Eugenol derivatives with 1,2,3-triazole moieties: Oral treatment of cutaneous leishmaniasis and a quantitative structure-activity relationship model for their leishmanicidal activity.

ABSTRACT

Leishmaniasis is a group of neglected vector-borne tropical diseases caused by protozoan parasites of the genus Leishmania that multiply within phagocytic cells and have a wide range of clinical manifestations. Cutaneous leishmaniasis (CL) is a serious public health that affects more than 98 countries, putting 350 million people at risk. There are no vaccines that have been proven to prevent CL, and the treatment relies on drugs that often have severe side effects, justifying the search for new antileishmanial treatments. In the present investigation, it is demonstrated that 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-methylbenzyl)-1H-1,2,3-triazole (7k) presents significant antileishmanial activity (IC50 of 7.4 µmol L-1 and 1.6 µmol L-1 for promastigote and amastigote forms, respectively), low cytotoxicity against macrophage cells (IC50 of 211.9 µmol L-1), and a selective index of 132.5. Under similar conditions, compound 7k outperformed glucantime and pentamidine, two commonly used drugs in clinics. In vivo assays on CL-infected female BALB/c mice demonstrated that compound 7k had activity similar to intralesional glucantime when administered orally, with decreased lesion and parasitic load, and a low systemic toxic effect. Given the importance of understanding the relationship between compound structure and biological activity in the research and development of new drugs, the development of a quantitative structure-activity relationship (QSAR) model for the leishmanicidal activity presented by the eugenol derivatives with 1,2,3-triazole functionalities is also described herein. This study demonstrates the therapeutic potential of orally active eugenol derivatives against CL and provides useful insights into the relationship between the chemical structures of triazolic eugenol derivatives and their biological profile.