Pyrazoline derivatives as promising novel antischistosomal agents

• Published in: Scientific reports Vol. 11; no. 1; p. 23437
• Main Authors: Morais, Cristiane S., Mengarda, Ana C., Miguel, Fábio B., Enes, Karine B., Rodrigues, Vinícius C., Espírito-Santo, Maria Cristina C., Siyadatpanah, Abolghasem, Wilairatana, Polrat, Couri, Mara R. C., de Moraes, Josué
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/326; 631/326/22; 631/326/22/1294; Animals; Antiparasitic agents; Antiparasitic Agents - pharmacology; Cell lines; Chalcones - chemistry; Chemistry, Pharmaceutical - methods; Chlorocebus aethiops; Computer Simulation; Cytotoxicity; Drug Discovery; Fecundity; Haplorhini; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Parasitic diseases; Pharmaceutical industry; Pharmacokinetics; Praziquantel; Praziquantel - pharmacology; Pyrazoles; Pyrazoles - chemistry; Schistosoma mansoni - drug effects; Schistosomiasis; Schistosomiasis mansoni - drug therapy; Schistosomiasis mansoni - parasitology; Schistosomicides - pharmacology; Science; Science (multidisciplinary); Solvents; Structure-Activity Relationship; Tetrazolium Salts - chemistry; Thiazoles - chemistry; Tropical diseases; Vero Cells
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-02792-0

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 (EC 50 ) below 30 μM. Our best hit, pyrazoline 22 , showed promising activity against adult schistosomes, with an EC 50  < 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.