Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity

For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.