Trypanocidal potential of synthetic p-aminochalcones: In silico and in vitro evaluation

Naiara Dutra Barroso Gomes; Emanuel Paula Magalhães; Lyanna Rodrigues Ribeiro; John Washington Cavalcante; Marcelo Morais Gomes Maia; Felipe Ramon Cunha da Silva; Arif Ali; Márcia Machado Marinho; Emmanuel Silva Marinho; Hélcio Silva Dos Santos; Alice Maria Costa Martins; Ramon Róseo Paula Pessoa Bezerra de Menezes

doi:10.1016/j.bioorg.2023.106931

Trypanocidal potential of synthetic p-aminochalcones: In silico and in vitro evaluation

Bioorg Chem. 2023 Dec:141:106931. doi: 10.1016/j.bioorg.2023.106931. Epub 2023 Oct 20.

Affiliations

¹ Post-Graduate Program in Pharmaceutical Sciences, Federal University of Ceará, Fortaleza, CE, Brazil.
² Faculty of Pharmacy, Federal University of Ceará, Fortaleza, CE, Brazil.
³ Post-Graduate Program in Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
⁴ Theoretical and Eletrochemical Chemistry Research Group, State University of Ceará, Limoeiro do Norte, CE, Brazil; State University of Vale do Acaraú, Center for Exact Sciences and Technology, Sobral, CE, Brazil.
⁵ Theoretical and Eletrochemical Chemistry Research Group, State University of Ceará, Limoeiro do Norte, CE, Brazil.
⁶ State University of Vale do Acaraú, Center for Exact Sciences and Technology, Sobral, CE, Brazil.
⁷ Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil.
⁸ Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, CE, Brazil. Electronic address: ramonppessoa@ufc.br.

PMID: 37879182
DOI: 10.1016/j.bioorg.2023.106931

Abstract

Chagas disease (CD) is a neglected tropical disease of worldwide health concern, caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi), endemic in Latin America and present in North America and Europe. The WHO recommended drug for CD, benznidazole has low safety profile and several limitations. Therefore, an entity with better therapeutic potential to treat CD is required. Chalcones are an important class of compounds, which have shown antichagasic potential. Thus, the objective of this study was to evaluate the activity of synthetic p-aminochalcones against T. cruzi. Chalcones 1 and 2 were synthesized by Claisen-Schmidt condensation and characterized by both spectroscopic and theoretical methods. Initially, they were submitted to molecular docking simulations using cruzain and trypanothione reductase (TR) enzymes. It was expected to observe the possible interactions of chalcones with the catalytic site and other important regions of these main pharmacological targets of T. cruzi. Their cytotoxicity within host cells were assessed by MTT reduction assay using LLC-MK₂ cells, with CC₅₀ = 85.6 ± 9.2 µM and 1115 ± 381.7 µM for chalcones 1 and 2, respectively. These molecules were also tested against epimastigote and trypomastigote life forms of T. cruzi, causing reduction in the number of viable parasites. For the evaluation of the effect on intracellular amastigotes, infected LLC-MK2 cells were incubated with the chalcones for 24 h, causing reduction in the percentage of infected cells and the number of amastigotes/100 cells. Finally, flow cytometry assays were performed for analyzing cell death mechanisms (7-AAD/AxPE labelling), cytoplasmic ROS accumulation (DCFH-DA assay) and mitochondrial transmembrane potential disruption (Rho123 assay). Both chalcones (1 and 2) caused membrane damage, ROS accumulation and mitochondrial depolarization. In conclusion, the synthetic p-aminochalcones presented trypanocidal effect, causing membrane damage and oxidative stress. Their mechanism of action may be related to cruzain and TR inhibition.

Keywords: Chagas disease; Chalcone; Trypanosoma cruzi.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chagas Disease* / drug therapy
Chalcones* / pharmacology
Chalcones* / therapeutic use
Humans
Molecular Docking Simulation
Reactive Oxygen Species
Trypanocidal Agents* / chemistry
Trypanosoma cruzi*

Substances

Trypanocidal Agents
Reactive Oxygen Species
Chalcones