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.

Figure 1

General synthesis of chalcone derivatives.

Figure 2

General synthesis of pyrazolines derivatives.

Figure 3

General synthesis of pyrazoles derivatives.

Figure 4

Viability of ex vivo adult S. mansoni worms following exposure to pyrazolines 16, 18, 19, 21, 22 and 23. Parasites were obtained from mice by perfusion 49 days after infection. Parasites were monitored for up to 72 h, and results are expressed as the percent mortality recorded by Kaplan–Meier survival curves. Mean values of viability were derived from a minimum of three experiments (n = 3). Control: drug-free medium. PZQ: praziquantel at 2 µM.

Figure 5

Number of eggs released by paired adult schistosomes exposed to pyrazolines 16, 18, 19, 21, 22 and 23. Control: drug-free medium. Data are presented as the mean ± SD from three experiments (n = 3).

Figure 6

Bioavailability radar plots of pyrazolines 16, 18, 19, 21, 22 and 23. The pink area represent the optimal range for each property, and the red line represents the values of the six calculated properties. lipophilicity: XLOGP3 between − 0.7 and + 5.0, size: molecular weight between 150 and 500 g/mol, polarity: topological polar surface area (TPSA) between 20 and 130 Ų, solubility: log S not higher than 6, saturation: fraction of carbons in the sp3 hybridization not less than 0.25, and flexibility: no more than 9 rotatable bonds. Plots were performed using the SwissADME tool.