Synthesis and Evaluation of the Antileishmanial Activity of Novel Eugenol Analogs Containing 1,2,3-Triazole Fragments against Intracellular Leishmania braziliensis

• Published in: Journal of the Brazilian Chemical Society Vol. 34; no. 12; pp. 1810 - 1824
• Main Authors: Evangelista, Roberta, Pereira, Larissa, de Souza, Luciana, Costa, Adilson, da Silva, Danilo, de Oliveira, Fabrício, Vaz, Boniek, Bressan, Gustavo, Fietto, Juliana, Teixeira, Róbson
• Format: Journal Article
• Language: English
• Published: Sociedade Brasileira de Química 2023
• Subjects: CHEMISTRY, MULTIDISCIPLINARY; eugenol analogs; ortho-eugenol; leishmaniasis; cutaneous leishmaniasis; 1,2,3-triazoles
• ISSN: 0103-5053; 1678-4790
• DOI: 10.21577/0103-5053.20230073

This investigation describes the synthesis of eugenol analogs presenting 1,2,3-triazole fragments and evaluation of their antileishmanial activity. The alkylation of guaiacol (1) with allyl bromide afforded 1-(allyloxy)-2-methoxybenzene (2) (93% yield). The Claisen rearrangement conducted with 1 gave ortho eugenol (3) (82% yield). Alkylation procedures performed with 3 produced 1-allyl3-methoxy-2-(prop-2-yn-1-yloxy)benzene (4) (73% yield) and 1-allyl-3-methoxy-2-(pent-4-yn1-yloxy)benzene (6) (53% yield). The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reactions involving alkynes 4 and 6 with different benzylic azides afforded twenty-two eugenol analogs with 1,2,3-triazole functionalities (48-93% yield). We screened the compounds at 10 μmol L-1 against Leishmania braziliensis intracellular amastigotes during macrophage infection. The action of these compounds was compared with the known leishmanicidal drug amphotericin B. None of the analogs were toxic to macrophages at 10 μmol L-1. The cytotoxic concentration at 50% (CC50), effective concentration at 50% (EC50), and selectivity index (SI) were determined to the best compounds 4-((2-allyl-6-methoxy)phenoxymethyl)-1-(4-chlorobenzyl)-1H-1,2,3-triazole (8c) and 4-((2-allyl-6-methoxy)phenoxymethyl)-1-(4-trifluoromethoxybenzyl)-1H-1,2,3-triazole (8h). They showed a significant leishmanicidal effect, with EC50 of 28.09 µmol L-1 (8c) and 52.03 µmol L-1 (8h). The SIs were 9.7 for 8c and > 5.7 for 8h. These compounds have the potential as new leishmanicidal agents against L. braziliensis and may represent a starting point for the development of alternative treatments for cutaneous leishmaniasis.