Antischistosomal activities of mefloquine-related arylmethanols

Abstract

Interesting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine mefloquine-related compounds belonging to the 4-pyridinemethanols, 9-phenanthrenmethanols, and 4-quinolinemethanols. Eight compounds revealed high activities against Schistosoma mansoni in vitro, with two drugs (the 4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower half-maximal inhibitory concentrations (IC(50)s) (2.7 and 3.5 μM, respectively) compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC(50)s when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR, 82.7%; dosage, 200 mg/kg of body weight) and its threo isomers (+)-threo (WBR, 100%) and (-)-threo (WBR, 89%) and with WR7930 (WBR, 87%; dosage, 100 mg/kg) against adult S. mansoni in mice. Furthermore, excellent in vitro and in vivo antischistosomal activity was observed for two WR7930-related structures (WR29252 and WR7524). In addition, mefloquine (WBR, 81%), enpiroline (WBR, 77%), and WR7930 (WBR, 100%) showed high activities against S. haematobium harbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the arylmethanols that rule antischistosomal activity. Further studies should be launched with enpiroline and WR7930.

Fig 1

Chemical structures of the arylmethanols investigated: halofantrine (compound 1); n-desbutylhalofantrine (compound 2); WR190420 (compound 3); WR148946 (compound 4); WR151312 (compound 5); WR154904 (compound 6); enpiroline/WR180409 (compound 7); WR7573 (compound 8); WR7930 (compound 9).

Fig 2

Chemical structures of the enantiomers of enpiroline: (−)-threo enpiroline (compound 10); (+)-threo enpiroline (compound 11).

Fig 3

Chemical structures of the WR7930-related compounds WR29252 (compound 12) and WR7524 (compound 13).

Fig 4

Heat flow of schistosomes recorded over 5 days (d) posttreatment with (A) mefloquine, (B) enpiroline, or (C) WR7930 at concentrations of 30, 10, and 1 μg/ml. Bars indicate standard deviations. Experiments were conducted in quadruplicate with 4 worms each. Asterisks (*) indicate heat flow values which are significantly (P ≤ 0.05) lower than control values obtained with untreated worms. pi, postinjection.

Fig 5

IC₅₀s calculated following exposure of adult S. mansoni worms to mefloquine, enpiroline, or WR7930 using different culture media (RPMI medium or RPMI medium supplemented with 120 μM hemin, 23 μM hemoglobin, or 2% RBC). Error bars indicate standard deviations of experiments (n = 5). Asterisks (*) indicate IC₅₀s which are significantly (P ≤ 0.05) lower than the control values determined using RPMI medium.