Lipid-Optimized Sulfone-Bridged Cidofovir Prodrugs as Potent Antivirals Against Orthopoxviruses

The unprecedented global mpox outbreak highlights the urgent need for novel orthopoxvirus antivirals. In this study, we rationally designed and synthesized a series of cidofovir (CDV) prodrugs conjugated with diverse lipid chains via sulfur-containing bridge moieties. Structure–activity relationship analyses identified the sulfone group as optimal, with a C2H4 linker and an approximately 20-atom chain length providing ideal antiviral potency. Compound 13f exhibited antiviral activity against vaccinia virus (VACV) comparable to that of the reference brincidofovir (BCV), while 13i displayed 8.2-fold enhanced potency. Both derivatives demonstrated superior potency against monkeypox virus (MPXV) compared to BCV. Stability tests in biorelevant media and pharmacokinetic evaluations confirmed favorable oral formulation characteristics for 13f and 13i. Notably, 13i exhibited a favorable safety profile and significant therapeutic efficacy in both VACV-challenged BALB/c and MPXV-challenged severe combined immunodeficiency mouse models. Through systematic lipid-chain optimization, we identified 13i as a promising antiviral candidate with enhanced efficacy and favorable pharmaceutical properties.