Design, Synthesis, and Antileishmanial Activity of Novel C6-Substituted Eugenol Derivatives with a Triazole Linker

Abstract

Among tropical neglected diseases, leishmaniasis stands out. This parasitic infection occurs in numerous countries, affecting thousands of people worldwide. The currently available therapies present important limitations, including high toxicity, long treatment periods requiring parenteral administration, and the emergence of parasite resistance. Based on the known antileishmanial properties of eugenol and its derivatives, a series of novel disubstituted 1,2,3-triazoles was prepared via the classical 1,3-dipolar cycloaddition reaction, employing a eugenol-azide derivative. These compounds were subsequently evaluated against Leishmania amazonensis (promastigotes and amastigotes). Compound 4d emerged as the most active molecule in the series, exhibiting an IC50 = 3.98 ± 1.05 μM against amastigotes and a selectivity index greater than 50.25, thereby retaining and even enhancing the antileishmanial activity of its natural-product precursor.