Dual antileishmanial and immunoregulatory activities of synthetic chalcones against Leishmania braziliensis.

Leishmaniasis remains a neglected tropical disease with limited therapeutic options and significant drug toxicity. In this study, two synthetic chalcones, (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-dimethylaminophenyl)prop-2-en-1-one (FER42) and (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (FER45), were evaluated for their antileishmanial and immunomodulatory activities. Both compounds were tested in vitro using J774 macrophages and parasite cultures by Leishmania braziliensis. Cytotoxicity (CC50) and antiparasitic activity (CI50) were assessed by the AlamarBlue assay and determined for promastigotes and amastigotes stages. Infection rates were quantified through optical microscopy analysis. Cytokine levels (TNF-α, IL-6, IL-1β, IL-10) were measured by ELISA, nitric oxide (NO) by the Griess reaction, and NF-κB gene expression was determined by RT-qPCR. FER42 and FER45 exhibited potent inhibitory activity against promastigote and amastigote forms while maintaining low cytotoxicity toward macrophages. Additionally, the compounds exhibited synergistic effects with amphotericin B. Treatment led to a marked decrease in the infection index and modulated the production of key pro- and anti-inflammatory mediators, including TNF-α, IL-6, IL-1β, IL-10, and nitric oxide. Treatment of infected macrophages with FER42 and FER45 further reduced NF-κB transcriptional expression, suggesting an immunoregulatory mechanism associated with the suppression of immune response. The results demonstrate that FER42 and FER45 combine antiparasitic activity with immunoregulatory properties, supporting their potential as candidates for safer and more effective treatments for leishmaniasis.