7-Hydroxy-(E)-3-phenylmethylene-chroman-4-one analogues as efflux pump inhibitors against Mycobacterium smegmatis mc² 155

Eur J Med Chem. 2013 Aug:66:499-507. doi: 10.1016/j.ejmech.2013.06.024. Epub 2013 Jun 19.

Abstract

Efflux pump (EP) induces resistance in mycobacteria and hence could be explored as a new target for the discovery of anti-TB agents. In search for efflux pump inhibitors from natural products, bonducellin, a homoisoflavonoid was isolated from Caesalpinia digyna roots and evaluated for modulation and EP inhibitory activity. Bonducellin showed modulation in the MIC of EtBr by eight fold at a concentration of 62.5 mg/L and also showed significant EP inhibitory activity. A synthetic scheme was designed to prepare analogues of 7-hydroxy-(E)-3-phenylmethylene-chroman-4-one by modification at the phenylmethylene-ring and the synthesized compounds were evaluated in accumulation and efflux assays. Analogues 1, 7-11, 13-15, 17 and 19 were found to be good modulators and decreased the MIC of EtBr by ≥4 fold at sub-inhibitory concentration. The compounds 8, 13 and 17 were the most potent inhibitors of ethidium bromide efflux in Mycobacterium smegmatis mc(2) 155.

Keywords: Bonducellin; Caesalpinia digyna; Efflux pump; Homoisoflavonoid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Chromans / chemistry*
  • Chromans / pharmacology*
  • Chromones / chemistry*
  • Chromones / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial / drug effects*
  • Microbial Sensitivity Tests
  • Mycobacterium smegmatis / drug effects*
  • Structure-Activity Relationship

Substances

  • 7-hydroxy-(E)-3-phenylmethylene-chroman-4-one
  • Anti-Bacterial Agents
  • Chromans
  • Chromones