Chagas Disease Drug Discovery: Multiparametric Lead Optimization against in Acylaminobenzothiazole Series.

Acylaminobenzothiazole hits were identified as potential inhibitors of replication, a parasite responsible for Chagas disease. We selected compound for lead optimization, aiming to improve in parallel its anti- activity (IC = 0.63 μM) and its human metabolic stability (human clearance = 9.57 mL/min/g). A total of 39 analogues of were synthesized and tested in vitro. We established a multiparametric structure-activity relationship, allowing optimization of antiparasite activity, physicochemical parameters, and ADME properties. We identified compound as an advanced lead with an improved anti- activity in vitro (IC = 0.079 μM) and an enhanced metabolic stability (human clearance = 0.41 mL/min/g) and opportunity for the oral route of administration. After tolerability assessment, demonstrated a promising in vivo efficacy.