Functional correlation of molecular electronic properties with potency of synthetic carbinolamine antimalarial agents

Specific calculated molecular electronic properties of structurally diverse synthetic aromatic carbinolamines containing phenanthrene, quinoline, and N-substituted biphenyl rings are associated with antimalarial potency allowing use of these electronic features in the prediction of antimalarial efficacy, thus aiding the design of new antimalarial agents. These electronic features include the magnitude and location of 3-dimensional molecular electrostatic potentials, lowest unoccupied molecular orbitals, and highest occupied molecular orbitals. Stereoelectronic properties were calculated using quantum chemical AM1 methods on the optimized geometry of the lowest energy or most populated conformer in both gaseous and aqueous environments. In the phenanthrene carbinolamines, the aliphatic nitrogen atom and the hydroxyl proton are intrinsically more nucleophilic and less electrophilic, respectively, than in the non-phenanthrene compounds. Hydrogen bonding ability and the electrophilic nature of the aromatic ring appear to be two important features responsible for interaction with receptor molecules.