Maleate salts of bedaquiline

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-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}, C₃₂H₃₂BrN₂O₂ ⁺·C₄H₃O₄ ^-, 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 in situ 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 cis-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.

Keywords: bedaquiline; crystal structure; desolvation; drug-resistant tuberculosis; isomorphous organic salts.

Figure 1

Probability ellipsoid plot (50% probability) of the hemihydrate. C-bound H atoms and H-atom labels are omitted for clarity. Water mol­ecules O7 and O8 are partially occupied [0.276 (17) for O7 and 0.40 (4) for O8].

Figure 2

Probability ellipsoid plot (50% probability) of the THF solvate (see Fig. 1 ▸ for cation and anion carbon-atom labels). C-bound H atoms and labels for C and H atoms are omitted for clarity. THF mol­ecules are disordered around a twofold axis (O7) or in a general position (O8).

Figure 3

Probability ellipsoid plot (50% probability) of the acetone/hexane solvate (see Fig. 1 ▸ for cation and anion carbon-atom labels). C-bound H atoms and labels for C and H atoms are omitted for clarity. Acetone mol­ecules are disordered: fourfold around a twofold axis plus general disorder (O8, disorder by the twofold axis not shown for clarity) or with a hexane mol­ecule (O7, the hexane mol­ecule is located on a twofold axis).

Figure 4

Probability ellipsoid plot (50% probability) of the ethyl acetate solvate, showing both ion pairs (suffixes A and B) related by pseudo-translation (see Fig. 1 ▸ for cation and anion carbon-atom labels). C-bound H atoms, labels for C and H atoms and disorder of ethyl acetate mol­ecules are omitted for clarity.

Figure 5

Probability ellipsoid plot (50% probability) of the desolvated structure (see Fig. 1 ▸ for cation and anion carbon-atom labels). C-bound H atoms and labels for C and H atoms are omitted for clarity.

Figure 6

Least-squares overlay based on the atoms C1, C2, C7, C17 and C23. Color coding: hemihydrate – orange; THF solvate – green; ethyl acetate solvate – red and pink (two independent mol­ecules); acetone/hexane solvate – blue; desolvated structure – cyan.

Figure 7

The main hydrogen-bonding inter­actions in common to all structures (turquoise and red dashed lines). Shown is the hemihydrate. Partially occupied water mol­ecules, C-bound H atoms and labels for C-bound H atoms are omitted for clarity. Probability ellipsoids are at the 50% level. Symmetry codes: (i) − + x, − + y, z; (ii)  + x,  + y, z; (iii)  + x,  + y, z.

Figure 8

Packing view of the hemihydrate structure showing the propagation directions of the hydrogen-bonded chains. In the lower half of the unit cell, chains propagate horizontally (right–left, along [110]; in the upper half they propagate longitudinally (forward–backward, along [10]). Hydrogen bonds are shown as turquoise dashed lines. Green dashed lines connect the centroids of the bromo­quinoline substituents [3.432 (14) Å]. Partially occupied water mol­ecules shown as spheres of arbitrary radius. For all other atoms, probability ellipsoids are at the 50% level. C-bound H atoms and labels for C H atoms are omitted for clarity.

Figure 9

Residual void space in the acetone/hexane structure after artificial removal of solvent mol­ecules. The solvent-accessible volume would be 781 ų [20.9% of the unit-cell volume; probe radius 1.2 Å; numerical values from PLATON SQUEEZE calculation (van der Sluis & Spek, 1990; Spek, 2015 ▸)]. Probability ellipsoids are at the 50% level.

Figure 10

Residual void space in the desolvated structure. The solvent-accessible volume is 607 ų [16.8% of the unit cell volume; probe radius 1.2 Å; numerical values from PLATON SQUEEZE calculation (van der Sluis & Spek, 1990; Spek, 2015 ▸)]. Probability ellipsoids are at the 50% level.