Synthesis and leishmanicidal activity of eugenol triazolic derivatives

Eugenol (4-allyl-2-methoxy phenol) is a natural product found in several aromatic plants. It presents important biological activities including leishmanicidal [1,2]. It is herein described the synthesis and the evaluation of the leishmanicidal activity of eugenol derivatives bearing 1,2,3-triazole functionalities. Eugenol was extracted via hydrodistillation from dried flower buds of Eugenia caryophyllata (=Syzygium aromaticum). Alkylation reactions of eugenol afforded terminal alkynes in good yields. The key reaction involved in the preparation of eugenol derivatives with triazolic moieties corresponded to the Copper(I)-catalyzed Azide- Alkyne Cycloaddition (CuAAC), also known as click reaction, between alkynylated eugenol derivatives and different benzyl azides. Reactions were conducted in EtOH/H2O (1:1 v/v) at room temperature and afforded compounds with synthetically useful yields (77%─91%, Scheme 1). In most cases, click reactions last less than 1 minute. The evaluation of the twenty-six synthesized 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 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. It is believed that eugenol triazolic derivatives may represent a scaffold to be explored toward the development of new agents to treat leishmaniasis.