Structure of 9-epiquinine hydrochloride dihydrate versus antimalarial activity.

9-Epiquinine hydrochloride dihydrate [(9S)-6'-methoxycinchonan-9-ol hydrochloride dihydrate], C20H25N2O2+.Cl-.2H2O, M(r) = 396.9, orthorhombic, P212121, a = 8.059 (2), b = 11.537 (3), c = 22.311 (6) A, V = 2074.1 (9) A3, Z = 4, Dx = 1.271 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 18.58 cm-1, F(000) = 848, room temperature, final R = 6.56% for 1344 reflections with magnitude of Fo > 3 sigma (F). 9-Epiquinine crystallized as a hydrated tertiary amine hydrochloride salt. The intramolecular N(1)+ ...O distance is 2.816 A. All H atoms attached to O or N atoms form intermolecular hydrogen bonds. The Cl ion is involved in four hydrogen bonds including one with the hydroxyl group of 9-epiquinine. The N(1)+-H moiety hydrogen bonds to a water molecule. The O(12)-C(9)...N(1)+-H(1) torsion angle was equal to -0.2 (3.8) degrees in comparison to 97.0 degrees for quinidine sulfate [Karle & Karle (1981). Proc. Natl Acad. Sci. USA, 78, 5938-5941]. Two theories have been proposed in the literature to explain the low antimalarial activity of 9-epiquinine. The crystal structure of 9-epiquinine hydrochloride is not consistent with the hypothesis that 9-epiquinine prefers to form intramolecular rather than intermolecular hydrogen bonds, but is consistent with the hypothesis that N(1) and the hydroxyl group of 9-epiquinine are in an orientation which is unfavorable towards exerting antimalarial activity.