Abstract
In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions of people worldwide and are creating a public health problem. The present work evaluates the leishmanicidal and antiplasmodial action of a series of twelve p-coumaric acid derivatives. Of the tested derivatives, eight presented antiparasitic activities 1–3, 8–12. The hexyl p-coumarate derivative (9) (4.14 ± 0.55 μg/mL; selectivity index (SI) = 2.72) showed the highest leishmanicidal potency against the Leishmania braziliensis amastigote form. The results of the molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), and DNA topoisomerase 2 (TOP2), all of which are key enzymes in the development of Leishmania braziliensis. The data indicate that these enzymes interact via Van der Waals bonds, hydrophobic interactions, and hydrogen bonds with phenolic and aliphatic parts of this same compound. Of the other compounds analyzed, methyl p-coumarate (64.59 ± 2.89 μg/mL; IS = 0.1) demonstrated bioactivity against Plasmodium falciparum. The study reveals that esters presenting a p-coumarate substructure are promising for use in synthesis of derivatives with good antiparasitic profiles.
Highlights
Neglected diseases typically affect tropical and subtropical regions, principally developing countries [1,2], with poor and marginalized people [3] being the most affected
We explored GSK3: the ATP binding site (GSK3) for ligand binding to these two sites in Leishmania braziliensis
Twelve compounds were evaluated for antiparasitic potential against L. braziliensis amastigotes, against Plasmodium falciparum, and for cytotoxicity in U-937 macrophages
Summary
Neglected diseases typically affect tropical and subtropical regions, principally developing countries [1,2], with poor and marginalized people [3] being the most affected. World Health Organization, neglected diseases affect more than 1 billion people around the world [4]. These diseases cause great impacts on public health and include Chagas disease, leishmaniasis, malaria, schistosomiasis, onchocerciasis, lymphatic filariasis, trypanosomiasis and dengue [5]. Leishmaniasis, caused by parasitic protozoans of the Leishmania genus, is a neglected disease that affects both humans, and domestic and wild mammals [6,7,8,9,10]. Caused by unicellular eukaryotic protozoans of the Plasmodium genus such as Plasmodium falciparum and Plasmodium vivax, leishmaniasis quickly develops
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