1. Antileishmanial activity evaluation of a natural amide and its synthetic analogs against Leishmania (V.) braziliensis: an integrated approach in vitro and in silico.
- Author
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da Silva MA, Fokoue HH, Fialho SN, Dos Santos APA, Rossi NRDLP, Gouveia AJ, Ferreira AS, Passarini GM, Garay AFG, Alfonso JJ, Soares AM, Zanchi FB, Kato MJ, Teles CBG, and Kuehn CC
- Subjects
- Amides chemistry, Animals, Cell Line, Tumor, Chlorocebus aethiops, Computer Simulation, Humans, Molecular Docking Simulation, NADH, NADPH Oxidoreductases antagonists & inhibitors, Piperidones chemistry, Vero Cells, Amides pharmacology, Leishmania braziliensis drug effects, Piperidones pharmacology, Trypanocidal Agents pharmacology
- Abstract
Leishmaniasis is considered a neglected disease, which makes it an unattractive market for the pharmaceutical industry; hence, efforts in the search for biologically active substances are hampered by this lack of financial motivation. Thus, in the present study, we report the leishmanicidal activity and the possible mechanisms of action of compounds with promising activity against the species Leishmania (V.) braziliensis, the causative agent of the skin disease leishmaniasis. The natural compound 1a (piplartine) and the analog 2a were the most potent against promastigote forms with growth inhibition values for 50% of the parasite population (IC
50 ) = 8.58 and 11.25 μM, respectively. For amastigote forms, the ICa50 values were 1.46 and 16.7 μM, respectively. In the molecular docking study, piplartine showed favorable binding energy (-7.13 kcal/mol) and with 50% inhibition of trypanothione reductase (IC50 ) = 91.1 μM. Preliminary investigations of the mechanism of action indicate that piplartine increased ROS levels, induced loss of cell membrane integrity, and caused accumulation of lipid bodies after 24 h of incubation at its lowest effective concentration (IC50 ), which was not observed for the synthetic analog 2a. The mode of action for the leishmanicidal activity of piplartine (1a) was assigned to involve affinity for the trypanothione reductase of Leishmania (V.) braziliensis TR.- Published
- 2021
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