A quinoxaline derivative as a potent chemotherapeutic agent, alone or in combination with benznidazole, against Trypanosoma cruzi

• Published in: PloS one Vol. 9; no. 1; p. e85706
• Main Authors: Rodrigues, Jean Henrique da Silva, Ueda-Nakamura, Tânia, Corrêa, Arlene Gonçalves, Sangi, Diego Pereira, Nakamura, Celso Vataru
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17-01-2014; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Autophagy; Benznidazole; Biology; Blood; Blood cells; Cell death; Cell Line; Cell Membrane - drug effects; Cell Proliferation - drug effects; Cell size; Cell Size - drug effects; Chagas disease; Chemistry; Chemotherapy; Chromatography; Cytotoxicity; Drug Therapy, Combination; Drugs; Epimastigotes; Golgi apparatus; Humans; In vitro methods and tests; Intracellular Space - drug effects; Intracellular Space - parasitology; Life Cycle Stages - drug effects; Low concentrations; Macaca; Medical research; Medical treatment; Medicine; Mice; Nitroimidazoles - pharmacology; NMR; Nuclear magnetic resonance; Organelles; Parasites; Parasites - cytology; Parasites - drug effects; Parasites - ultrastructure; Parasitic diseases; Protozoa; Quinoxaline; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Quinoxalines - toxicity; Side effects; Synergistic effect; Toxicity; Toxicity Tests; Tropical diseases; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - toxicity; Trypanosoma cruzi; Trypanosoma cruzi - cytology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - growth & development; Trypanosoma cruzi - ultrastructure; Trypomastigotes; Vector-borne diseases; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0085706

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.
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.
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.