Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

Abstract

BackgroundChagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.MethodsThe benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.ResultsPolar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.ConclusionB-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

“…Nevertheless it may furnish significant insights for the infection chemotherapy, as β-lapachone was reported to produce similar alterations in T. cruzi epimastigotes, amastigotes and trypomastigotes (Docampo et al., 1978), the developmental forms that multiply within mammalian host cells and spread via blood, respectively. In addition, different antiparasitic compounds may display similar effects upon epimastigotes and trypomastigotes and/or amastigotes, the developmental forms (Urbina et al., 1988, Urbina et al., 1993; Moreira et al., 2013a; Costa et al., 2011, Azeredo et al., 2014, Díaz et al., 2014; Jimenez et al., 2014; Veiga-Santos et al., 2014, Britta et al., 2015, Meira et al., 2015, Volpato et al., 2015, Beer et al., 2016) and the epimastigotes may therefore comprise and/or take part in experimental models (Kessler et al., 2013, Benítez et al., 2014, Sangenito et al., 2014, Wong-Baeza et al., 2015, Khare et al., 2015, Pessoa et al., 2016, Valera Vera et al., 2016). Thus, numerous studies perform screening experiments with epimastigotes and/or trypomastigotes further approach the selected active compounds in intracellular amastigotes (e.g.…”

Dipyridamole potentiated the trypanocidal effect of nifurtimox and improved the cardiac function in NMRI mice with acute chagasic myocarditis

“…The data presented here represent one of the most comprehensive studies to date. Other studies have used high doses of the drug, obtaining conflicting results, while Bustamante et al (2014) obtained a 95 to 100% cure rate at 100 mg/kg in a continuous or intermittent protocol applied in C57BL/6 (Ly5.2) mice and Wong-Baeza et al (2015) obtained a slight decrease in parasitaemia with the same dose for 50 days in NIH albino mice. This discrepancy may be explained by the strains of mice used; however, the response could also depend on the assayed strain of T. cruzi , which is apparent from the work of Andrade et al (1985) , who found that type I strains (high and early parasitaemia with macrophage tropism) had high susceptibility (56 ± 16% cure), type II strains (high and late parasitaemia with heart tropism) had medium to high susceptibility (52 ± 11% cure), and type III strains (low parasitaemia with skeletal muscle tropism) had low susceptibility (0.45 ± 0.45% cure) to therapeutic schemes based on Nfx 200 mg/kg for four days followed by 50 mg/kg for five days/week for 90 days.…”

Targets and Patented Drugs for Chemotherapy of Chagas Disease in the Last 15 Years-Period

“…The high lipophilicity from B-NPOx compared to Et-NPOx, facilitates a better penetration into T. cruzi, resulting in the enzymatic cleavage of B-NPOx and the releasing of NPOx and benzyl alcohol as potential trypanocidal agents. These results in conjunction with its low toxicity, suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease [677].…”