2. Academic Validation
  3. Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

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

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: daniele.castagnolo@kcl.ac.uk.
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.

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