Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity

For most potent antimalarial activity, the cinchona alkaloids appear to req uire certain electronic features, particularly a sufficiently acidic hydrox yl proton and an electric field direction pointing from the aliphatic nitro gen atom towards the quinoline ring. These observations are the result of a n analysis of molecular electronic properties of eight cinchona alkaloids a nd an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensi tive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for po tent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. D istinguishing features of the weakly active epiquinine and epiquinidine inc lude 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 p otent quinine metabolite possesses some, but not all, of the same electroni c features as the most potent cinchona alkaloids. Both the positioning of t he 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 i ntermolecular hydrogen bonds. (C) 1999 Elsevier Science Ltd. All rights res erved.