Trypanocidal Mechanism of Action and in silico Studies of p-Coumaric Acid Derivatives.

Susiany P Lopes,Damião P De Sousa,Ramon R P P B De Menezes Menezes,Alice M C Martins,Marilia L Monteiro,Reinaldo N Almeida,Yunierkis P Castillo

doi:10.3390/ijms20235916

Abstract

Trypanosoma species are responsible for chronic and systemic infections in millions of people around the world, compromising life quality, and family and government budgets. This group of diseases is classified as neglected and causes thousands of deaths each year. In the present study, the trypanocidal effect of a set of 12 ester derivatives of the p-coumaric acid was tested. Of the test derivatives, pentyl p-coumarate (7) (5.16 ± 1.28 μM; 61.63 ± 28.59 μM) presented the best respective trypanocidal activities against both epimastigote and trypomastigote forms. Flow cytometry analysis revealed an increase in the percentage of 7-AAD labeled cells, an increase in reactive oxygen species, and a loss of mitochondrial membrane potential; indicating cell death by necrosis. This mechanism was confirmed by scanning electron microscopy, noting the loss of cellular integrity. Molecular docking data indicated that of the chemical compounds tested, compound 7 potentially acts through two mechanisms of action, whether by links with aldo-keto reductases (AKR) or by comprising cruzain (CZ) which is one of the key Trypanosoma cruzi development enzymes. The results indicate that for both enzymes, van der Waals interactions between ligand and receptors favor binding and hydrophobic interactions with the phenolic and aliphatic parts of the ligand. The study demonstrates that p-coumarate derivatives are promising molecules for developing new prototypes with antiprotozoal activity.

Highlights

Neglected diseases are a group of diseases which compromise quality of life and bring death to a considerable part of the world’s population, especially in underdeveloped and developing countries [1,2]
Compounds 1–8 were prepared by Fischer esterification, the products were obtained within 5–27 h, presenting satisfactory yields (34.50–90.63%)
Due to the high selectivity of compound 7, in flow cytometry analyses we observed reductions in the percentage of viable cells, and increases in the percentage of cells labeled with 7-AAD, increases in reactive oxygen species, and loss of mitochondrial membrane potentials

Summary

Introduction

Neglected diseases are a group of diseases which compromise quality of life and bring death to a considerable part of the world’s population, especially in underdeveloped and developing countries [1,2]. It is estimated that these diseases affect more than one billion people around the world [3,4,5]. Chagas’ disease (CD) presents two clinical stages, an acute phase where symptoms are more asymptomatic, and a chronic phase which leads to heart failure or even death [13]. Two drugs are used against the disease; benznidazole and nifurtimox [14]. Both present side effects ranging from allergic reactions, to fever, insomnia, and gastrointestinal symptoms such as weight loss and nausea [15,16]. The search for new effective and safe compounds to treat Chagas disease has been the aim of various studies [20]

Methods

Results

Conclusion