Crystal structures of salts of bedaquiline

Abstract

Bedaquiline [systematic name: 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol, C32H31BrN2O2] 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 {systematic name: [4-(6-bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate, C32H32BrN2O2 +·C4H3O4 −}, and about a dozen other salts of bedaquiline have been described in patent literature, but none have so far been structurally described. In a first communication, we present the crystal structure of bedaquilinium fumarate and of two new benzoate salts, as well as that of a degradation product of the reaction of bedaquilinium fumarate with sodium ethoxide, 3-benzyl-6-bromo-2-methoxyquinoline, C17H14BrNO. The fumarate and benzoate salts both feature cations monoprotonated at the dimethylamino group. The much less basic quinoline N atom remains unprotonated. Both salts feature a 1:1 cation-to-anion ratio, with the fumarate being present as monoanionic hydrofumarate. The conformations of the cations are compared to that of free base bedaquiline and with each other. The flexible backbone of the bedaquiline structure leads to a landscape of conformations with little commonalities between the bedaquiline entities in the various structures. The conformations are distinctively different for the two independent molecules of the free base, the two independent molecules of the hydrofumarate salt, and the one unique cation of the benzoate salt. Packing of the salts is dominated by hydrogen bonding. Hydrogen-bonding motifs, as well as the larger hydrogen-bonded entities within the salts, are quite similar for the salts, despite the vastly differing conformations of the cations, and both the hydrofumarate and the benzoate structure feature chains of hydrogen-bonded anions that are surrounded by and hydrogen bonded to the larger bedaquilinium cations, leading to infinite broad ribbons of anions, cations, and (for the benzoate salt) water molecules. The benzoate salt was isolated in two forms: as a 1.17-hydrate (C32H32BrN2O2 +·C7H5O2 −·1.166H2O), obtained from acetone or propanol solution, with one fully occupied water molecule tightly integrated into the hydrogen-bonding network of anions and cations, and one partially occupied water molecule [refined occupancy 16.6 (7)%], only loosely hydrogen bonded to the quinoline N atom. The second form is an acetonitrile solvate (C32H32BrN2O2 +·C7H5O2 −·0.742CH3CN·H2O), in which the partially occupied water molecule is replaced by a 74.2 (7)%-occupied acetonitrile molecule. The partial occupancy induces disorder for the benzoate phenyl ring. The acetonitrile solvate is unstable in atmosphere and converts into a form not distinguishable by powder XRD from the 1.17-hydrate.

Maleate salts of bedaquiline

“…Variations of only a few degrees can be seen between equivalent angles of the various interplanar angles in the cations, as would be expected for mostly isomorphous structures. The 6-bromo-2methoxyquinoline vs phenyl angle ranges from 63.0 (2) to 71.31 (7) , which is slightly smaller but similar to what was observed in the previously reported structures [73.29 (7) to 86.02 (8) ; Petit et al, 2007;Okezue et al, 2020]. Phenyl to naphthyl angles are between 63.7 (1) and 66.60 (7) .…”

“…chain are related to each other via half-unit translations of the C-centered cell (AE 1 2 + x, AE 1 2 + y, +z). This differentiates the maleate structures described here from the other previously described bedaquilinium salt structures, the fumarate and benzoate structures, in which hydrogen-bonding interactions between cations and anions led to formation of layered structures (Okezue et al, 2020). For highly solvated structures such as the maleate salts described here, the formation of 1D rather than 2D structures can be of relevance for the resilience of the lattice upon removal of solvent, or the persistence of the packing motif if a different solvent is used.…”

“…A number of other bedaquilinium salts have been reported since the emergence of its pharmacological relevance, but until recently only free base bedaquiline had been fully structurally described (Petit et al, 2007). To fill this gap, which severely hampers understanding of the chemical, physical and physiological properties of bedaquiline and its derivatives, we have recently reported and analyzed the single-crystal structures of several bedaquilinium salts, including that of the commercially traded fumarate as well as two differently solvated benzoate salts (Okezue et al, 2020). This study revealed that bedaquiline and its salts have a very rich and diverse structural chemistry.…”

“…the second pK a of maleic acid (6.22, European Chemical Agency, 2015), which is not sufficiently basic for a proton transfer to this site. The first pK a of maleic acid (1.94, European Chemical Agency, 2015) should be sufficient to protonate the quinoline site if higher ratios of maleic acid to bedaquiline are used (Okezue et al, 2020). We were, however, unable to identify or isolate any different crystalline materials when increasing the amounts of acid (screening was done by powder XRD).…”

“…Only four structures of bedaquiline or its salts have been previously reported in the literature (Cambridge Structural Database; Groom et al, 2016), viz. free base bedaquiline (Petit et al, 2007), the fumarate salt (Okezue et al, 2020), and two isomorphous solvates of the benzoate salt (Okezue et al, 2020). The structures of the salts are dominated by a multitude of N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen-bonding interactions that connect the cations and anions into strongly hydrogenbonded motifs, while in free base bedaquiline the packing is dominated by weaker and less directional interactions such as BrÁ Á ÁBr interactions and -stacking (Petit et al, 2016).…”