Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin

Substituting hydrogen atoms with fluorine alters physicochemical properties often resulting in improved drug action relative to the parent molecule. The high electronegativity of fluorine changes the electron density distribution of the molecule; however, the substitution does not significantly chan...

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Main Authors: Hannah L. Cure, Thomas A. Shell
Format: Article
Language:English
Published: Elsevier 2025-01-01
Series:Results in Chemistry
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Online Access:http://www.sciencedirect.com/science/article/pii/S2211715624006143
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author Hannah L. Cure
Thomas A. Shell
author_facet Hannah L. Cure
Thomas A. Shell
author_sort Hannah L. Cure
collection DOAJ
description Substituting hydrogen atoms with fluorine alters physicochemical properties often resulting in improved drug action relative to the parent molecule. The high electronegativity of fluorine changes the electron density distribution of the molecule; however, the substitution does not significantly change the size of the molecule because hydrogen and fluorine have similar atomic radii. A trifluoroacetamido derivative (TFA-phenacetin) of phenacetin, an analgesic antipyretic drug, was synthesized to compare its lipophilicity to the parent molecule by determining octanol–water partition coefficients. TFA-phenacetin is over seven times more lipophilic than phenacetin, which suggests that TFA-phenacetin would have better bioavailability relative to phenacetin. The kinetics of cytochromes P-450 (CYP) catalyzed oxidation of phenacetin and TFA-phenacetin were compared using Sprague Dawley (SD) rat liver microsomes. Phenacetin and TFA-phenacetin have the same apparent binding affinity for the SD rat liver microsome CYP proteome and undergo CYP catalyzed oxidation at the same rate in the presence of SD rat liver microsomes.
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spelling doaj-art-01f7a852313b4a5ca1476e753ec34bdb2025-01-29T05:00:34ZengElsevierResults in Chemistry2211-71562025-01-0113101918Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetinHannah L. Cure0Thomas A. Shell1Department of Chemistry and Physics, College of Mathematics, Sciences, and Health Professions, Lincoln Memorial University, 6965 Cumberland Gap Parkway, Harrogate, TN, 37752, United StatesCorresponding author.; Department of Chemistry and Physics, College of Mathematics, Sciences, and Health Professions, Lincoln Memorial University, 6965 Cumberland Gap Parkway, Harrogate, TN, 37752, United StatesSubstituting hydrogen atoms with fluorine alters physicochemical properties often resulting in improved drug action relative to the parent molecule. The high electronegativity of fluorine changes the electron density distribution of the molecule; however, the substitution does not significantly change the size of the molecule because hydrogen and fluorine have similar atomic radii. A trifluoroacetamido derivative (TFA-phenacetin) of phenacetin, an analgesic antipyretic drug, was synthesized to compare its lipophilicity to the parent molecule by determining octanol–water partition coefficients. TFA-phenacetin is over seven times more lipophilic than phenacetin, which suggests that TFA-phenacetin would have better bioavailability relative to phenacetin. The kinetics of cytochromes P-450 (CYP) catalyzed oxidation of phenacetin and TFA-phenacetin were compared using Sprague Dawley (SD) rat liver microsomes. Phenacetin and TFA-phenacetin have the same apparent binding affinity for the SD rat liver microsome CYP proteome and undergo CYP catalyzed oxidation at the same rate in the presence of SD rat liver microsomes.http://www.sciencedirect.com/science/article/pii/S2211715624006143PhenacetinFluorine derivativeLipophilicity
spellingShingle Hannah L. Cure
Thomas A. Shell
Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
Results in Chemistry
Phenacetin
Fluorine derivative
Lipophilicity
title Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
title_full Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
title_fullStr Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
title_full_unstemmed Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
title_short Physicochemical properties and cytochromes P-450 kinetics of the trifluoroacetamido derivative of phenacetin
title_sort physicochemical properties and cytochromes p 450 kinetics of the trifluoroacetamido derivative of phenacetin
topic Phenacetin
Fluorine derivative
Lipophilicity
url http://www.sciencedirect.com/science/article/pii/S2211715624006143
work_keys_str_mv AT hannahlcure physicochemicalpropertiesandcytochromesp450kineticsofthetrifluoroacetamidoderivativeofphenacetin
AT thomasashell physicochemicalpropertiesandcytochromesp450kineticsofthetrifluoroacetamidoderivativeofphenacetin