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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection

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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]
Total Authors: 8
[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
Total Affiliations: 3
Document type: Journal article
Source: Experimental Parasitology; v. 219, DEC 2020.
Web of Science Citations: 1

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)

FAPESP's process: 18/03985-1 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme
Grantee:Anwar Shamim
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants
FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
Grantee:Andrei Leitão
Support type: Regular Research Grants
FAPESP's process: 14/07292-0 - Molecular design, trypanocidal and anticancer activities of covalent reversible inhibitors of cysteine proteases
Grantee:José Carlos Quilles Junior
Support type: Scholarships in Brazil - Doctorate