
  • Antitubercular Agents
  • Benzofurans
  • Benzothiazoles
  • Piperazines
  • Topoisomerase II Inhibitors
  • DNA Gyrase
  • benzofuran