AUTHOR=Ferreira Rafael A. A. , Pauli Ivani , Sampaio Thiago S. , de Souza Mariana L. , Ferreira Leonardo L. G. , Magalhães Luma G. , Rezende Celso de O. , Ferreira Rafaela S. , Krogh Renata , Dias Luiz C. , Andricopulo Adriano D. 

TITLE=Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00798

DOI=10.3389/fchem.2019.00798

ISSN=2296-2646

ABSTRACT=<p>Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of <italic>Trypanosoma cruzi</italic>, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (<bold>3a</bold>, IC<sub>50</sub> = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor <bold>10j</bold> (IC<sub>50</sub> = 0.6 μM), which is highly active against <italic>T. cruzi</italic> intracellular amastigotes (IC<sub>50</sub> = 1.0 μM). Moreover, most compounds were selective toward <italic>T. cruzi</italic> over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.</p>