Biological Evaluation of 3-Aryl and/or 4-(N-Aryl)aminocoumarins Against Human Pathogens: Antileishmanial and Antiviral Activities

Background: Vector-borne diseases, such as leishmaniasis and arboviral infections, represent a great challenge to human health with limited therapeutic options. In addition, sexually transmitted infections, such as herpes, affect billions of people worldwide and the emergence of new strains resistant to common antivirals, such as acyclovir (ACV), poses a serious threat to humans. In this context, coumarins have proved to be a valuable source of new derivatives with promising biological activities to fight these diseases. Methodology: 3-aryl and/or 4-(N-aryl)aminocoumarins were synthesized, and their drug-like profile was evaluated using silico tools. Their biological activity against Leishmania amazonensis promastigotes was evaluated using the MTT assay, while their antiviral activity against replication of Chikungunya, Mayaro, Zika, and type 1 Herpes simplex virus (HSV-1) in Vero cells was analyzed using plaque reduction assays. Results: The in silico studies pointed to satisfactory pharmacokinetic and toxicological properties as drug candidates. Hence, their antileishmanial activity was evaluated. None of the compounds exhibited significant activity and compound 2b showed the highest activity (IC50 = 47.10 µM). We further evaluated their cytotoxicity and antiviral activity. Compound 2e showed good activity against ACV-sensitive and -resistant HSV-1 strains with EC50 values of 48.68 µM and 66.26 µM, respectively (selectivity index values of 12.5 and 9.2). Mechanism of action studies indicated that this compound acts at late steps of HSV-1 replication, such as virus egress. Conclusions: Compound 2e possesses a different mechanism of action compared to ACV and presents a promising alternative for the treatment of HSV-1 infections.