Synthesis and leishmanicidal activity of eugenol derivatives bearing 1,2,3-triazole functionalities

Abstract

In this paper, it is described the synthesis and the evaluation of the leishmanicidal activity of twenty-six eugenol derivatives bearing 1,2,3-triazole functionalities. The evaluation of the compounds on promastigotes of Leishmania amazonensis (WHOM/BR/75/Josefa) showed that eugenol derivatives present leishmanicidal activities with varying degrees of effectiveness. The most active compound, namely 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) (IC₅₀ = 7.4 ± 0.8 μmol L^-1), also targeted Leishmania parasites inside peritoneal macrophages (IC₅₀ = 1.6 μmol L^-1) without interfering with cell viability. The cytotoxicity of 7k against macrophage cells presented IC₅₀ of 211.9 μmol L^-1 and the selective index was equal to 132.5. Under similar conditions, compound 7k was more effective than glucantime and pentamidine, two drugs currently in the clinic. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that eugenol bearing 1,2,3-triazole functionalities may represent a scaffold to be explored toward the development of new agents to treat leishmaniasis.

Keywords: Antileishmanial; Eugenol; Leishmaniasis; Leishmanicidal; Triazole.