Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni

Abstract

Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents.

Aldose reductase from Schistosoma japonicum: crystallization and structure-based inhibitor screening for discovering antischistosomal lead compounds

“…As a positive control, PZQ induced local drastic contracture, which was consistent with previous studies [28] (Figure 3C). In contrast, these morphological alterations were not observed in the compound-carrier treated group (Figure 3D).…”

“…After ethanol dehydration and critical point drying, they were mounted on microscope stubs, followed by gold sputtering for 3 min in an IB-3 ion-sputtering instrument. The SEM scanning was performed on an S-520 SEM (Hitachi, Japan) instrument with an accelerating voltage of 20 kV [28]. …”

Natural Products with Antischistosomal Activity

“…Interestingly, Vennerstrom et al [75] synthesized several synthetic trioxolane derivatives incorporating the critical endoperoxide pharmacophore of artemisinins, among which ozonide OZ-277 has proved to be more effective than artemisinin against malaria. Currently, the rational design of structurally simpler analogs of artemisinins has led to the synthesis of a large number of peroxides such as trioxaquines (1,2,4-trioxanes) [32,76] and ozonides (1,2,4-trioxolanes) [77,78], some of which have displayed interesting antischistosomal activities. For example, ozonide OZ418 was identified as a promising lead compound possessing high activity on both juvenile and adult schistosome infections in mice (worm burden reductions 80-90%) [78].…”

Chemotherapie gegen Schistosomiasis

“…[152] Andererseits zeigten elektronenmikroskopische Aufnahmen, dass die Tegumentmatrix nach der Behandlung nur leicht modifiziert war, während die unterliegenden Muskelbündel erheblich anschwollen. [154] Daraus folgt aber, dass PZQ hauptsächlich die Muskulatur angreift und nicht das Tegument, wie zuvor berichtet. [155] .…”

“…Auf eine Stçrung des Redoxzustands wies auch eine doppelt so hohe Produktion von Superoxid-Anionen im Vergleich zu Kontrollwürmern hin. [154] 4.3.2.5. Resistenzbildung oder Therapieversagen?…”