Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine

Bioorg Chem. 2020 Sep:102:104135. doi: 10.1016/j.bioorg.2020.104135. Epub 2020 Jul 22.

Abstract

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 μM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Keywords: Antimycobacterial activity; Benzothiazinones; N-((methylene)amino)piperazine; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Rifampin / administration & dosage
  • Rifampin / analogs & derivatives*
  • Rifampin / chemistry
  • Rifampin / pharmacology*
  • Structure-Activity Relationship
  • Thiazines / administration & dosage
  • Thiazines / chemistry
  • Thiazines / pharmacology*
  • Vero Cells

Substances

  • Anti-Bacterial Agents
  • Thiazines
  • Rifampin
  • rifapentine