Structure-activity relationship and in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of N-aryl 3-trifluoromethyl pyrido[1,2-a]benzimidazoles that are efficacious in a mouse model of Schistosomiasis

We have previously reported on the antischistosomal activity of pyrido[1,2- a]benzimidazole (PBI) derivatives. As a follow-up, we designed and prosecuted further structure-activity relationship (SAR) studies that incorporate N-aryl substitutions on the PBI scaffold. Investigations into the in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms revealed several leads with promising potency. Active compounds with a good cytotoxicity profile were tested in vivo whereby 6 and 44 induced noteworthy reduction (62-69%) in the worm load in the Schistosoma mansoni mouse model. Pharmacokinetic analysis on 44 pointed to slow absorption, low volume of distribution, and low plasma clearance indicating the potential of these compounds to achieve a long duration of action. Overall, our work demonstrates that PBI chemotype is a promising scaffold in the discovery of new antischistosomal leads.