Crystal structure of (-)-mefloquine hydrochloride reveals consistency of configuration with biological activity.
The absolute configuration of (-)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquine's optical isomers to those of quinine and quinidine. (-)-Mefloquine has the same stereochemistry as quinine, and (+)-mefloquine has the same stereochemistry as quinidine. Since (+)-mefloquine is more potent than (-)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (-)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. The crystallographic parameters for (-)-mefloquine hydrochloride hydrate were as follows: C17H17F (6)N(2)O(+)Cl(-) .0.25 H2O; M(r), 419.3; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a = 12.6890 +/- 0.0006 A (1 A = 0.1 nm), b = 18.9720 +/- 0.0009 A, c = 32.189 +/- 0.017 A; volume of unit cell, 7,749 +/- 4 A(3); number of molecules per unit cell, 16; calculated density, 1.44 g cm(-3); source of radiation, Cu Kalpha (lambda = 1.54178 A); mu (absorption coefficient), 2.373 mm(-1); room temperature was used; final R(1) (residual index), 0.0874 for 3,692 reflections with intensities greater than 2sigma. All of the hydroxyl and amine hydrogen atoms participate in intermolecular hydrogen bonds with chloride ions. The orientation of the amine and hydroxyl groups in (+)-mefloquine may define the optimal geometry for hydrogen bonding with cellular constituents.
Karle
Jean M
JM
Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500, USA. jean.karle@na.amedd.army.mil
Karle
Isabella L
IL
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D006860:Hydrogen Bonding; D015767:Mefloquine / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects*; D011802:Quinidine / Q000737:chemistry / Q000494:pharmacology; D011803:Quinine / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000962:Antimalarials; D011803:Quinine; D011802:Quinidine; D015767:Mefloquine