New spirohydantoins derived from β-tetralone: Design, synthesis and evaluation of their pharmacokinetically relevant propertie

Abstract

To create new anticonvulsant drugs, two series of spirohydantoins derived from ?-tetralone bearing a 4-substituted benzyl group (1a?1g) or a 2-(4-substituted phenyl)-2-oxoethyl group (2a?2f) in position 3 of the hydantoin ring were synthesized. The chemical structure of these compounds was confirmed by determination of the melting point, elemental analysis and FT-IR, 1H NMR, 13C NMR and UV-Vis spectroscopic methods. Effects of the substituents in the benzyl moiety on the shift of the absorption maxima of compounds 1a?1g and 2a?2f were analyzed using the Hammett's equation. Namely, a split in the Hammett plot at the parent compounds 1a and 2a revealed different electronic transitions within the molecules with the electron-donating substituents from those bearing the electron-accepting substituents, thus the electron-accepting effect on the shift of the absorption maxima being considerably stronger. The influence of the chemical structure on the pharmacokinetically relevant properties of the investigated hydantoin derivatives was evaluated using the Lipinski?s rule of five, Veber, Egan and Ghose's empirical criteria, as well as different in silico methods. When compared to phenytoin (5,5-diphenylhydantoin) as the referent drug, compounds with a halogen or electron-donating substituent are expected to possess better intestinal absorption and passage through the blood-brain barrier. Depending on the nature of the substituent present in the benzyl moiety, compounds 1a?1g and 2a?2f can be potent activators/inhibitors of some cytochrome P450 izoenzymes including CYP1A2, CYP2C19 and CYP2C9. Regarding biological activity profile, compounds with the electron-accepting substituents are likely to reveal the pharmacological potential similar to that of phenytoin, while those bearing electron-donating substituents are predicted to have the antimigrenic activity. All compounds were found to bear a low risk of being mutagenic or tumorigenic. The calculated molecular descriptors indicate that the investigated compounds fulfill necessary empirical criteria which qualify them as interesting drug candidates.