title: Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy.
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.
authors.affiliation: †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.affiliation: ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Machado
authors.affiliation: †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Azzali
authors.affiliation: ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Santos Costa
authors.affiliation: ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Couto
authors.affiliation: †P4T Group, Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.affiliation: ‡Grupo de Micobactérias, Unidade de Microbiologia Médica, Global Health and Tropical Medicine (GHTM), Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT, UNL), Rua da Junqueira, 100, 1349-008 Lisbon, Portugal.
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004357:Drug Synergism; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013881:Thioridazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D013881:Thioridazine