Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents

Eur J Med Chem. 2020 Aug 15:200:112409. doi: 10.1016/j.ejmech.2020.112409. Epub 2020 May 19.

Abstract

A series of new benzothiazinone derivatives containing a symmetric 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, based on the structure of LK02 discovered in our lab, were designed and synthesized. With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016 μg/mL). Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169.

Keywords: 2,7-diazaspiro[3.5]nonane; Antimycobacterial activity; Benzothiazinones; Synthesis.

MeSH terms

  • Alkanes / chemistry*
  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Drug Design*
  • Drug Resistance
  • Mice
  • Mycobacterium tuberculosis / drug effects
  • Structure-Activity Relationship
  • Thiazines / chemistry*
  • Tuberculosis, Multidrug-Resistant / drug therapy

Substances

  • Alkanes
  • Antitubercular Agents
  • Thiazines
  • nonane