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: C(17)H(17)F (6)N(2)O(+)Cl(−) · 0.25 H(2)O; 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 Å (1 Å = 0.1 nm), b = 18.9720 ± 0.0009 Å, c = 32.189 ± 0.017 Å; volume of unit cell, 7,749 ± 4 Å(3); number of molecules per unit cell, 16; calculated density, 1.44 g cm(−3); source of radiation, Cu Kα (λ = 1.54178 Å); μ (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 2σ. 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.

通过盐酸盐的X射线晶体学（X-ray crystallography）分析，确定了(−)-甲氟喹（mefloquine）的绝对构型为11R,12S，从而可将甲氟喹光学异构体的构型与奎宁（quinine）及奎尼丁（quinidine）的构型进行对照分析。(−)-甲氟喹与奎宁的立体化学特征一致，而(+)-甲氟喹则与奎尼丁的立体化学特征一致。鉴于(+)-甲氟喹在体外对恶性疟原虫（Plasmodium falciparum）D6株与W2株的抗疟活性强于(−)-甲氟喹，且奎尼丁的抗疟活性强于奎宁，由此可推断抗疟活性存在共同的立体化学决定因素。(−)-甲氟喹盐酸盐的晶体存在四种不同构象，这些构象的差异主要源于哌啶环（piperidine ring）的小幅旋转。这些构象与外消旋甲氟喹甲磺酸盐一水合物、甲氟喹盐酸盐及甲氟喹游离碱的晶体构象基本一致。(−)-甲氟喹盐酸盐水合物的晶体学参数如下：化学式为C(17)H(17)F(6)N(2)O(+)Cl(−) · 0.25 H₂O；相对分子质量M_r为419.3；晶胞对称类型为正交晶系（orthorhombic）；空间群（space group）为P2₁2₁2₁；晶胞参数：a = 12.6890 ± 0.0006 Å（1 Å = 0.1 nm），b = 18.9720 ± 0.0009 Å，c = 32.189 ± 0.017 Å；晶胞体积为7749 ± 4 ų；每个晶胞含16个分子；计算密度为1.44 g·cm⁻³；辐射源为Cu Kα（波长λ = 1.54178 Å）；吸收系数（absorption coefficient）μ为2.373 mm⁻¹；测试采用室温条件；对于强度大于2σ的3692个衍射点，最终残差指数（residual index）R₁为0.0874。所有羟基与胺基的氢原子均参与了与氯离子的分子间氢键相互作用。(+)-甲氟喹中胺基与羟基的取向，可能决定了其与细胞组分形成氢键的最优几何构型。