Leishmaniasis is a neglected tropical disease, caused by distinct Leishmania species, which have significant public health challenges due to treatment limitations such as toxicity, high cost, and drug resistance. This study explores the in vitro potential of Malvidin and Echioidinin as probable antileishmanial agents against Leishmania amazonensis, L. braziliensis, and L. infantum, comparing their efficacy to Amphotericin B (AmpB), a standard drug. Malvidin was more potent than Echioidinin across all parasite stages and species. For L. amazonenses, Malvidin's inhibitory concentration (IC50) values were 197.71±17.20 μM and 258.07±17 μM (stationary and axenic amastigotes, respectively); whereas Echioidinin revealed IC50 values of 272.99±29.90 μM and 335.96±19.35 μM (stationary and axenic amastigotes, respectively). AmpB showed IC50 values of 0.06±0.01 μM and 0.10±0.03 μM, respectively. Malvidin demonstrated lower cytotoxicity activity in mammalian cells with a cytotoxic concentration (CC50) value of 2.920.31±80.29 μM, while AmpB's showed a value of 1.06±0.12 μM. Malvidin also exhibited favorable selectivity index (SI) values. Malvidin reduced infection rates by up to 35.75% in L. amazonensis-infected macrophages. In silico analysis uncovered strong binding interactions between Malvidin and enzyme arginase in the three species, with key residues such as HIS139 and PRO258 playing a crucial role. Tissue-specific markers expression analysis highlighted the potential Malvidin's modulation of genes involved in oxidative stress and DNA repair, including glyoxalase 1 (GLO1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1). The in vitro and in silico data corroborate the hypothesis that Malvidin is safe and can control the Leishmania parasites as a new natural compound for treatment. To further assess its therapeutic potential, in vivo studies are required to evaluate Malvidin's efficacy, safety, and pharmacokinetics in animal models, which will be essential for validating its role as a candidate for leishmaniasis treatment.
