Physicochemical properties and cytochromes P-450 kinetics of 5,5-bis(4-fluorophenyl)imidazolidine-2,4-dione, the bis(para-fluorophenyl) derivative of phenytoin

Abstract

Phenytoin (PHT, brand name: Dilantin) is an anticonvulsant drug that is used in the treatment of epilepsy. PHT is metabolically inactivated by cytochromes P-450 (CYP) catalyzed aromatic hydroxylation at the para position. Therefore, Nelson et al. hypothesized that this metabolic pathway would be slowed or blocked for a PHT derivative with fluorines at the para positions of the aromatic rings (pF-PHT) resulting in a molecule with increased antiseizure activity and longer duration of action relative to PHT. Interestingly, pF-PHT is less active than PHT, but has a much longer duration of action. Nelson et al. hypothesized that differences in physicochemical properties must contribute to the poor activity of pF-PHT. Thus, pF-PHT was synthesized to compare its physicochemical properties with those of PHT. In addition, the kinetics of CYP catalyzed oxidation were compared using Sprague Dawley (SD) rat liver microsomes because PHT is metabolically inactivated by CYP in the liver. The previously reported synthesis of pF-PHT employs a highly toxic reagent and produces a highly poisonous gas. Therefore, a safer synthetic route for pF-PHT was developed. This synthetic approach utilizes three steps: 1) a thiamine catalyzed benzoin condensation of para-fluorobenzaldehyde, 2) a nitric acid oxidation of the benzoin product to the corresponding benzil derivative, and 3) a microwave-assisted phenytoin synthesis of this benzil derivative with urea. There are no significant differences in conjugation, acidity, and lipophilicity between PHT and pF-PHT. Therefore, our results do not support the hypothesis that the low activity of pF-PHT relative to PHT results from variations in physicochemical properties. While PHT and pF-PHT have the same apparent binding affinity for the CYP proteome of the SD rat liver microsome, pF-PHT undergoes CYP catalyzed oxidation at half the rate in comparison to PHT.