Zeller Matthias, Bogdanowich-Knipp Susan, Smith Pamela, Purcell Dale K, Okezue Mercy, Smith Daniel T, Byrn Stephen R, Clase Kari L
Department of Chemistry, Purdue University, 560 Oval Dr., W. Lafayette, IN 47907-2084, USA.
Ravine Pharmaceuticals LLC, 3425 DuBois St., West Lafayette, IN 47906, USA.
Acta Crystallogr E Crystallogr Commun. 2021 Mar 26;77(Pt 4):433-445. doi: 10.1107/S2056989021002991. eCollection 2021 Apr 1.
Bedaquiline is one of two important new drugs for the treatment of drug-resistant tuberculosis (TB). It is marketed in the US as its fumarate salt, but only a few salts of bedaquiline have been structurally described so far. We present here five crystal structures of bedaquilinium maleate {systematic name: [4-(6-bromo-2-meth-oxy-quinolin-3-yl)-3-hy-droxy-3-(naphthalen-1-yl)-4-phenyl-but-yl]di-methyl-aza-nium 3-carb-oxy-prop-2-enoate}, CHBrNO ·CHO , namely, a hemihydrate, a tetra-hydro-furan (THF) solvate, a mixed acetone/hexane solvate, an ethyl acetate solvate, and a solvate-free structure obtained from the acetone/hexane solvate by single-crystal-to-single-crystal desolvation. All salts exhibit a 1:1 cation-to-anion ratio, with the anion present as monoanionic hydro-maleate and a singly protonated bedaquilinium cation. The maleate exhibits the strong intra-molecular hydrogen bond typical for -di-carb-oxy-lic acid anions. The conformations of the cations and packing inter-actions in the maleate salts are compared to those of free base bedaquiline and other bedaquilinium salts.
贝达喹啉是治疗耐药结核病的两种重要新药之一。它在美国以富马酸盐形式上市，但迄今为止，仅对少数贝达喹啉盐的结构进行了描述。本文展示了马来酸贝达喹啉鎓盐{系统名称：[4-(6-溴-2-甲氧基喹啉-3-基)-3-羟基-3-(萘-1-基)-4-苯基丁基]二甲基氮鎓 3-羧基丙烯酸酯}，CHBrNO·CHO 的五种晶体结构，即半水合物、四氢呋喃（THF）溶剂化物、丙酮/己烷混合溶剂化物、乙酸乙酯溶剂化物，以及通过单晶到单晶去溶剂化从丙酮/己烷溶剂化物获得的无溶剂结构。所有盐均呈现 1:1 的阳离子与阴离子比例，阴离子以单阴离子氢马来酸盐形式存在，阳离子为单质子化的贝达喹啉鎓阳离子。马来酸盐呈现出二羧酸阴离子典型的强分子内氢键。将马来酸盐中阳离子的构象和堆积相互作用与游离碱贝达喹啉及其他贝达喹啉鎓盐的进行了比较。
