Synthesis, Antiparasitic Activity, and ADME Profile of Morpholinephenylbenzamides: A Pharmacological Study Against Chagas Disease and Visceral Leishmaniasis.

Chagas disease and leishmaniasis are neglected tropical diseases with limited treatment options. This study reports a hit-to-lead optimization of morpholinephenylbenzamides, starting from hit 1, which showed potent activity against Trypanosoma cruzi (IC50 0.29-0.76 μM) and Leishmania infantum (IC50 10.7 μM), despite a suboptimal ADME profile. A structure-activity relationship study of twenty-four novel derivatives provided key pharmacophoric insights. While Trypanosoma cruzi was less susceptible to chemical modifications, compound 20 exhibited potency comparable to benznidazole (IC50 3.58 μM) with significantly improved selectivity, lipophilicity, and solubility relative to compound 1. Against Leishmania infantum, six derivatives maintained activity, with compound 24 showing a 1.5-fold potency increase IC50 7.6 μM). Additionally, compound 16 stood out for its superior ADME profile, including enhanced permeability and metabolic stability. These findings validate the morpholinephenylbenzamide scaffold as a robust class with dual antiparasitic activity.