Dual Strategy to Design New Agents Targeting : Advancing Phenotypic and CB1 Inhibitors for Improved Efficacy.

In this study, we have identified and optimized two lead structures from an in-house screening, with promising results against the parasitic flatworm and its target protease cathepsin B1 (CB1). Our correlation analysis highlighted the significance of physicochemical properties for the compounds' in vitro activities, resulting in a dual approach to optimize the lead structures, regarding both phenotypic effects in newly transformed schistosomula (NTS), adult worms, and CB1 inhibition. The optimized compounds from both approaches ("phenotypic" vs "CB1" approach) demonstrated improved efficacy against NTS and adult worms, with from the "CB1" approach emerging as the most potent compound. displayed nanomolar inhibition of CB1 ( = 0.050 μM) while maintaining selectivity toward human off-target cathepsins. Additionally, the greatly improved efficacy of compound toward adults (86% dead worms at 10 μM, 68% at 1 μM, 35% at 0.1 μM) demonstrates its potential as a new therapeutic agent for schistosomiasis, underlined by its improved permeability.