Design, synthesis and preliminary biological evaluation of novel carbamoyl pyridone derivatives as potent inhibitors of Crimean-Congo hemorrhagic fever virus

The ongoing threat posed by Crimean-Congo hemorrhagic fever virus (CCHFV) highlights the urgent need for novel Antiviral agents. In this study, a drug repurposing strategy using baloxavir acid as the lead compound guided the design and synthesis of a series of carbamoyl pyridone (CAB) derivatives. A novel open-ring non-rigid CAB substitution scaffold was identified as a promising chemotype with strong inhibitory activity against CCHFV. Among the synthesized analogues, compound Z10 exhibited 99.94 % inhibition of viral replication at 5 μΜ in the preliminary screening. Subsequent concentration-gradient in vitro Antiviral assays determined an EC₅₀ value of 0.60 μΜ, which confirms its potent anti-CCHFV activity. Conversion of Z10 to its sodium salt (Z10Na) significantly improved solubility and enabled pharmacokinetic evaluation. Compared with baloxavir acid, Z10Na showed markedly higher systemic exposure after intravenous administration and maintained prolonged persistence under oral dosing, although with limited bioavailability. These findings highlight Z10Na as promising Antiviral candidates that combine structural novelty with favorable pharmacokinetic features, supporting their further optimization and in vivo validation as potential anti-CCHFV agents.

Crimean-Congo hemorrhagic fever virus; Design and synthesis; Pyridone; Viral L protein inhibitor; bunyavirus.