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

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.