Pyrazoline derivatives as promising novel antischistosomal agents

Author(s)

Morais, Cristiane S. ^[1] ; Mengarda, Ana C. ^[1] ; Miguel, Fabio B. ^[2] ; Enes, Karine B. ^[2] ; Rodrigues, Vinicius C. ^[1] ; Espirito-Santo, Maria Cristina C. ^{[3, 4]} ; Siyadatpanah, Abolghasem ^[5] ; Wilairatana, Polrat ^[6] ; Couri, Mara R. C. ^[2] ; de Moraes, Josue ^[1]

Affiliation

^[1] Univ Guarulhos, Res Ctr Neglected Dis, Praca Tereza Cristina 229, BR-07023070 Guarulhos, SP - Brazil

^[2] Univ Fed Juiz de Fora, Dept Chem, BR-36036900 Juiz De Fora, MG - Brazil

^[3] Univ Sao Paulo, Dept Infect & Parasit Dis, Lab Immunopathol Schistosomiasis LIM 06, Fac Med, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Trop Med, Lab Helminthol, Sao Paulo, SP - Brazil

^[5] Birjand Univ Med Sci, Ferdows Sch Paramed & Hlth, Birjand 9717853577 - Iran

^[6] Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok 10400 - Thailand

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 11, n. 1 DEC 6 2021.
• Web of Science Citations: 0

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 mu M. Our best hit, pyrazoline 22, showed promising activity against adult schistosomes, with an EC50 < 10 mu M. 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. (AU)

• FAPESP's process: 19/25905-2 - Preclinical evaluation for oral administration of nanostructured formulations containing drugs with anthelmintic activity
• Grantee: Ana Carolina Araujo Mengarda
• Support Opportunities: Scholarships in Brazil - Doctorate