Synthesis, in silico studies, and biological evaluation of carvone derivatives as potential neuraminidase inhibitors

Abstract

Current outbreaks of highly pathogenic influenza strains have shown that new anti-influenza drugs need to be developed. To date, four antiviral agents have been approved for the treatment of influenza infection; zanamivir (RelenzaTM), oseltamivir (TamifluTM), peramivir, and most recently, laninamivir. However, increasing reports of these drugs resistance and side effects lead researchers to discover novel inhibitors against influenza. Carvone, which naturally can be found in spearmint essential oil, was studied as antiviral agents for its property. To explore the potential of carvone as neuraminidase (NA) inhibitors, a series of fourteen carvone derivatives compounds have been successfully synthesised using several strategies including epoxidation, epoxide ring opening, aminolysis, reductive amination, and condensation reaction. All the synthesised compounds obtained were elucidated using FT-IR, 1H NMR, 13C NMR, and ESI-MS. Molecular docking was conducted to gain insight into possible binding modes and preferred conformations of complex synthesised compounds in the NA active site. Based on the docking analysis, compound 3e was found to have the lowest energy binding (∆Gbind) value of -8.35 kcal/mol, which is closed to the reference drug oseltamivir (OTV) with ∆Gbind value of -8.58 kcal/mol. Molecular dynamics (MD) simulation was later performed to analyse the flexibility and stability of protein-ligand binding complex with NA protein. Our simulation study showed that the 3e-NA complex is as stable as the OTV-NA complex during the MD simulation of 50 ns. Compounds with good solubility in 2.5% DMSO were further evaluated for neuraminidase inhibition assay. Among ten compounds tested, compound 3e showed the highest inhibition activity of 60.95% inhibition with an IC50 value of 44.13 µM.