Synthesis of 1,2,3-Triazole-Containing Methoxylated Cinnamides and Their Antileishmanial Activity against the Leishmania braziliensis Species

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 8; p. 1113
• Main Authors: Santos, Fabíola Suelen dos, Freitas, Rossimiriam Pereira de, Freitas, Camila Simões de, Mendonça, Débora Vasconcelos Costa, Lage, Daniela Pagliara, Tavares, Grasiele de Sousa Vieira, Machado, Amanda Sanchez, Martins, Vivian Tamieti, Costa, Adilson Vidal, Queiroz, Vagner Tebaldi de, de Oliveira, Mariana Belizario, Oliveira, Fabrício Marques de, Antinarelli, Luciana Maria Ribeiro, Coimbra, Elaine Soares, Pilau, Eduardo Jorge, da Silva, Geovane Perez, Coelho, Eduardo Antonio Ferraz, Teixeira, Róbson Ricardo
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 07-08-2023; MDPI
• Subjects: Acids; Biological activity; cinnamic acid derivatives; click chemistry; CuAAC; Cytotoxicity; Infections; Leishmania braziliensis; NMR; Nuclear magnetic resonance; Parasites; Parasitic diseases; tegumentary leishmaniasis; Toxicity; Tropical diseases
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph16081113

Leishmaniasis is a group of infectious diseases caused by protozoan parasites that belong to the genus Leishmania. Currently, there is no human vaccine, and the available treatments are associated with toxicity, high cost, and the emergence of resistant strains. These factors highlight the need to identify new antileishmanial candidates. In this study, we synthesized twenty-four methoxylated cinnamides containing 1,2,3-triazole fragments and evaluated their antileishmanial activity against the Leishmania braziliensis species, which is the main etiological agent responsible for American Tegumentary Leishmaniasis (ATL). The cinnamides were synthetically prepared using nucleophilic acyl substitution and copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions. The compounds were characterized using infrared, nuclear magnetic resonance, and high-resolution mass spectrometry techniques. We performed preliminary studies to evaluate the biological activity of these compounds against L. braziliensis promastigotes and axenic amastigotes. Compound 28, N-((1-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-1H-1,2,3-triazole-4-yl) methyl)-3,4-dimethoxy cinnamide, demonstrated relevant antileishmanial activity with low toxicity in murine cells. The selectivity index values for this compound were superior compared with data obtained using amphotericin B. Furthermore, this cinnamide derivative reduced the infection percentage and number of recovered amastigotes in L. braziliensis-infected macrophages. It also induced an increase in reactive oxygen species production, depolarization of the mitochondrial potential, and disruption of the parasite membrane. Taken together, these findings suggest that this synthetic compound holds potential as an antileishmanial candidate and should be considered for future studies in the treatment of ATL.