X-ray crystal structure of the antimalarial agent (-)-halofantrine hydrochloride supports stereospecificity for cardiotoxicity

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 ... O distance is 4.177 +/- 0.006 Angstrom (1 Angstrom = 0.1 nm), which is close to the N ... O 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, C26H31Cl2F6NO+. Cl-; M(r) 492.4; symmetry of unit cell orthorhombic; space group(delta) P2(l)2(l)2(l); parameters of unit cell, a was 6.290 +/- 0.001 Angstrom, b was 13.533 +/- 0.003 Angstrom, and c was 30.936 +/- 0.006 Angstrom; volume of the unit cell, 2,633.2 +/- 0.7 Angstrom(3); number of molecules per unit cell, 4; calculated density, 1.354 g cm(-3); source of radiation, Cu K alpha (lambda = 1.54178 Angstrom); mu (adsorption coefficient), 3.50 (-1); F(000) (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-0\ > 3 sigma(F), where F-0 is the observed structure factor and F is the structure factor.