Abstract
BackgroundChagas’ 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.Methodology/Principal FindingsQuinoxaline 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.Conclusion/SignificanceOur 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.
Highlights
The American trypanosomiasis, known as Chagas’ disease, is a major public health problem that affects more than 10 million people worldwide, mostly in Latin America where it is considered endemic. [1] The causative agent of Chagas’ disease is the hemoflagellate protozoan Trypanosoma cruzi that belongs to Trypanosomatidae family
[5] the present study investigated the anti-protozoan activity and the main alterations induced by a quinoxaline derivative, 3-chloro-6-methoxy-2(methylsulfonyl)quinoxaline (4), against the three main forms of T. cruzi and assessed the safety of this compound by testing its toxicity against cultured mammalian cells and human red blood cells
The cyclization of 2 using POCl3 yielded quinoxaline 3, which was oxidized with mchloroperbenzoic acid to furnish quinoxaline 4 in 87% yield (Fig. 1)
Summary
The American trypanosomiasis, known as Chagas’ disease, is a major public health problem that affects more than 10 million people worldwide, mostly in Latin America where it is considered endemic. [1] The causative agent of Chagas’ disease is the hemoflagellate protozoan Trypanosoma cruzi that belongs to Trypanosomatidae family. [1] The causative agent of Chagas’ disease is the hemoflagellate protozoan Trypanosoma cruzi that belongs to Trypanosomatidae family. This taxon includes other parasites that are responsible for relevant diseases, such as Trypanosoma brucei (Human African Trypanosomiasis) and Leishmania spp. [6] Their efficacy is still considered low and restricted to acute manifestations of the disease These drugs successfully cure approximately 20% and 80% of chronic and acute Chagas’ disease patients, respectively. 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. 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
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