Publication date: Jul 17, 2026
Molnupiravir, an oral prodrug of β-D-N-hydroxycytidine (NHC), is a broad-spectrum antiviral agent. However, its clinical efficacy is hampered by suboptimal plasma stability and inefficient intracellular monophosphorylation. To circumvent these pharmacological limitations, a novel series of NHC dual-prodrug derivatives was designed and synthesized by integrating 5′-ProTide and N-ester modification strategies. Structure-activity relationship (SAR) analysis revealed that derivatives functionalized with short-chain N-esters achieved a more favorable balance between antiviral potency and cytotoxicity. Specifically, 5b exhibited favorable anti-SARS-CoV-2 activity with low cytotoxicity, displaying anti-SARS-CoV-2 activity (EC = 3. 22 μM) with negligible cytotoxicity. Subsequent mechanistic studies supported that the ProTide moiety mediates rapid enzymatic activation, effectively bypassing the rate-limiting first phosphorylation step to release the nucleoside monophosphate. Furthermore, pharmacokinetic evaluations revealed a tunable profile: 4 demonstrated significantly enhanced metabolic stability in human plasma, suggesting its potential as a long-circulating systemic reservoir, whereas 5b displayed favorable in vitro antiviral activity, likely associated with its balanced physicochemical properties and rapid esterase-mediated conversion to the more plasma-stable ProTide intermediate 4. Consequently, these findings demonstrate prodrugs 4 and 5b represent promising antiviral agents with favorable metabolic stability and high potency.
| Concepts | Keywords |
|---|---|
| Antiviral activity | |
| N(4)-ester modification | |
| Plasma stability | |
| ProTide | |
| SARS-CoV-2 | |
| β-D-N(4)-hydroxycytidine |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | NHC |
| drug | DRUGBANK | Isoxaflutole |
| pathway | REACTOME | Release |