In Vivo Activity of Aryl Ozonides against Schistosoma Species

Abstract

We evaluated the in vivo antischistosomal activities of 11 structurally diverse synthetic peroxides. Of all compounds tested, ozonide (1,2,4-trioxolane) OZ418 had the highest activity against adult Schistosoma mansoni, with total and female worm burden reductions of 80 and 90% (P < 0.05), respectively. Furthermore, treatment of S. haematobium-infected mice with OZ418 reduced the total worm burden by 86%. In conclusion, OZ418 is a promising antischistosomal lead compound. S chistosomiasis, caused by blood flukes of the genus Schistosoma, is an important cause of morbidity and mortality, mainly among the rural poor in sub-Saharan Africa (5, 16). The need for new antischistosomal drugs is quite evident, given that praziquantel is the only drug available and is in widespread use in population-based morbidity control programs (16).Various classes of synthetic peroxides, including trioxaquines (1,2,4-trioxanes) (1, 12), the tetraoxaspirononadecane N-89 (15), and ozonides (1,2,4-trioxolanes) (19), have been studied for their antischistosomal properties. Our previous data demonstrate that, like the artemisinins, ozonides possess promising antischistosomal properties (10, 19). We investigated three representative ozonides, namely, carboxylic acid OZ78, amine OZ209, and phenol OZ288 (Fig. 1). Of these, 8=-aryl ozonide OZ288 had the highest antischistosomal activity; this ozonide reduced the total worm burden by 95% (200 mg/kg body weight) in mice harboring juvenile Schistosoma mansoni and by 52% (400 mg/kg) in mice harboring adult worms (19). Although 8=-alkyl ozonides OZ78 and OZ209 had activities greater than 80% against juvenile worms, lower activities (0 and 17%, respectively) were observed for these two ozonides against adult worms. We suggest that the increased iron(II) stabilities of 8=-aryl ozonides compared to those of 8=-alkyl ozonides (2) might contribute to the superior antischistosomal efficacy of OZ288.The aim of the present study was to evaluate in a first step the in vivo antischistosomal activities of nine structurally diverse OZ288 analogs (Fig. 2), including antimalarial drug candidate OZ439, currently in phase II clinical testing (2). Since schistosomiasis and malaria are coendemic in many parts of the world, it is important to assess the potential auxiliary effects of antimalarial drug candidates such as OZ439 on Schistosoma species.Our animal studies were carried out following national and cantonal regulations on animal welfare (permission no. 2070). All compounds were synthesized as described in previous publications and patents (3,4,17,18). Compounds were freshly prepared in homogenous aqueous suspensions in 7% Tween 80 and 3% ethanol.Female NMRI mice (n ϭ 147; age, 4 weeks; weight, ϳ20 g) were purchased from Charles River (Sulzfeld, Germany) and Harlan Laboratories (Blackthorn, United Kingdom). Mice were maintained in groups of 10 in Makrolon cages under environmentally controlled conditions (temperature, ϳ25°C; humidity, ϳ50%; 12-h light and 12-h dark cycle) with free access to water and food. Mi...

Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry

“…OZ418 activity in vitro. While the antischistosomal activity of OZ418 in in vivo S. mansoni, S. haematobium, and S. japonicum infection models has already been demonstrated (32,39), its in vitro activity has been studied in S. japonicum only. The data shown in Table 3 reveal a nonnegligible effect of OZ418 on adult S. mansoni (IC 50 of 18.3 to 27.4 g/ml or 44.2 to 66.2 M after 72 h), similar to that reported previously for juvenile and adult S. japonicum (IC 50 of 16 g/ml after 72 h) (39).…”

“…Interestingly, data from in vivo studies suggest that acid functional groups can significantly boost the antischistosomal effect of the ozonides compared to neutral and weak basic substituents (32). Besides OZ418, an acid substituent is also present in another synthetic ozonide with strong trematocidal activity, OZ78 (33,50).…”

“…This cis-8=-phenyl ozonide had significant activity against juvenile S. mansoni infection (95.4% worm burden reduction) and a moderate effect on adult S. mansoni infection (52%) in mice (35). Follow-up studies of nine different cis-8=-phenyl ozonides in vivo revealed OZ418 as a potential lead candidate (32). A single oral dose (200 mg/kg of body weight for juvenile and 400 mg/kg for adult infections) of OZ418 reduced the total worm burden by 100, 80, and 86% in mice infected with juvenile S. mansoni, adult S. mansoni, and adult S. haematobium, respectively (32).…”

“…Most importantly, they often offer improved bioavailability, pharmacokinetic (PK) properties, and antiparasitic activity (29)(30)(31). The artemisinins and ozonides have also shown promising efficacy against several parasitic worms, including schistosomes (27,(32)(33)(34)(35)(36)(37)(38)(39)(40). In more detail, the first screening of seven structurally diverse synthetic ozonides identified OZ288 as a possible antischistosomal compound.…”

“…Follow-up studies of nine different cis-8=-phenyl ozonides in vivo revealed OZ418 as a potential lead candidate (32). A single oral dose (200 mg/kg of body weight for juvenile and 400 mg/kg for adult infections) of OZ418 reduced the total worm burden by 100, 80, and 86% in mice infected with juvenile S. mansoni, adult S. mansoni, and adult S. haematobium, respectively (32). Recently, in vivo assays with OZ418 in S. japonicum-infected mice demonstrated 70 to 84% total adult (200-mg/kg single oral dose) and 27 to 76% total juvenile (400-mg/kg single oral dose) worm burden reductions (39).…”