Design, synthesis, and biological evaluation of novel 4H-chromen-4-one derivatives as antituberculosis agents against multidrug-resistant tuberculosis

Eur J Med Chem. 2020 Mar 1:189:112075. doi: 10.1016/j.ejmech.2020.112075. Epub 2020 Jan 19.

Abstract

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.

Keywords: 4H-chromen-4-one; Antitubercular agents; Multidrug-resistant tuberculosis; Polyketide synthase 13; Scaffold morphing.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / pharmacology*
  • Benzofurans / chemistry
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / pharmacology*
  • Drug Design*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Microsomes, Liver / drug effects*
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Structure-Activity Relationship
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology

Substances

  • Antitubercular Agents
  • Benzofurans
  • Benzopyrans
  • benzofuran