ci9b00802_si_001.pdf (7.21 MB)
Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
journal contribution
posted on 2019-12-11, 17:38 authored by Mariana
L. de Souza, Celso de Oliveira Rezende Junior, Rafaela S. Ferreira, Rocio Marisol Espinoza Chávez, Leonardo L. G. Ferreira, Brian W. Slafer, Luma G. Magalhães, Renata Krogh, Glaucius Oliva, Fabio Cardoso Cruz, Luiz Carlos Dias, Adriano D. AndricopuloA virtual screening conducted with nearly 4 000 000
compounds from lead-like and fragment-like subsets enabled the identification
of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug
target for Chagas disease. Subsequent comprehensive structure-based
drug design and structure–activity relationship studies led
to the discovery of carbamoyl imidazoles as potent, reversible, and
competitive cruzain inhibitors. The most potent carbamoyl imidazole
inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in
vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds
reduced parasite burden in vivo and showed no toxicity
at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally
attractive, nonpeptidic, and easy to prepare and synthetically modify.
Finally, these results further advance our understanding of the noncovalent
mode of inhibition of this pharmaceutically relevant enzyme, building
strong foundations for drug discovery efforts.