SAPAP

Acetaminophen (APAP) overdose is a leading cause of acute liver failure, and N-acetylcysteine therapy is highly time dependent. APAP hepatotoxicity results from cytochrome P450-mediated oxidative bioactivation to N-acetyl-p-benzoquinone imine (NAPQI). Here, we report an electron effect-guided metabolic reprogramming strategy based on amide-to-thioamide modification to suppress APAP bioactivation while preserving efficacy. We synthesized a thioamide-modified APAP analogue, SAPAP, and evaluated its metabolism, hepatic safety, and pharmacological activity. SAPAP redirected metabolic flux toward glucuronide and sulfate conjugation while minimizing oxidative metabolite formation. In acute overdose and 28-day subchronic dosing models, SAPAP caused markedly less liver injury than equimolar APAP, with improved histopathology, reduced serum transaminases, and attenuated inflammatory responses. SAPAP also retained analgesic and antipyretic efficacy in established models. These findings demonstrate that thiocarbonyl-driven electronic effects can decouple therapeutic efficacy from hepatotoxic liability, offering a preventive strategy against APAP-induced liver injury.