Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads

Abstract

To investigate the physicochemical properties of anti-schisto­somal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schisto­somal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schisto­somal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schisto­somal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ’s anti-schisto­somal activity make PZQ an essential medicine for the treatment of schisto­somiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 μM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 μM) to provide high-quality hits and/or leads for the discovery of new oral anti-schisto­somal therapeutics