Regioisomerism and 5-substitution as promising approaches for molecular design of safer acetaminophen derivatives

Abstract

Acetaminophen is a widely used over-the-counter analgesic and antipyretic drug, but in large doses can produce hepatic and/or renal injury. Based on its human toxicity by N-acetyl-p- benzoquinone imine formation as reactive toxic intermediate, an acetaminophen regioisomer substituted on 5-position, named chloraminophen, was proposed. The electron and hydrogen transfers were related to the ionization potential and bond dissociation energies on phenol and acetamide moieties. These calculations were performed by using quantum chemical calculations at the density functional theory (DFT/B3LYP) with the 6-311 + + G(d,p) basis set. For acute toxicity study was performed using a single dose test of 300 or 2000 mg/kg. No differences were found in the biochemical parameters except for aspartate aminotransferase levels, probably due to corn oil used as dilution solvent. The second energy of hydrogen abstraction may have great impact on amino-phenols toxicity. The regioisomerism can be a useful strategy in drug design for safer acetaminophen derivatives.