DFT study on the radical anions formed by primaquine and its derivatives

The electron affinities (EA) of the 8-aminoquinoline antimalarial drug primaquine and several of its metabolites were studied using the density functional theory method. We first considered six substituents at the 5-position, -CH(3), -OH, -OCH(3), -Ph, -OPh, and -CHO. We found that in the gas phase the adiabatic EAs are similar to that of the parent primaquine for the -CH(3), -OH, and -OCH(3) substituents. In contrast, the -Ph, -OPh, and -CHO substituents all markedly increase the adiabatic EA. However, only the -CHO substituted compound is predicted to form a stable covalently bound radical anion in the gas phase due to its significant positive vertical EA relative to that of the parent primaquine. In addition, when the 8-position is substituted by the N-hydroxyl group or a quinone-imine structure is formed, the electron capture ability is significantly increased. In aqueous solution, all these molecules have significantly larger adiabatic EAs than in the gas phase. In addition, all of the vertical EAs are positive in aqueous solution. The implications of these findings for contributing to our mechanistic understanding of the red cell toxicity of 8-aminoquinoline compounds are further discussed.