Pyrazoline derivatives as promising novel antischistosomal agents

Abstract

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.

Identification of Asiaticoside from Centella erecta (Apiaceae) as Potential Apyrase Inhibitor by UF-UHPLC-MS and Its In Vivo Antischistosomal Activity

“…For in vivo efficacy studies, female mice were each infected subcutaneously with 80 S. mansoni cercariae. Then, animals were randomly divided into experimental groups (five mice per group), and asiaticoside and PZQ were administered at single oral doses (400 mg/kg), by oral gavage, 49 days post infection (adult worm stage, patent infection) [ 1 , 2 , 3 ]. Group I: asiaticoside (400 mg/kg), which was dissolved in 2% ethanol in PBS ( v / v ); group II: control group, which was infected and received treatment only with vehicle (2% ethanol in PBS v / v ); and group III: PZQ (400 mg/kg, p.o.)…”

“…Schistosomiasis, caused by helminth parasites of the genus Schistosoma , is a neglected tropical disease with an estimated global prevalence of 240 million infected people in 78 countries and significant mortality and social and economic consequences [ 1 , 2 , 3 ]. Praziquantel (PZQ) is the only drug currently available for the treatment of all Schistosoma species [ 2 , 3 , 4 , 5 ], including Schistosoma mansoni , which is the species prevalent in South America, the Middle East, and Africa [ 1 , 3 , 6 ]. However, despite its effectiveness, PZQ has no efficacy against juvenile worms, which is a limit to schistosomiasis control and elimination [ 1 , 4 , 5 ].…”

“…However, despite its effectiveness, PZQ has no efficacy against juvenile worms, which is a limit to schistosomiasis control and elimination [ 1 , 4 , 5 ]. Additionally, the emerging PZQ-resistance and its reduced efficacy after use over the last decades have also been reported [ 1 , 2 , 3 ]. Therefore, the need for identification of new therapeutic targets and antischistosomal drugs is crucial.…”

“…In this regard, S. mansoni NTPDases (known as ATP diphosphohydrolases, ecto-apyrases or SmNTPDases) have gained interest as potential drug target for discovering of new antischistosomal drugs [ 1 , 2 , 3 , 7 , 8 ]. It has been suggested that SmNTPDases inhibitors might act in Schistosoma due to several possible mechanisms, such as reducing the parasite’s survival and improving the host’s immune response [ 1 , 2 , 7 , 8 ].…”

“…In this regard, S. mansoni NTPDases (known as ATP diphosphohydrolases, ecto-apyrases or SmNTPDases) have gained interest as potential drug target for discovering of new antischistosomal drugs [ 1 , 2 , 3 , 7 , 8 ]. It has been suggested that SmNTPDases inhibitors might act in Schistosoma due to several possible mechanisms, such as reducing the parasite’s survival and improving the host’s immune response [ 1 , 2 , 7 , 8 ]. Additionally, previous studies have showed that the SmNTPDases isoforms have immune cross-reactivity with the potato ( Solanum tuberosum ) apyrase [ 9 , 10 , 11 ], sharing high homology and similarity in their active sites [ 9 , 10 , 11 , 12 ].…”