Discovery of Synthetic Imine-Chalcones Targeting Mayaro Virus Replication

Mayaro virus (MAYV) is an arthritogenic alphavirus transmitted by mosquitoes and is the causative agent of Mayaro fever. This disease is associated with symptoms such as arthralgia and myalgia, which may persist for months or even years. Currently, no vaccine or specific antiviral therapy is available. This study aimed to assess the antiviral activity of synthetic imine-chalcone derivatives (1a-1d) against MAYV replication in Vero cells and predict their pharmacokinetic and toxicological properties. All compounds presented low cytotoxicity, with CC₅₀ values ranging from 249.92 µM to >1000 µM. Additionally, the derivatives showed good antiviral activity, with compound 1a being the most potent (EC₅₀ = 12.15 μM; SI = 31.47), and 1b being the most selective (EC₅₀ = 16.92 μM; SI > 59.10). Mechanistic assays revealed that compounds 1a and 1b primarily inhibit early events in the MAYV life cycle, such as viral adsorption (1a: 51.53%; 1b: 59.35%) and entry (1a: 71.26%; 1b: 54.21%). Compound 1b also impaired virus egress, while none of the compounds exhibited strong virucidal activity. Finally, in silico ADMET predictions suggested favorable pharmacokinetic and toxicological parameters for compounds 1a and 1b. Overall, our work demonstrated for the first time the activity and safety of imine-chalcones against MAYV.