A quinoxaline derivative as a potent chemotherapeutic agent, alone or in combination with benznidazole, against Trypanosoma cruzi.
BACKGROUND
Chagas' disease is a condition caused by the protozoan Trypanosoma cruzi that affects millions of people, mainly in Latin America where it is considered endemic. The chemotherapy for Chagas disease remains a problem; the standard treatment currently relies on a single drug, benznidazole, which unfortunately induces several side effects and it is not successful in the cure of most of the chronic patients. In order to improve the drug armamentarium against Chagas' disease, in the present study we describe the synthesis of the compound 3-chloro-7-methoxy-2-(methylsulfonyl) quinoxaline (quinoxaline 4) and its activity, alone or in combination with benznidazole, against Trypanosoma cruzi in vitro.


RESULTS
Quinoxaline 4 was found to be strongly active against Trypanosoma cruzi Y strain and more effective against the proliferative forms. The cytotoxicity against LLCMK2 cells provided selective indices above one for all of the parasite forms. The drug induced very low hemolysis, but its anti-protozoan activity was partially inhibited when mouse blood was added in the experiment against trypomastigotes, an effect that was specifically related to blood cells. A synergistic effect between quinoxaline 4 and benznidazole was observed against epimastigotes and trypomastigotes, accompanied by an antagonistic interaction against LLCMK2 cells. Quinoxaline 4 induced several ultrastructural alterations, including formations of vesicular bodies, profiles of reticulum endoplasmic surrounding organelles and disorganization of Golgi complex. These alterations were also companied by cell volume reduction and maintenance of cell membrane integrity of treated-parasites.


CONCLUSIONS
Our results demonstrated that quinoxaline 4, alone or in combination with benznidazole, has promising effects against all the main forms of T. cruzi. The compound at low concentrations induced several ultrastructural alterations and led the parasite to an autophagic-like cell death. Taken together these results may support the further development of a combination therapy as an alternative more effective in Chagas' disease treatment.
Programa de Pós-Graduação em Ciências Biológicas - Biologia Celular e Molecular, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
Jean Henrique da Silva
JH
Rodrigues
Departamento de Ciências Básicas da Saúde - Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
Tânia
T
Ueda-Nakamura
Departamento de Química - Laboratório de Síntese de Produtos Naturais, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.
Arlene Gonçalves
AG
Corrêa
Departamento de Química - Laboratório de Síntese de Produtos Naturais, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil.
Diego Pereira
DP
Sangi
Departamento de Ciências Básicas da Saúde - Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Maringá, Paraná, Brazil.
Celso Vataru
CV
Nakamura
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects; D008251:Macaca; D051379:Mice; D009593:Nitroimidazoles / Q000494:pharmacology*; D010271:Parasites / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018675:Toxicity Tests; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
D009593:Nitroimidazoles; D011810:Quinoxalines; D014344:Trypanocidal Agents; C009999:benzonidazole