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Leishmaniasis is a group of infectious diseases transmitted to humans during vector bites and caused by protozoans of the genus Leishmania. Conventional therapies face challenges due to their serious side effects, prompting research into new anti-leishmania agents. In this context, we investigated the effectiveness of morolic acid, a pentacyclic triterpene, on L. amazonensis promastigotes and amastigotes. The present study employed the MTT assay, cytokine analysis using optEIATM kits, an H2DCFDA test, and nitric oxide dosage involving nitrite production and Griess reagent. Morolic acid inhibited promastigote and axenic amastigote growth forms at IC50 values of 1.13 µM and 2.74 µM, respectively. For cytotoxicity to macrophages and VERO cells, morolic acid obtained respective CC50 values of 68.61 µM and 82.94 µM. The compound causes damage to the parasite membrane, leading to cellular leakage. In the infection assay, there was a decrease in parasite load, resulting in a CI50 of 2.56 µM. This effect was associated with immunomodulatory activity, altering macrophage structural and cellular parasite elimination mechanisms. Morolic acid proved to be an effective and selective natural compound, making it a strong candidate for future in vivo studies in cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

Leishmaniasis, caused by Leishmania parasites, presents a major global health challenge due to limitations of existing treatments, including toxicity, side effects, drug resistance, and high costs. This study utilized the MuDRA (Multi-Descriptor Read Across) model for virtual screening to identify potential anti-Leishmania infantum compounds. A set of 15 terpenes and steroids was screened, leading to the identification of four promising candidates-lupeol, xylodiol, morolic acid, and trachyloban-18-oic acid. These compounds demonstrated significant activity in both virtual screening and in vitro assays. To elucidate their potential mechanisms of action, we conducted molecular docking and dynamics studies, which revealed stable interactions with key target enzymes, such as trypanothione reductase and 14-alpha demethylase (CYP51), crucial to the parasite's survival and pathogenesis. These findings provide valuable insights into novel mechanisms for targeting leishmaniasis, offering a promising basis for the development of new therapeutics. The integration of computational and experimental methods in this study not only advances our understanding of potential anti-leishmanial agents but also highlights the effectiveness of this approach in discovering new drugs for neglected diseases. Further in vivo studies and clinical trials will be essential to validate the therapeutic potential of these., (© 2024 Wiley‐VCH GmbH.)