Back to Search Start Over

Antitrypanosomal Activity of 1,2,3-Triazole-Based Hybrids Evaluated Using In Vitro Preclinical Translational Models

Authors :
Lorraine Martins Rocha Orlando
Leonardo da Silva Lara
Guilherme Curty Lechuga
Giseli Capaci Rodrigues
Omar Ginoble Pandoli
Druval Santos de Sá
Mirian Claudia de Souza Pereira
Source :
Biology, Vol 12, Iss 9, p 1222 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC50 values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC50 ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure–activity relationship aimed at identifying new compounds potentially active against T. cruzi.

Details

Language :
English
ISSN :
20797737
Volume :
12
Issue :
9
Database :
Directory of Open Access Journals
Journal :
Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.1f983e5646b441299b7b5c4305f3522d
Document Type :
article
Full Text :
https://doi.org/10.3390/biology12091222