In vitro evaluation of 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against replicative and infective stages of Trypanosoma cruzi.

Autor: Faria AFM; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., de Souza Ferreira Pereira C; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Teixeira GP; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Dos Santos Galvão RM; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Pacheco PAF; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil., Bello ML; Department of Pharmaceuticals and Medicines, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., de Jesus DH; Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil., Calabrese K; Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil., Gonzaga DTG; Department of Pharmacy, West Zone Campus, State University of Rio de Janeiro (UERJ), Rio de Janeiro, Brazil., Boechat N; Fiocruz Institute of Drug Technology, Farmanguinhos, Fiocruz, Brazil., Faria RX; Laboratory for Evaluation and Promotion of Evaluation and Promotion of Environmental Health (L, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. salvador@ioc.fiocruz.com.br.
Jazyk: angličtina
Zdroj: Journal of bioenergetics and biomembranes [J Bioenerg Biomembr] 2023 Dec; Vol. 55 (6), pp. 409-421. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1007/s10863-023-09982-7
Abstrakt: Current treatment of Chagas disease (CD) is based on two substances, nifurtimox (NT) and benzonidazole (BZ), both considered unsatisfactory mainly due to their low activities and high toxicity profile. One of the main challenges faced in CD management concerns the identification of new drugs active in the acute and chronic phases and with good pharmacokinetic profiles. In this work, we studied the bioactivity of twenty 2-(1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against Trypanosoma cruzi epimastigotes and trypomastigotes. We identified seven derivatives with promising activity against epimastigote forms with IC50 values ranging from 6 µM to 44 µM. Most of the compounds showed no significant toxicity against murine macrophages. Our initial investigation on the mechanism of action indicates that this series of compounds may exert their anti-parasitic effect, inducing cell membrane damage. The results in trypomastigotes showed that one derivative, PDAN 78, satisfactorily inhibited metabolic alteration at all concentrations. Moreover, we used molecular modeling to understand how tridimensional and structural aspects might influence the observed bioactivities. Finally, we also used in silico approaches to assess the potential pharmacokinetic and toxicological properties of the most active compounds. Our initial results indicate that this molecular scaffold might be a valuable prototype for novel and safe trypanocidal compounds.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: