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

Acylaminobenzothiazole hits were identified as potential
inhibitors
of Trypanosoma cruzi replication, a
parasite responsible for Chagas disease. We selected compound 1 for lead optimization, aiming to improve in parallel its
anti-T. cruzi activity (IC50 = 0.63 μM) and its human metabolic stability (human clearance
= 9.57 mL/min/g). A total of 39 analogues of 1 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 50 as an advanced lead with an improved anti-T. cruzi activity in vitro (IC50 = 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, 50 demonstrated a promising in vivo efficacy.