Synthesis, characterization and biological activity of fluorescently labeled bedaquiline analogues

Rombouts, Jeroen A.; Veenboer, Richard M. P.; Villellas, Cristina; Lü, Ping; Ehlers, Andreas W.; Andries, Koen; Koul, Anil; Lill, Holger; Ruijter, Eelco; Orru, Romano V. A.; Lammertsma, Koop; Bald, Dirk; Slootweg, J. Chris

doi:10.1039/c6ra22693k

Cited by 8 publications

(8 citation statements)

References 39 publications

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“…Using much less basic sodium bicarbonate as the neutralizing agent avoids this decomposition reaction. Bedaquiline free base could be recovered that way from the fumarate salt, following the procedure described by Rombouts et al (2016), thus allowing us to proceed to use the free base in salt screening experiments ( Fig. 1).…”

Section: Salt Screening and Methodsmentioning

confidence: 99%

“…Free base bedaquiline (1). The free base used during synthesis was prepared by extracting a CH 2 Cl 2 solution of the fumarate three times with saturated NaHCO 3 solution (Rombouts et al, 2016). The identity and purity of the free base thus afforded from the material supplied by Johnson & Johnson was verified using NMR spectroscopy [m.p.…”

Section: Synthesis and Crystallizationmentioning

confidence: 99%

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Crystal structures of salts of bedaquiline

et al. 2020

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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.

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Section: Salt Screening and Methodsmentioning

confidence: 99%

Section: Synthesis and Crystallizationmentioning

confidence: 99%

Crystal structures of salts of bedaquiline

et al. 2020

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“…At the start of the experiment only the fumarate salt was available. The free base was recovered from the commercially available fumarate salt by extracting a dichloromethane (CH 2 Cl 2 ) solution three times with saturated sodium bicarbonate (NaHCO 3 ) solution (12,26). The recovered base was evaporated over 24 h to remove excess solvents.…”

Section: Recovery Of Bedaquiline Base From the Fumarate Saltmentioning

confidence: 99%

Salts and Polymorph Screens for Bedaquiline

et al. 2021

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Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale.

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“…Residual void space in the desolvated structure. solution of the fumarate three times with saturated NaHCO 3 solution (Rombouts et al, 2016).…”

Section: Figure 10mentioning

confidence: 99%

Maleate salts of bedaquiline

Zeller

Bogdanowich-Knipp²,

Smith³

et al. 2021

Acta Cryst E

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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.

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Synthesis, characterization and biological activity of fluorescently labeled bedaquiline analogues

Abstract: Labeling the tuberculosis drug bedaquiline with a fluorescent alkynyl-BODIPY moiety does not disrupt its antibacterial properties.

Cited by 8 publications

References 39 publications

Crystal structures of salts of bedaquiline

Crystal structures of salts of bedaquiline

Salts and Polymorph Screens for Bedaquiline

Maleate salts of bedaquiline

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