X-ray crystal structure of the antimalarial agent (-) -halofantrine hydrochloride supports stereospecificity for cardiotoxicity
Karle, J.M.
Antimicrobial Agents and ChemoTherapy 41(4): 791-794
1997
ISSN/ISBN: 0066-4804 PMID: 9087491 Document Number: 473806
The crystal and molecular structures and absolute configuration of (-)-halofantrine hydrochloride were determined by X-ray diffraction. The absolute configuration of the single chiral center of (-)-halofantrine was established to be in the S configuration. Thus, (+)-halofantrine, the more cardiotoxic isomer, has the R configuration. The carbon atom adjacent to the aromatic ring has the same configuration in both (+)halofantrine and quinidine, suggesting a stereospecific component to the cardiotoxicity produced by both agents. The intramolecular N cntdot cntdot cntdot 0 distance is 4.177 +- 0.006 A (1 ANG = 0.1 nm), which is close to the N cntdot cntdot cntdot 0 distance found in the crystal structure of (+-)-halofantrine hydrochloride, even though the N-H group points in opposite directions in racemic halofantrine and (-)-halofantrine. Both the hydroxyl group and the amine group form hydrogen bonds with the chloride anions. The crystallographic parameters for (-)-halofantrine hydrochloride were as follows: chemical formula, C-26H-31Cl-2F-6NO+ cntdot Cl-; M-r, 492.4; symmetry of unit cell, orthorhombic; space group, P2-12-12-1; parameters of unit cell, a was 6.290 +- 0.001 A, b was 13.533 +- 0.003 A, and c was 30.936 +- 0.006 A; volume of the unit cell, 2,633.2 +- 0.7 ANG -3; number of molecules per unit cell, 4; .calculated density, 1.354 g cm-1; source of radiation, Cu K-alpha (lambda = 1.54178 A); mu (absorption coefficient), 3.50 mm-1;F(OOO) (sum of atomic scattering factors at zero scattering angle), 1,120; room temperature was used; final R (residual index), 4.75% for 2,988 reflections, with F-o gt 3-sigma(F), where F-o is the observed structure factor and F is the structure factor.