ABSOLUTE CONFIGURATION OF THE POTENT ANTIMALARIAL AGENT HALOFANTRINE. Jean M. Karle, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C., USA

The absolute configuration of the single chiral center of halofantrine has been determined by x-ray diffraction to be S for (-)-halofantrine and R for (+)-halofantrine. This assignment allows comparison of (+)- and (-)-halofantrine's biological activity with either quinine or quinidine. Halofantrine, quinine, and quinidine are all clinically used amino alcohol antimalarial agents. Even though quinine and quinidine are diastereomers, the quinoline, amine, and alcohol portions of the molecule mirror each other. Although quinidine is more potent than quinine in vitro, halofantrine's enantiomers have not shown a difference in in vitro antimalarial activity. This may be due to the flexibility of halofantrine's acyclic amine portion of the molecule. The flexibility is exemplified by the O-C--N-H torsion angle being 32.9deg. for (-)-halofantrine HCl and 165.4deg. and 172.6deg. for the two (-)-halofantrine conformers in crystalline racemic halofantrine HCl (Karle & Karle, Acta Cryst. C45, 1248-1250, 1989). However, like quinidine, at higher doses of halofantrine, prolongation of the cardiac QT interval was observed clinically. Quinidine is more cardiotoxic than quinine and shares the same configuration with (+)-halofantrine of the carbon atom adjacent to the aromatic ring bearing the hydroxyl group and the same conformation of the hydroxyl group with respect to the aromatic ring. Quinine, the less toxic compound, shares the same absolute configuration with (-)-halofantrine as well as close to the same conformation of the hydroxyl oxygen atom with respect to the aromatic ring. Following oral administration of racemic halofantrine, the (+)-isomer has higher plasma concentrations than the (-)-isomer. Intermolecular hydrogen bonding with the alcohol and amine groups of halofantrine may be important for biological activity. Both groups form hydrogen bonds to different chloride anions.

(-)-Halofantrine hydrochloride, C₂₆H₃₁Cl₂F₃NO⁺*Cl-, crystallized in space group P2₁2₁2₁ with a=6.290(1), b=13.533(3), and c=30.936(6) Å, V=2633.2(7) ų, Z=4, R=4.68% for reflections with |F_o |> 3[[sigma]](F). For the enantiomorph, R=5.99%.