Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

Eur J Med Chem. 2017 Feb 15:127:147-158. doi: 10.1016/j.ejmech.2016.12.042. Epub 2016 Dec 23.

Abstract

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.

Keywords: Efflux pump; Indole; MDR-TB; Thioridazine; Tuberculosis.

MeSH terms

  • Antitubercular Agents / chemical synthesis*
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Cell Line
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Drug Resistance, Multiple / drug effects*
  • Humans
  • Mycobacterium tuberculosis / drug effects*
  • Structure-Activity Relationship
  • Thioridazine / chemical synthesis*
  • Thioridazine / chemistry
  • Thioridazine / pharmacology*

Substances

  • Antitubercular Agents
  • Thioridazine