Structure-based design, optimization of lead, synthesis, and biological evaluation of compounds active against Trypanosoma cruzi.

de Almeida, Gleybson Correia; de Oliveira, Gerliny Bezerra; da Silva Monte, Zenaide; Costa, Érick Caique Santos; da Silva Falcão, Emerson Peter; Scotti, Luciana; Scotti, Marcus Tullius; Oliveira Silva, Ricardo; Pereira, Valéria Rêgo Alves; da Silva, Elis Dionisio; Junior, Policarpo Ademar Sales; de Andrade Cavalcante, Marton Kaique; de Melo, Sebastião José

de Almeida, Gleybson Correia; de Oliveira, Gerliny Bezerra; da Silva Monte, Zenaide; Costa, Érick Caique Santos; da Silva Falcão, Emerson Peter; Scotti, Luciana; Scotti, Marcus Tullius; Oliveira Silva, Ricardo; Pereira, Valéria Rêgo Alves; da Silva, Elis Dionisio; Junior, Policarpo Ademar Sales; de Andrade Cavalcante, Marton Kaique; de Melo, Sebastião José.

Afiliação

de Almeida GC; Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Federal University of Pernambuco/UFPE, Recife, Brazil.
de Oliveira GB; Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Federal University of Pernambuco/UFPE, Recife, Brazil.
da Silva Monte Z; Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Federal University of Pernambuco/UFPE, Recife, Brazil.
Costa ÉCS; Postgraduate Program in Biological Sciences, Department of Biosciences, Federal University of Pernambuco/UFPE, Recife, Brazil.
da Silva Falcão EP; Vitória Academic Center, Federal University of Pernambuco - St Alto do Reservatório, Vitória de Santo Antão, Brazil.
Scotti L; Laboratory of Cheminformatics, Program of Natural and Synthetic Bioactive Products (PgPNSB), Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil.
Scotti MT; Laboratory of Cheminformatics, Program of Natural and Synthetic Bioactive Products (PgPNSB), Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil.
Oliveira Silva R; Department of Fundamental Chemistry, Center for Exact and Natural Sciences, Federal University of Pernambuco, Av. Journalist Anibal Fernandes, Recife, Brazil.
Pereira VRA; Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Federal University of Pernambuco - Campus da Av. Prof. Moraes Rego, Recife, Brazil.
da Silva ED; Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Federal University of Pernambuco - Campus da Av. Prof. Moraes Rego, Recife, Brazil.
Junior PAS; Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Federal University of Pernambuco - Campus da Av. Prof. Moraes Rego, Recife, Brazil.
de Andrade Cavalcante MK; Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Federal University of Pernambuco - Campus da Av. Prof. Moraes Rego, Recife, Brazil.
de Melo SJ; Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Federal University of Pernambuco/UFPE, Recife, Brazil.

Chem Biol Drug Des ; 102(4): 843-856, 2023 10.

Article em En | MEDLINE | ID: mdl-37455325

RESUMO

Chagas' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease-Trypanosoma cruzi-has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4-amino-5-carbonitrile-pyrimidine analogues were proposed, synthesized (5a-f and 7g-h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC50 = 2.79 ± 0.00 µM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain.

Assuntos

Doença de Chagas; Tripanossomicidas; Trypanosoma cruzi; Humanos; Animais; Simulação de Acoplamento Molecular; Doença de Chagas/tratamento farmacológico; Domínio Catalítico; Tripanossomicidas/química; Mamíferos

Palavras-chave

Trypanosoma cruzi; cruzipain; lead compound; molecular docking; pyrimidines; structure-based

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tripanossomicidas / Trypanosoma cruzi / Doença de Chagas Limite: Animals / Humans Idioma: En Revista: Chem Biol Drug Des Assunto da revista: BIOQUIMICA / FARMACIA / FARMACOLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Brasil País de publicação: Reino Unido

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