The effect of fluorine substitution on the physicochemical properties and the cytochromes P-450 kinetics of acetaminophenThomas A. Shell and Hannah L. Cure Department of Biology and Chemistry, College of Mathematics, Sciences, and Health Professions, Lincoln Memorial University, Harrogate, USA
E-mail: thomas.shell@lmunet.edu Received: 13 September 2024 Accepted: 5 November 2025 Abstract: Substituting fluorine for hydrogen atoms of drugs alters their physicochemical properties, which often improves these properties for drug action. Fluorine and hydrogen have similar atomic radii; therefore, this substitution does not significantly change molecular size. However, the high electronegativity of fluorine does change the electron density distribution of the molecule. The physicochemical properties of four derivatives of acetaminophen (APAP), an analgesic antipyretic, with a fluorine substituent on the aromatic ring were evaluated. In addition, the kinetics of cytochromes P-450 (CYP) catalysed oxidation of these fluorinated APAP derivatives were studied using Sprague–Dawley (SD) rat liver microsomes. The trifluoroacetamido APAP derivatives are significantly more acidic and more lipophilic than their acetamido analogue. APAP derivatives with a fluorine substituent at the 2 position are slightly more acidic and less lipophilic their constitutional isomer with fluorine at the 3 position. The studied fluorinated acetaminophen derivatives undergo CYP catalysed oxidation in the presence of SD rat liver microsomes at half the rate or slower than APAP. The APAP derivatives with fluorine at the 2 position have significantly lower apparent binding affinities than APAP, while the derivatives with fluorine at the 3 position have even lower apparent binding affinities. Keywords: Acetaminophen; Paracetamol; Fluorine derivative; Lipophilicity Full paper is available at www.springerlink.com. DOI: 10.1007/s11696-025-04492-9
Chemical Papers 80 (2) 1831–1840 (2026) |
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