Basicities of some 9-substituted acridine-4-carboxamides: A density functional theory (DFT) calculation

Acid–base properties of drugs are important in understanding the behaviour of these compounds under physiological condition. In order to understand such behaviour the proton affinities of acridine 4-carboxamides with substitution (R) at the 9-position are theoretically studied, and considered for the basic sites of both the heterocyclic ring as well as side chain nitrogens. In 9-amino acridine 4-carboxamide, the –NH2 group is observed to be an additional basic site. The heterocyclic nitrogen of substituted carboxamides (R = –NH2, –O-methyl, –O-ethyl, and –O-phenyl) is more basic than the side chain nitrogen, however, side chain nitrogen corresponds to more basic site for some carboxamides (R = –OH and –Cl) and the –NH2 group represents the least basic site of 9-amino acridine 4-carboxamide. In addition to presenting the basicities of these drugs an indication of another hydrogen-bond between heterocyclic ring N and carboxamide chain O is observed. The difference of basicities with substituents at 9-position are very narrow and carboxamides with substituents at 9-position are found to be suitable for studying intramolecular H-bonds between the heterocyclic N and carboxamide O. The resultant stabilization of a configuration due to such H-bonding is determined.