João Sousa Janela
| New O-Prenylated Caffeic Acid Amides with Selective Toxicity Against Trypanosoma cruzi Amastigotes. Design, Synthesis and Structure-Activity Relationships |
| João Sousa Janela1, Lucas de Oliveira Pires2, Afonso Santine M. M. Velez2, Fábio da Costa Rocha2, Débora Decoté-Ricardo3, Marco Edilson Freire de Lima2, Rosane Nora Castro2, Fernanda M. F. Roleira1, Elisiário J. Tavares da Silva1 1 CERES, Universidade de Coimbra, Faculdade de Farmácia, Laboratório de Química Farmacêutica, Azinhaga de Santa Comba, Pólo III – Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal; 2 Universidade Federal Rural do Rio de Janeiro, Instituto de Química, Departamento de Química Orgânica, BR 465, Km 07, CEP: 23.890-000, Seropédica, RJ, Brasil; 3 Universidade Federal Rural do Rio de Janeiro, Instituto de Veterinária, Departamento de Microbiologia e Imunologia Veterinária, BR 465, Km 07, CEP: 23.890-000, Seropédica, RJ, Brasil; |
| Abstract Chagas’ disease arises as an emergent parasitosis caused by the infection with Trypanosoma cruzi, with only two drugs available for its treatment [1]. Cinnamic acid derivatives, such as esters and amides, are naturally occurring compounds from plant’s metabolism. Their phenylpropanoid scaffold is privileged due to its structural simplicity and broad-spectrum biological properties, such as antiproliferative, antimicrobial, anti-inflammatory, antiparasitic, and antioxidant. In this context, they can be considered promising compounds in search for new drugs for Chagas’ disease. Among them, caffeic acid and their esters and amides are often highlighted as the most attractive due to its assorted biological profile [2]. O-prenylation is described as a structural modification that benefits the crossing of cell membranes [3], which seems appropriate when designing compounds to target single-celled protozoa. Based on this, it was designed and synthesized caffeic acid amides and their respective new 4-O-prenylated analogues and tested their activity on amastigotes of T. cruzi, and their selectivity using host cells. N-alkylamides were more active against amastigotes in comparison to aromatic amides and displayed no toxicity against host cells. The most active compound (4-O-prenyl-N-pentylcaffeic acid amide) presented an IC50 of 7.54 ± 1.71 µM highlighting the importance of O-prenylation on the catechol moiety for both toxicity and selectivity against T. cruzi. |
| References [1] Jackson, Y. et al. Tolerance to nifurtimox and benznidazole in adult patients with chronic Chagas’ disease. J Antimicrob Chemother 2020, 75, 690-696. doi:10.1093/jac/dkz473 [2] Birková, A. et al. Caffeic acid: a brief overview of its presence, metabolism, and bioactivity. Bioact Compd health dis 2020, 3(4), 74-81. doi:10.31989/bchd.v3i4.692 [3] Oufensou, S. et al. Prenylated trans-cinnamic esters and ethers against clinical Fusarium spp.: repositioning of natural compounds in antimicrobial discovery. Molecules 2021, 26, 658. doi:10.3390/molecules26030658 Acknowledgments: The authors wish to acknowledge FCT – Fundação para a Ciência e a Tecnologia for their financial support, including research unit funding (projects UID/00102/2025 and UID/PRR/00102/2025) and PhD grant funding (reference 2022.13608.BD). |