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Front. Chem. | doi: 10.3389/fchem.2019.00798

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

 Rafael A. Ferreira1*, Ivani Pauli2, Thiago S. Sampaio1,  Mariana L. Souza2,  Leonardo L. Ferreira2,  Luma G. Magalhães2,  Celso O. Rezende Jr1, Rafaela S. Ferreira3, Renata Krogh2, Luiz C. Dias1* and  Adriano D. Andricopulo2*
  • 1Institute of Chemistry, State University of Campinas, Brazil
  • 2Institute of Physics of São Carlos, University of Sao Paulo, Brazil
  • 3Federal University of Minas Gerais, Brazil

Chagas disease causes approximately 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 Trypanosoma cruzi, 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 (3a, IC50 = 2.2 µM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 µM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 µM). Moreover, most compounds were selective towards T. cruzi 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.

Keywords: Chagas Disease, Trypanosoma cruzi, Cruzain, SAR, Medicinal Chemistry, Synthesis, inhibitors, molecular docking

Received: 01 Oct 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Ferreira, Pauli, Sampaio, Souza, Ferreira, Magalhães, Rezende Jr, Ferreira, Krogh, Dias and Andricopulo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Rafael A. Ferreira, Institute of Chemistry, State University of Campinas, Campinas, 13083-970, São Paulo, Brazil,
Prof. Luiz C. Dias, Institute of Chemistry, State University of Campinas, Campinas, 13083-970, São Paulo, Brazil,
Prof. Adriano D. Andricopulo, Institute of Physics of São Carlos, University of Sao Paulo, São Carlos, 13566-590, São Paulo, Brazil,