Antischistosomal Activities of Mefloquine-Related Arylmethanols

Abstract

H uman schistosomiasis is a neglected tropical disease whose burden is mainly concentrated in sub-Saharan Africa and affects approximately 207 million people (30). The three main schistosome species parasitizing humans are Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum. Today, treatment with praziquantel is the core component of schistosomiasis control programs (32,34,35). There is no question that heavy reliance on a single drug bears a risk of drug resistance development. Indeed, in different regions of endemicity, lower cure rates have already been observed (9). An additional disadvantage of praziquantel is its stage-dependent susceptibility, showing only poor efficacy against immature schistosome stages (23). Therefore, drug discovery in the field of schistosomiasis remains an important task. Antischistosomal properties of the antimalarial drug mefloquine were first mentioned in 2008, when it was shown that a dosage of 150 mg/kg of body weight significantly reduced the egg burden in S. mansoni-infected mice (33). Further investigations revealed that mefloquine possesses good in vivo efficacy, with a single oral dosage of 200 mg/kg resulting in a total worm burden reduction of 72.3% in S. mansoni-infected mice. Another interesting characteristic of mefloquine is its efficacy against the juvenile immature stage (13). Finally, a randomized clinical trial that investigated the effect of mefloquine and mefloquine-artesunate in S. haematobium-infected patients was recently performed. It was shown that a combination therapy of mefloquine-artesunate resulted in moderate cure and high egg reduction rates (15).Based on these promising findings, we were motivated to test mefloquine-related compounds belonging to the three major groups of arylmethanols well described in antimalarial research, namely, 4-quinolinemethanols, 9-phenanthrenmethanols, and 4-pyridinemethanols (4), in order to elucidate their potential as antischistosomal lead candidates. In addition, a study on mefloquine-related compounds might provide us with a deeper understanding of structural features needed for antischistosomal activity of arylmethanols. The selected nine arylmethanols were first tested against S. mansoni schistosomula and adults in vitro. Promising compounds were followed up in vivo. Candidates characterized by high in vivo activity against S. mansoni were tested against S. haematobium. In addition, promising candidates were incubated in the presence of hemoglobin, hemin, or red blood cells to compare drug activities in relation to the postulated mechanistic heme dependency of arylmethanols (6). Finally, isothermal microcalorimetry (IMC) was used to investigate the antischistosomal properties of lead candidates in greater detail and to compare their levels of activity with mefloquine.

Disposition of Mefloquine and Enpiroline Is Highly Influenced by a Chronic Schistosoma mansoni Infection

“…Mefloquine presented plasma concentrations above the IC 50 (half-maximal inhibitory concentration) value determined in vitro (4.7 Ϯ 2.8 g/ml at 24 h postexposure) for approximately 32 h (12). Interestingly, the plasma levels of enpiroline did not reach the IC 50 determined at 24 h in vitro (7.4 Ϯ 2.7 g/ml).…”

“…Interestingly, the plasma levels of enpiroline did not reach the IC 50 determined at 24 h in vitro (7.4 Ϯ 2.7 g/ml). However, enpiroline is a slow-acting drug in vitro, presenting an IC 50 of 3.1 g/ml after 72 h of drug exposure (12). The plasma level remained above this concentration for up to 150 h. Since C max levels are reached much earlier (12 h for mefloquine and 24 h for enpiroline) than the onset of action (24 to 72 h for mefloquine and 168 h for enpiroline), one can speculate that the antischistosomal activities of both drugs are AUC rather than C max driven.…”

“…Oral formulations of enpiroline and mefloquine were prepared 3 h before treatment as water-based suspensions in 7% (vol/vol) Tween 80 and 3% (vol/vol) ethanol. Groups of mice (n ϭ 3 per group) were treated orally with 200 mg per kg of body weight of enpiroline or mefloquine by gavage and sacrificed by the CO 2 method at selected time points posttreatment (1,2,4,8,12,24,48,72, or 168 h). Whole-blood samples of 0.5 to 1 ml were collected by cardiac puncture of each mouse.…”

“…The onset of action was determined at different time points following treatment with single oral doses of enpiroline and mefloquine administered to mice (n ϭ 3 per group). After each PK sampling point (1,2,4,8,12,24,48,72, or 168 h posttreatment), the liver and gut, including the portal vein and mesenterial veins, were dissected from infected mice. Livers were pressed and examined under the microscope, and all worms were sexed and counted (16).…”

“…Enpiroline was included in this study since recent in vitro and in vivo studies on mefloquine-related arylmethanols identified enpiroline as a promising lead candidate with excellent activity on both S. mansoni and S. haematobium (12). Drug plasma levels were analyzed between 1 and 168 h after oral treatment with mefloquine and enpiroline.…”