Chemical Modification of Acetaminophen to Reduce Liver Toxicity and Enhance Drug Efficacy

Overview

Acetaminophen is a widely used non-opioid analgesic and antipyretic medication. Unfortunately, its toxicity is a leading cause of liver transplantation worldwide. NAPQi, the toxic form of acetaminophen produced after oxidizing in the body, is an electrophi le that depletes glutathione and eventually attacks liver proteins, which are nucleophilic. Existing approaches to acetaminophen modification to decrease toxicity are impractical as they modify functional groups necessary for acetaminophen’s analgesic prop erties. Thus, this research aims to reduce toxicity without sacrificing the drug’s efficacy by modifying acetaminophen’s benzene ring structure. It was hypothesized that sequential transition metal catalysis, involving precise C -Hsilylation of acetaminophen, followed by the nucleophilic addition of an alkyne to the silicon center, could decrease acetaminophen toxicity while maintaining its therapeutic effectiveness. The lowest unoccupied molecular orbital (LUMO) energy values of acetaminophen analogues were computed through Orca 5.0 and retrieved in Avogadro to assess toxicity. Docking simulations were then performed through AutoDock Vina to analyze the efficacy of acetaminophen analogues by evaluating their binding to transient receptor potential vanilloid 1 (TRPV1). An original scheme was developed and optimized to synthesize 2 -phenylalkynylsilyl acetaminophen. All acetaminophen analogues had higher LUMO energies than the original compound, indicating reduced nucleophilic reactivity and decreased liver toxicity. They also exhibited enhanced binding to TRPV1, demonstrating improved analgesic efficacy. 2 -phenylalkynylsilyl acetaminophen was synthesized through precise C -Hsilylation via sequential transition metal catalysis, followed by nucleophilic addition of an alkyne. The research further suggests a previously unknown mechanism of transition metal catalyst chemoselectivity.

Competition history

• JSHS 2025 Category not listed

Resources

• National JSHS abstract book ↗

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