Computational Study of Michellamines: Naphthylisoquinoline Alkaloids with Anti-HIV Activity

Abstract

Michellamine A, michellamine B and michellamine C are naphthylisoquinoline alkaloids with anti-HIV activity isolated from the leaves of Ancistrocladus korupensis, a plant indigenous in Cameroun. Michellamine B and michellamine C are atropisomeric of michellamine A, and michellamine B is the most active. The molecules consist of two units, each containing an isoquinoline moiety and a naphthalene moiety. This work presents the results of a conformational study of michellamine A performed in vacuo and in three solvents (chloroform, acetonitrile and water), at the (HF/6-31G(d,p) and DFT/B3LYP/6-31+G(d,p) levels. The potential energy profiles for the rotations of single bonds between moieties were determined to identify relevant conformers corresponding to different orientations of the moieties. The harmonic vibrational frequencies of the conformers were calculated in vacuo. The conformational preferences are influenced by intramolecular hydrogen bonds (having a stabilizing effect) and by the mutual orientations of the various moieties. The lowest energy conformers contain two cooperative O–H⋅⋅⋅O intramolecular hydrogen bonds. The isoquinoline moiety prefers to be perpendicular to the naphthalene moiety in the same unit. All the properties obtainable from a conformational study are considered: relative energies in vacuo and in solution, dipole moments, HOMO-LUMO energy gaps, free energy of solvation in the solvents considered, and vibrational frequencies and predicted vibrational spectra in vacuo.