6H-Pyrimido[2,1-a]isoindoles: acid–base and complexation properties and electrooxidation model of metabolic degradation

Abstract

Physicochemical properties of pharmacological interest were determined for ten 6H-pyrimido[2,1-a]isoindoles. The compounds studied were found to be weak bases with a pKa ranging from 2.38 to 3.46. Furthermore, the association constants of the studied compounds with cyclodextrins were examined. The formation of complexes was observed with 1:1 stoichiometry, γ-cyclodextrin was found to be the best complexing. Finally, the electrochemical oxidation of 6H-pyrimido[2,1-a]-isoindoles in 0.1 mol dm−3 sodium perchlorate in acetonitrile was studied as a model of their possible metabolic degradation. It was found to be a one-electron process, and the values of the half-wave potentials are in the range of 1.34–1.62 V (vs. Ag/AgNO3/NaClO4). The electrooxidation products of three selected compounds were prepared by preparative electrolysis and subsequently identified by mass spectrometry. From the data obtained, it is evident that the electrochemical oxidation of the 6H-pyrimido[2,1-a]isoindoles begins with the formation of N-oxides, followed by dimerization of the molecule or, contrary to this, by oxidative cleavage of the pyrimidine ring. From a metabolic point of view, N-oxidation is the corresponding process to this pathway.Graphical abstract