Carbamoyl Imidazoles As Potent, Reversible and Competitive Cruzain Inhibitors with
in vitro and
in vivo Trypanocidal Activity: A Structure-Based Drug Design Approach
A 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.
Keywords: Chagas disease, virtual screening, organic synthesis, structure-activity relationships, drug design, drug discovery, SBDD, neglected tropical diseases
de Souza, Mariana L. and Junior, Celso de Oliveira Rezende and Ferreira, Rafaela S. and Espinoza Chávez, Rocio Marisol and Ferreira, Leonardo and Slafer, Brian W. and Magalhães, Luma G. and Krogh, Renata and Oliva, Glaucius and Cruz, Fabio Cardoso and Dias, Luiz Carlos and Andricopulo, Adriano D., Carbamoyl Imidazoles As Potent, Reversible and Competitive Cruzain Inhibitors with
in vitro and
in vivo Trypanocidal Activity: A Structure-Based Drug Design Approach (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3387684 or http://dx.doi.org/10.2139/ssrn.3387684
This version of the paper has not been formally peer reviewed.
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