Pyrazoline derivatives as promising novel antischistosomal agents.

Praziquantel is the only available drug to treat schistosomiasis, a parasitic disease that currently infects more than 240 million people globally. Due to increasing concerns about resistance and inadequate efficacy there is a need for new therapeutics. In this study, a series of 17 pyrazolines (15-31) and three pyrazoles (32-34) were synthesized and evaluated for their antiparasitic properties against ex vivo adult Schistosoma mansoni worms. Of the 20 compounds tested, six had a 50% effective concentration (EC50) below 30 µM. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 µM. Additionally, compound 22 had low cytotoxicity, with selectivity index of 21.6 and 32.2 for monkey and human cell lines, respectively. All active pyrazolines demonstrated a negative effect on schistosome fecundity, with a marked reduction in the number of eggs. Structure-activity relationship analysis showed that the presence of the non-aromatic heterocycle and N-substitution are fundamental to the antischistosomal properties. Pharmacokinetics, drug-likeness and medicinal chemistry friendliness studies were performed, and predicted values demonstrated an excellent drug-likeness profile for pyrazolines as well as an adherence to major pharmaceutical companies' filters. Collectively, this study demonstrates that pyrazoline derivatives are promising scaffolds in the discovery of novel antischistosomal agents.

Antiparasitic activity of piplartine (piperlongumine) in a mouse model of schistosomiasis.

Schistosomiasis is one of the most important parasitic infections in terms of its negative effects on public health and economics. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new anthelmintic agents. Piplartine, also known as piperlongumine, is a biologically active alkaloid/amide from peppers that can be detected in high amounts in the roots of Piper tuberculatum. Previously, it has been shown to have in vitro schistosomicidal effects. However, its anthelmintic activity in an animal host has not been reported. In the present work, in vivo antischistosomal properties of isolated piplartine were evaluated in a mouse model of schistosomiasis infected with either adult (patent infection) or juvenile (pre-patent infection) stages of Schistosoma mansoni. A single dose of piplartine (100, 200 or 400 mg/kg) or daily doses for five consecutive days (100 mg/kg/day) administered orally to mice infected with schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest piplartine dose (400 mg/kg) caused a significant reduction in a total worm burden of 60.4% (P < 0.001) in mice harbouring adult parasites. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also significantly inhibited by piplartine. Studies using scanning electron microscopy revealed substantial tegumental alterations in parasites recovered from mice. Since piplartine has well-characterized mechanisms of toxicity, is easily available, and is cost-effective, our results indicate that this bioactive molecule derived from medicinal plants could be a potential lead compound for novel antischistosomal agents.

Promethazine exhibits antiparasitic properties in vitro and reduces worm burden, egg production, hepato-, and splenomegaly in a schistosomiasis animal model.

The treatment and control of schistosomiasis, a neglected disease that affects more than 200 million people worldwide, rely on the use of a single drug, praziquantel. A vaccine has yet to be developed and since new drug design and development is a lengthy and costly process, drug repurposing is a promising strategy. In this study, the efficacy of promethazine, a first-generation antihistamine, was evaluated against Schistosoma mansoni ex vivo and in a murine model of schistosomiasis. In vitro assays demonstrated that promethazine affected parasite motility, viability, and it induced severe tegumental damage in schistosomes. The LC50 of the drug was 5.84 µM. Similar to promethazine, schistosomes incubated with atropine, a classical anticholinergic drug, displayed reduced motor activity. In an animal model, promethazine treatment was introduced at an oral dose of 100 mg/kg for five successive days at different intervals from the time of infection, for the evaluation of the stage-specific susceptibility (pre-patent and patent infections). Various parasitological criteria indicated the in vivo antischistosomal effects of promethazine: there were significant reductions in worm burden, egg production, and hepato- and splenomegaly. The highest worm burden reduction was achieved with promethazine in patent infections (> 90%). Taken together, considering the importance of the repositioning of drugs in infectious diseases, especially those related to poverty, our data revealed the possibility of promethazine repositioning as an antischistosomal agent.