Characterization of potential NMDA and cholecystokinin antagonists I. Acid–base properties of 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxylic acids at the molecular and submolecular levels

Abstract

The protonation macroconstants (log K) of 4(3H)-quinazolone ( 1) and two 2-methyl-4-oxo-3H-alkyl-quinazoline-3-carboxylic acid derivatives ( 2, 3) were determined by pH-potentiometry. The acid–base chemistry of compounds 2 and 3, where proton-bindings take place in an overlapping fashion, was described in terms of protonation microconstants as well. Microspeciation was carried out by two means: UV–pH titration (selective, pH-dependent monitoring of the N 1-binding site), and deductively (using a derivative compound as covalently fixed model of one of the protonation isomers). The microconstant values obtained by the two different methods are in agreement within 0.05 log K units. Microspeciation revealed remarkable differences between the two homologue compounds ( 2 and 3). The microconstant values show that insertion of a second methylene moiety into the aliphatic acid side-chain (1) increases the electron-density and most basicity parameters of both functional groups; (2) significantly modifies the extent of site–site interactions in the molecule; (3) opens new conformational preferences by N 1 ring nitrogen–carboxylic group intramolecular hydrogen bond formation and (4) reverses the predominantly zwitterion-involved protonation pathway into a neutral form-involved pathway. These molecules exemplify that microconstant values allow the comparative prediction and quantitative evaluation of pharmacokinetic behaviour, and signify the fact that microspeciation is a powerful tool in the process of drug development.