Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy

Marco Pieroni, Diana Machado, Elisa Azzali, Sofia Santos Costa, Isabel Couto, Gabriele Costantino, Miguel Viveiros

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.

Original languageEnglish
Pages (from-to)5842-5853
Number of pages12
JournalJournal Of Medicinal Chemistry
Volume58
Issue number15
DOIs
Publication statusPublished - 21 Jul 2015

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