Ligand-based design and optimization of tecovirimat derivatives as potent antiviral agents against monkeypox virus.

Among orthopoxviruses, monkeypox virus (MPXV) is currently the most significant human pathogen due to ongoing outbreaks and global spread. Tecovirimat, an FDA-approved antiviral for orthopoxviruses, inhibits the viral p37 protein essential for viral egress and is used under expanded access for monkeypox treatment. To develop more accessible inhibitors and enhance structure-activity relationship (SAR) research, a new library of tecovirimat derivatives has been designed and synthesized. These compounds underwent phenotype determination to evaluate their antiviral properties, leading to the identification of C12 (EC50 = 12.14 nM, CC50 = 304.63 μM) as a promising lead compound. C12 demonstrated stable high plasma exposure following oral administration in mice, achieving a bioavailability (F) of 162 % and extensive distribution within the plasma. It also demonstrated low toxicity and good tolerability in mice, with a single dose of 2000 mg/kg or repeated doses of 100 mg/kg once daily for 14 days. Additionally, the P37 protein structure of VACN was employed for molecular docking to investigate potential binding interactions. Computational simulations suggest that C12 targets the same protein as tecovirimat, offering valuable insights for the rational design of next-generation analogs.