New Series of 3-Pyridyl-1,3-Thiazoles: In Vitro and In Vivo Anti-Trypanosomatidae Profile, in vitro and in silico Mechanism of Action approach

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-12-20 DOI:10.1016/j.ejmech.2024.117191
Vanessa Gouveia de Melo Silva, Lucas Manoel da Silva Sousa, Expedito Lopes Fernandes Junior, Graziella Leite Brondani, Isabeli Maria de Albuquerque Oliveira, Danilo Cesar Galindo Bedor, Isabella Barbosa Pereira Lopes, Fabio André Brayner, Luiz Carlos Alves, Marton Kaique de Andrade Cavalcante, Daniele Santana de Souza Oliveira, Maria Carolina Accioly Brelaz-de-Castro, Policarpo Ademar Sales Junior, Valéria Rêgo Alves Pereira, Ana Cristina Lima Leite
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引用次数: 0

Abstract

Trypanosomatidae diseases, such as Chagas disease and leishmaniasis, are caused by protozoan parasites of the Trypanosomatidae family, namely Trypanosoma cruzi and Leishmania species, respectively. There is an urgent need for new therapies. Both pyridine and thiazole rings are recognized as important scaffolds in medicinal chemistry. This study reports the synthesis of 3-pyridyl-1,3-thiazole derivatives (1–18) and their evaluation through in vitro and in vivo assays. In vitro tests were conducted against T. cruzi, L. amazonensis, and L. infantum, with cytotoxicity assessed using L929 fibroblasts and RAW 264.7 macrophages. Mode of action studies included in vitro assays and in silico simulations. Fourteen compounds exhibited trypanocidal activity with IC50 values ranging from 0.2 to 3.9 μM, outperforming benznidazole (4.2 μM). Compound 7 displayed an IC50 of 0.4 μM and a selectivity index of 530.8. However, the compounds were inactive in in vivo assays at a dose of 100 mg/kg/day. Compounds 1, 7, 8, and 10 demonstrated trypanostatic effects, mitochondrial disruption, apoptosis induction, and parasite membrane damage. These compounds also modulated nitric oxide, IL-6, IL-10 and TNF production. In silico analysis indicated strong interactions with cruzain and favorable bioavailability, drug-likeness, and stability profiles. The leishmanicidal activity was negligible or absent. Despite promising in vitro trypanocidal activity, further structural optimization or formulation strategies are required to enhance oral stability and bioavailability, providing a foundation for the development of new therapeutic agents.

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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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