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.
Nicolò Scalacci  1 ,  Alistair K Brown  2 ,  Fernando R Pavan  3 ,  Camila M Ribeiro  3 ,  Fabrizio Manetti  4 ,  Sanjib Bhakta  5 ,  Arundhati Maitra  5 ,  Darren L Smith  6 ,  Elena Petricci  4 ,  Daniele Castagnolo  7
Affiliations
  • 1. Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom; Northumbria University Newcastle, Department of Applied Sciences, Ellison Building, Ellison Place, NE1 8ST, Newcastle upon Tyne, United Kingdom.
  • 2. School of Medicine, Pharmacy and Health, Durham University, Wolfson Research Institute, Queens Campus, Stockton on Tees, TS17 6BH, United Kingdom.
  • 3. São Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara, Brazil.
  • 4. Dipartimento di Biotecnologie, Chimica e Farmacia, Via A. Moro 2, 53100, Siena, Italy.
  • 5. Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London, WC1E 7HX, United Kingdom.
  • 6. Northumbria University Newcastle, Department of Applied Sciences, Ellison Building, Ellison Place, NE1 8ST, Newcastle upon Tyne, United Kingdom.
  • 7. Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London, SE1 9NH, United Kingdom. Electronic address: [email protected].
PMID: 28039773 DOI: 10.1016/j.ejmech.2016.12.042
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.