title: Synthesis and biological evaluation of novel 2,3-disubstituted quinoxaline derivatives as antileishmanial and antitrypanosomal agents.
abstract: Quinoxalines belong to the N-containing heterocyclic compounds that stand out as having promising biological activity due to their privileged scaffold. In this work, we report the synthesis, antileishmanial, and antitrypanosomal properties of 46 new 2,3-disubstituted quinoxaline and 40 previously reported derivatives. Among all of the compounds screened for in vitro activity against epimastigotes and trypomastigotes of Trypanosoma cruzi and promastigotes of Leishmania amazonensis as well as mammalian toxicity on LLCMK2 cells and J774 macrophages, analogues from series 5, 6, 7, 9, 12, and 13 displayed high activity at micromolar IC50 and EC50 concentrations. Sixteen quinoxaline derivatives were selected and evaluated on T. cruzi and/or L. amazonensis amastigotes. The most active compounds were 6a-b and 7d-e, on all evolutive forms of L. amazonensis and T. cruzi evaluated with IC50 values 0.1-0.8 μM on promastigotes and epimastigotes 1.4-8.6 on amastigotes. Compounds 5k, 12b and 13a were the most selective (SI = 19.5-38.4) on amastigotes of T. cruzi. In general their activity was directly related to the methylsulfoxyl, methylsulfonyl, and amine groups as well as the presence of chorine or bromine in the molecules. The current results indicate that these quinoxaline derivatives are novel and promising agents for further development towards a treatment for Chagas' disease and leishmaniasis.
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Cogo
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kaplum
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luis Km 235, 13565-905 São Carlos, SP, Brazil; Instituto de Ciências Exatas, Universidade Federal Fluminense, 27213-145 Volta Redonda, RJ, Brazil.
authors.forename: Diego Pereira
authors.initials: DP
authors.lastname: Sangi
authors.affiliation: Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil.
authors.forename: Tânia
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, Rodovia Washington Luis Km 235, 13565-905 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, Avenida Colombo 5790, 87020-900 Maringá, PR, Brazil. Electronic address: cvnakamura@gmail.com.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007891:Leishmania / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D011810:Quinoxalines
keywords: Anti-trypanosomatid agents; Leishmania amazonensis; Quinoxaline derivatives; Trypanosoma cruzi