Abstract
Malaria is responsible for thousands of deaths each year. Currently, artemisinin combination therapy (ACT) is used as first-choice medication against the disease. However, the emergence of resistant strains prompts the search for alternative compounds. The present study aimed to investigate the antiplasmodial activities of natural triterpenes (compounds 1 and 2), and semisynthetic derivatives 1a, 1b, 1c, and 1d. Antiplasmodial assays were carried out using the SYBR Green technique, whereas cytotoxicity was evaluated by the MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) method. Hemolytic assays were performed on human erythrocytes. An in silico analysis of the compounds against PfENR (Plasmodium falciparum 2-trans-enoyl-reductase) was carried out by molecular docking. Experiments with 1, and its derivatives against P. falciparum showed that 1a was very similar in terms of biological activity to compound 1 (half maximal inhibitory concentration (IC50) ca. 4 μM), whereas 1b, 1c, and 1d had reduced antiplasmodial activities (IC50 between 8-103 μM). The selectivity indexes of 1 and 1d for HepG2, and Vero cells were > 10. Docking results partially agreed with the in vitro experiments, with 1 and 1c having the best and worst affinities with PfENR, respectively. In conclusion, the results showed that 1 and 1d may serve as biotechnological tools in the development of antimalarial drugs.
Highlights
Malaria is a disease transmitted by female mosquitos of the genus Anopheles, in which the etiological agents are some protozoan species of the genus Plasmodium
The antiplasmodial assays showed that the natural compound 1 was the most active for P. falciparum with an IC50 = 4.4 μM
Concerning the comparison of the natural triterpene and its derivatives, it was observed that compound 1 obtained almost the same degree of activity as its diacetylated derivative (1a) at positions 3 and 16 of the molecule
Summary
Malaria is a disease transmitted by female mosquitos of the genus Anopheles, in which the etiological agents are some protozoan species of the genus Plasmodium. Its distinctive feature is the presence of whitish or yellowish, lepidote indumentum.[10] Concerning this species, several studies have demonstrated its potential against a variety of diseases, including leishmaniasis,[11,12,13] cell proliferation,[14] cancer,[15] and bacterial infections.[16] Based on this context, the present study aimed to investigate the antiplasmodial and cytotoxic activities of natural triterpenes (1 and 2) and semisynthetic derivatives of 1, as well as theoretically determine their binding affinities with the P. falciparum enzyme 2-trans-enoylACP‐reductase (PfENR) by molecular docking simulations. The fluorescence test was performed according to Lambros and Vanderberg.[20] After, the SYBR Green fluorimetric assay was conducted to evaluate antiplasmodial activity.[21] Plates containing the tested compounds and parasites had the supernatant discarded and for rinsing of the red cells, 100 μL of 1× phosphate buffer solution (PBS) was added per well and centrifuged at 700 g for 10 min. The analyses and visualizations were generated by the software USCF chimera.[31]
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