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Carbamoyl Imidazoles As Potent, Reversible and Competitive Cruzain Inhibitors with in vitro and in vivo Trypanocidal Activity: A Structure-Based Drug Design Approach

115 Pages Posted: 17 May 2019 Sneak Peek Status: Review Complete

See all articles by Mariana L. de Souza

Mariana L. de Souza

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Celso de Oliveira Rezende Junior

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry

Rafaela S. Ferreira

Federal University of Minas Gerais (UFMG) - Department of Biochemistry and Immunology

Rocio Marisol Espinoza Chávez

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry

Leonardo Ferreira

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Brian W. Slafer

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Luma G. Magalhães

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Renata Krogh

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Glaucius Oliva

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

Fabio Cardoso Cruz

Federal University of São Paulo (Unifesp) - Department of Pharmacology

Luiz Carlos Dias

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry

Adriano D. Andricopulo

University of São Paulo (USP); University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry

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Abstract

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

Suggested Citation

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). ISCIENCE-D-19-00469. Available at SSRN: https://ssrn.com/abstract=3387684 or http://dx.doi.org/10.2139/ssrn.3387684
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mariana L. De Souza

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

Celso de Oliveira Rezende Junior

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry ( email )

Campinas
Brazil

Rafaela S. Ferreira

Federal University of Minas Gerais (UFMG) - Department of Biochemistry and Immunology ( email )

Belo Horizonte
Brazil

Rocio Marisol Espinoza Chávez

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry ( email )

Campinas
Brazil

Leonardo Ferreira

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

Brian W. Slafer

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Campinas
Brazil

Luma G. Magalhães

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

Renata Krogh

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

Glaucius Oliva

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

Fabio Cardoso Cruz

Federal University of São Paulo (Unifesp) - Department of Pharmacology ( email )

Sao Paulo
Brazil

Luiz Carlos Dias

Universidade Estadual de Campinas (UNICAMP) - Institute of Chemistry ( email )

Campinas
Brazil

Adriano D. Andricopulo (Contact Author)

University of São Paulo (USP)

Largo Sao Francisco
sao paulo
Brazil

University of Sao Paulo (USP), Physics Institute of Sao Carlos, Laboratory of Medicinal and Computational Chemistry ( email )

Sao Paulo
Brazil

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