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

Nicolò Scalacci; Alistair K Brown; Fernando R Pavan; Camila M Ribeiro; Fabrizio Manetti; Sanjib Bhakta; Arundhati Maitra; Darren L Smith; Elena Petricci; Daniele Castagnolo

doi:10.1016/j.ejmech.2016.12.042

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.

Authors

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.

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

Abstract

MeSH terms

Substances

Grants and funding