Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection.

Abstract

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 μM. 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.

• Authors: José C Quilles Jr, Anwar Shamim, Daiane Y Tezuka, Pedro H J Batista, Carla D Lopes, Sérgio de Albuquerque, Carlos A Montanari, Andrei Leitão
• Journal: Experimental parasitology (Exp Parasitol) Vol. 219 Pg. 108032 (Dec 2020) ISSN: 1090-2449 [Electronic] United States
• PMID: 33137308 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antiparasitic Agents
• Cysteine Proteinase Inhibitors
• Nitriles
• Tetrazolium Salts
• Thiazoles
• thiazolyl blue

Topics

• Analysis of Variance
• Animals
• Antiparasitic Agents (chemistry, pharmacology)
• Area Under Curve
• Cell Line
• Cell Survival
• Cysteine Proteinase Inhibitors (chemistry, pharmacology, toxicity)
• Haplorhini
• Kidney (cytology)
• Nitriles (chemistry, pharmacology)
• Proteolysis
• Stereoisomerism
• Tetrazolium Salts
• Thiazoles
• Trypanosoma cruzi (drug effects, enzymology, growth & development, metabolism)