Investigation of the activity of 4-aminoquinolines as cysteine protease inhibitors with application in the treatment of Chagas disease.

IF 2.5 4区医学 Q2 PARASITOLOGY

Memorias do Instituto Oswaldo Cruz Pub Date : 2025-02-07 eCollection Date: 2025-01-01 DOI:10.1590/0074-02760240161

Rahamah Sheu-Idrees, Gabriel Vitor de Lima Marques, Pedro Augusto Lemos Santana, Lucas Abreu Diniz, Daniela de Melo Resende, Saidi Odoma, Omodamiro Olorunshola, Rafaela Salgado Ferreira, Silvane Maria Fonseca Murta, Vinícius Gonçalves Maltarollo, Renata Barbosa de Oliveira

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引用次数: 0

Abstract

Background: Chagas disease (CD) is a neglected tropical disease caused by Trypanosoma cruzi. The current drugs used to treat these diseases have limited efficacy and produce severe side effects. 4-aminoquinoline derivatives were shown to be a promising class of inhibitors of cysteine proteases cruzain and TbrCATL.

Objectives: To evaluate the trypanocidal activity of a new series of aminoquinolines as potential inhibitors of cruzain and TbrCATL.

Methods: Three aminoquinolines were synthesised and their in vitro activity was evaluated against cruzain and TbrCATL as well as against amastigotes and trypomastigotes forms of T. cruzi. In silico studies were also carried out to try to understand the experimental results.

Findings: Compound 5 showed promising activity against cruzain and TbrCATL, with better performance than E60, the reference drug. Compound 5 inhibited cruzain and TbrCATL at IC50 of 23 µM ±3 and 29 µM ±1, respectively, but this inhibition showed characteristics of promiscuous inhibition by colloidal aggregation. On the other hand, the compound 4 showed to be more promising activity against T. cruzi with IC50 2.57 µM ± 0.03 lower than the reference drug benznidazole 3.8 µM.

Main conclusions: The results of this study can guide new drug development for the treatment of trypanosomiasis.

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4-氨基喹啉类半胱氨酸蛋白酶抑制剂的活性及其在恰加斯病治疗中的应用。

背景：恰加斯病是由克氏锥虫引起的一种被忽视的热带病。目前用于治疗这些疾病的药物疗效有限，并且产生严重的副作用。4-氨基喹啉衍生物被证明是一类很有前途的半胱氨酸蛋白酶cruzain和TbrCATL抑制剂。目的：评价一类新的氨基喹啉类药物作为cruzain和TbrCATL的潜在抑制剂的杀锥虫活性。方法：合成3种氨基喹啉类药物，测定其对克氏T. cruzain和trbrcatl的体外活性，以及对克氏T. cruzain和trbrcatl的体外活性。也进行了计算机研究，试图理解实验结果。结果：化合物5对cruzain和TbrCATL具有良好的抗氧化活性，且优于对照药物E60。化合物5对cruzain和TbrCATL的抑制IC50分别为23µM±3和29µM±1，但这种抑制表现为胶体聚集的混杂抑制特征。化合物4对克氏锥虫的IC50值为2.57µM±0.03，比参比药物苯并硝唑的IC50值低3.8µM。主要结论：本研究结果可指导治疗锥虫病的新药开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Memorias do Instituto Oswaldo Cruz 医学-寄生虫学

CiteScore

5.00

自引率

3.60%

发文量

审稿时长

3-8 weeks

期刊介绍： Memórias do Instituto Oswaldo Cruz is a journal specialized in microbes & their vectors causing human infections. This means that we accept manuscripts covering multidisciplinary approaches and findings in the basic aspects of infectious diseases, e.g. basic in research in prokariotes, eukaryotes, and/or virus. Articles must clearly show what is the main question to be answered, the hypothesis raised, and the contribution given by the study. Priority is given to manuscripts reporting novel mechanisms and general findings concerning the biology of human infectious prokariotes, eukariotes or virus. Papers reporting innovative methods for diagnostics or that advance the basic research with these infectious agents are also welcome. It is important to mention what we do not publish: veterinary infectious agents research, taxonomic analysis and re-description of species, epidemiological studies or surveys or case reports and data re-analysis. Manuscripts that fall in these cases or that are considered of low priority by the journal editorial board, will be returned to the author(s) for submission to another journal.