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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection

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Autor(es):
Quilles, Jr., Jose C. [1] ; Shamim, Anwar [1] ; Tezuka, Daiane Y. [1, 2] ; Batista, Pedro H. J. [1] ; Lopes, Carla D. [1, 2] ; de Albuquerque, Sergio [3] ; Montanari, Carlos A. [1] ; Leitao, Andrei [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Sao Carlos Inst Chem IQSC, Med & Biol Chem Grp NEQUIMED, Av Trabalhador Sao Carlense 400, BR-13566590 Sao Carlos, SP - Brazil
[2] Univ Sao Paulo, Programa Posgrad Interunidades Bioengn PPGIB, Sao Paulo, SP - Brazil
[3] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, Ribeirao Preto, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Experimental Parasitology; v. 219, DEC 2020.
Citações Web of Science: 0
Resumo

Chagas disease affects several countries around the world with health and sanitation problems. Cysteine proteases are essential for the virulence and replication of the Trypanosoma cruzi, being modulated by dipeptidyl nitriles and derivatives. Here, four dipeptidyl nitrile derivatives were assayed in three T. cruzi morphologies and two strains (Tulahuen and Y) using a set of assays: (i) analysis of the inhibitory activity against cysteine proteases; (ii) determination of the cytotoxic activity and selectivity index; (iii) verification of the inhibition of the trypomastigote invasion in the host cell. These compounds could inhibit the activity of cysteine proteases using the selective substrate Z-FR-MCA for the trypomastigote lysate and extracellular amastigotes. Interestingly, these compounds did not present relevant enzymatic inhibition for the epimastigote lysate. Most of the substances were also cytotoxic and selective against the trypomastigotes and intracellular amastigotes. The best compound of the series (Neq0662) could reduce the enzymatic activity of the cysteine proteases for the trypomastigotes and amastigotes. It was equipotent to the benznidazole drug in the cytotoxic studies using these two parasite forms. Neq0662 was also selective for the parasite, and it inhibited the invasion of the mammalian host cell in all conditions tested at 10 mu M. The stereochemistry of the trifluoromethyl group was an important factor for the bioactivity when the two diastereomers (Neq0662 and Neq0663) were compared. All-in-all, these results indicate that these compounds could move further in the drug development stage because of its promising bioactive profile. (AU)

Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
Beneficiário:Carlos Alberto Montanari
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/07292-0 - Planejamento molecular, atividade tripanossomicida e anticancerígena de inibidores covalentes reversíveis de cisteíno proteases
Beneficiário:José Carlos Quilles Junior
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 18/15904-6 - Caracterização de inibidores de cisteíno proteases com atividade antineoplásica por meio de ensaios in silico, celulares e análise química.
Beneficiário:Andrei Leitão
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 18/03985-1 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
Beneficiário:Anwar Shamim
Linha de fomento: Bolsas no Brasil - Pós-Doutorado