title: Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L.) infantum.
abstract: Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs) are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti-Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs. Except for amrinone, our results demonstrated antiprotozoal activity for fendiline, mibefradil, and lidoflazine, with IC50 values in a range between 2 and 16 μM and Selectivity Index between 4 and 10. Fendiline demonstrated depolarization of mitochondrial membrane potential, with increased reactive oxygen species production in amlodipine and fendiline treated Leishmania, but without plasma membrane disruption. Finally, in vitro combinations of amphotericin B, miltefosine, and pentamidine against L. infantum showed in isobolograms an additive interaction when these drugs were combined with fendiline, resulting in overall mean sum of fractional inhibitory concentrations between 0.99 and 1.10. These data demonstrated that non-dihydropyridine-CCBs present antiprotozoal activity and could be useful candidates for future in vivo efficacy studies against Leishmaniasis and Chagas' disease.
authors.affiliation: Centre for Parasitology and Mycology, Institute Adolfo Lutz, Secretary of Health of São Paulo State, Avenida Dr. Arnaldo 351, 01246-000 São Paulo, SP, Brazil; Departamento de Morfologia e Patologia Básica, Faculdade de Medicina de Jundiaí, Rua Francisco Telles 250, 13202-550 Jundiai, SP, Brazil.
authors.forename: Juliana Quero
authors.identifier: 0000-0002-4418-0838
authors.initials: JQ
authors.lastname: Reimão
authors.affiliation: Centre for Parasitology and Mycology, Institute Adolfo Lutz, Secretary of Health of São Paulo State, Avenida Dr. Arnaldo 351, 01246-000 São Paulo, SP, Brazil.
authors.forename: Juliana Tonini
authors.identifier: 0000-0002-1734-3400
authors.initials: JT
authors.lastname: Mesquita
authors.affiliation: Centre for Parasitology and Mycology, Institute Adolfo Lutz, Secretary of Health of São Paulo State, Avenida Dr. Arnaldo 351, 01246-000 São Paulo, SP, Brazil.
authors.forename: Daiane Dias
authors.identifier: 0000-0003-1570-8039
authors.initials: DD
authors.lastname: Ferreira
authors.affiliation: Centre for Parasitology and Mycology, Institute Adolfo Lutz, Secretary of Health of São Paulo State, Avenida Dr. Arnaldo 351, 01246-000 São Paulo, SP, Brazil.
authors.forename: Andre Gustavo
authors.identifier: 0000-0002-9900-1470
authors.initials: AG
authors.lastname: Tempone