title: In Vitro and In Vivo Activities of 2,3-Diarylsubstituted Quinoxaline Derivatives against Leishmania amazonensis.
abstract: Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (ΔΨm), mitochondrial superoxide anion (O2·(-)) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ΔΨm, an increase in the O2·(-) concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kaplum
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Cogo
authors.affiliation: Instituto de Ciências Exatas, Universidade Federal Fluminense, Volta Redonda, RJ, Brazil Laboratório de Síntese de Produtos Naturais, Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
authors.forename: Diego Pereira
authors.initials: DP
authors.lastname: Sangi
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.
authors.forename: Tânia
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Laboratório de Síntese de Produtos Naturais, Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
authors.forename: Arlene Gonçalves
authors.initials: AG
authors.lastname: Corrêa
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil cvnakamura@uem.br.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000502:physiology; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010718:Phosphatidylserines / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: C000622552:2,3-di-(4-methoxyphenyl)-quinoxaline; C000622551:6,7-dichloro-2,3-diphenylquinoxaline; D000981:Antiprotozoal Agents; D010718:Phosphatidylserines; D011810:Quinoxalines; D013481:Superoxides; D000255:Adenosine Triphosphate