9Th Brazilian Symposium on Medicinal Chemistry

A virtual screening conducted with nearly 4,000,000 compounds from lead-like and fragment-like subsets enabled the identification of a promising small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas’ disease.1 Subsequent comprehensive structure–based drug design and structure–activity relationship studies lead to the discovery of carbamoylimidazoles, as potent and reversible cruzain inhibitors. The three structural fragments of hit 1 were explored and 42 compounds were synthesized. The most potent carbamoylimidazole (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, compounds 1 and 45 reduced parasite burden in vivo and showed no toxicity at doses of 100 mg/kg. These carbamoylimidazoles are structurally attractive, easy to prepare and synthetically modify. These results further advances our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.