Author/Authors :
Zeller, Matthias Department of Chemistry - Purdue University, USA , Bogdanowich-Knipp, Susan Ravine Pharmaceuticals LLC, USA , Smith, Pamela Leading with Smart Science LLC, USA , Purcell, Dale K. Chemical Microscopy LLC, USA , Okezue, Mercy Biotechnology Innovation and Regulatory Science Center - Lilly Hall of Life Sciences, USA , Smith, Daniel T. Industrial and Physical Pharmacy - Purdue University, USA , Byrn , Stephen R. Improved Pharma LLC, USA , Clase, Kari L. Biotechnology Innovation and Regulatory Science Center - Lilly Hall of Life Sciences, USA
Abstract :
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-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate}, C32H32BrN2O2+·C4H3O4−, namely, a hemihydrate, a tetrahydrofuran (THF) solvate, a mixed acetone/hexane solvate, an ethyl acetate solvate, and a solvate-free structure obtained from the acetone/hexane solvate by in situ single-crystal-to-single-crystal desolvation. All salts exhibit a 1:1 cation-to-anion ratio, with the anion present as monoanionic hydromaleate and a singly protonated bedaquilinium cation. The maleate exhibits the strong intramolecular hydrogen bond typical for cis-dicarboxylic acid anions. The conformations of the cations and packing interactions in the maleate salts are compared to those of free base bedaquiline and other bedaquilinium salts.
Keywords :
bedaquiline , drug-resistant tuberculosis , drug-resistant tuberculosis , crystal structure , desolvation , isomorphous organic salts
