Maleate salts of bedaquiline.
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ABSTRACT:
SUBMITTER: Zeller M
PROVIDER: S-EPMC8025853 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC8387259 | biostudies-literature
Project description: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.
| S-EPMC7642769 | biostudies-literature
Project description:THE TITLE COMPOUND [SYSTEMATIC NAME: 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethyl-propan-1-aminium hydrogen maleate], C(20)H(27)N(2) (+)·C(4)H(3)O(4) (-), a maleate salt of trimipramine, crystallizes with four independent cation-anion pairs in the asymmetric unit. The trimipramine cation contains a seven-membered azepine ring with two fused benzene rings whose mean planes are separated by 51.7?(1)°. Inter-molecular N-H?O and intra-molecular O-H?O hydrogen bonds pack the ions into chains along [101]. Additional weak inter-molecular C-H?O inter-actions help to influence the twist angles of the mean planes of the benzene rings fused to the azepine ring in the cation. A geometry-optimized MOPAC AM1 theoretical calculation supports these observations.
| S-EPMC2979907 | biostudies-literature
Project description:In the title compound, C(4)H(8)N(3)O(+)·C(4)H(3)O(4) (-), the cations and anions are linked through N-H?O hydrogen bonds making a ionic pair with an R(2) (2)(8) ring motif. These ionic pairs are further connected through another N-H?O hydrogen bond, leading to an R(6) (6)(16) ring motif around the inversion centres of the unit cell. These approximately planar aggregates are further connected through weak van der Waals inter-actions in the unit cell. The anions have a characteristic intra-molecular O-H?O hydrogen bond with a self-associated ring S(7) motif.
| S-EPMC3247321 | biostudies-other
Project description:In the cation of the title salt {systematic name: 4-[bis-(4-fluoro-phen-yl)meth-yl]-1-[(2E)-3-phenyl-prop-2-en-1-yl]piperazin-1-ium hydrogen maleate}, C26H27F2N2 (+)·C4H3O4 (-), the protonated piperazine ring is in a chair conformation. The dihedral angle between the 4-fluoro-phenyl rings is 68.2?(2)°. An intra-molecular O-H?O hydrogen bond occurs in the anion. In the crystal, N-H?O, C-H?O and C-H?F inter-actions are observed, which link the ions into [001] chains.
| S-EPMC3793824 | biostudies-other
Project description:Mol-ecules in the title compound, C(4)H(7)N(2) (+)·C(4)H(3)O(4) (-), are linked by inter-molecular N-H?O hydrogen bonds into one-dimensional chains parallel to [101]. These chains are in turn linked by an R(2) (2)(8) motif, formed by weak C-H?O hydrogen bonds, into corrugated sheets running parallel to (10). These sheets are further linked by weak inter-molecular C-H?O hydrogen bonds, forming a three-dimensional network. Intra-molecular N-H?O and O-H?O inter-actions are also present.
| S-EPMC2968590 | biostudies-literature
Project description:Background: Infectious diseases are still a leading cause of death and, with the emergence of drug resistance, pose a great threat to human health. New drugs are thus continually being developed, without their effects on the immune system being studied in-depth. Here we aim to evaluate the impact of a recently release anti-TB drug, named bedaquiline (BDQ), on the response of human macrophages infected with Mycobacterium tuberculosis (MTB). Results: Here, we used MTB resistant to BDQ as a model of bacterial infection to examine the impact of BDQ on the human macrophage response. Gene expression profiling has revealed about 1,500 genes differentially expressed in MTB infected macrophages incubated with BDQ. The expression of 499 genes was upregulated and that of 996 downregulated upon treatment. The gene set up-regulated by BDQ was significantly enriched for genes involved in glucose/phospholipid metabolism, lysosome and autophagy. We found similar results with uninfected macrophages-treated with BDQ. Conclusions: Our results highlight the importance to study the interactions between antibiotics and host cells at the molecular level to better understand the consequences of antibiotic treatment during infection
2020-01-01 | GSE133145 | GEO
Project description:We have employed the Zebrafish gene expression microarray (MZH_Zebrafish_16k_v1.0) as a discovery platform to analyze the trancriptome of 108hpf (hours post fertilization) embryos exposed from the 96hpf to 108hpf to 100µM of diethylmaleate (DEM).
2011-09-24 | GSE32267 | GEO
Project description:Influenza A viruses (IAV) comprise some of the most common infectious pathogens in humans, and they cause significant mortality and morbidity in immunocompromised people as well as children and the elderly. After screening an FDA-approved drug library containing 1280 compounds by cytopathic effect (CPE) reduction assay using the Cell Counting Kit-8, we found two antihistamines, carbinoxamine maleate (CAM) and S-(+)-chlorpheniramine maleate (SCM) with potent antiviral activity against A/Shanghai/4664T/2013(H7N9) infection with IC50 (half-maximal inhibitory concentration) of 3.56 and 11.84 ?M, respectively. Further studies showed that CAM and SCM could also inhibit infection by other influenza A viruses, including A/Shanghai/37T/2009(H1N1), A/Puerto Rico/8/1934(H1N1), A/Guizhou/54/1989(H3N2), and one influenza B virus, B/Shanghai/2017(BY). Mice were challenged intranasally with A/H7N9/4664T/2013 (H7N9) virus and intraperitoneally injected with CAM (10 mg/kg per day) or SCM (1 mg/kg per day) for 5 days. CAM or SCM (10 mg/kg per day) were fully protected against challenge with A/Shanghai/4664T/2013(H7N9). The results from mechanistic studies indicate that both could inhibit influenza virus infection by blocking viral entry into the target cell, the early stage of virus life cycle. However, CAM and SCM neither blocked virus attachment, characteristic of HA activity, nor virus release, characteristic of NA activity. Such data suggest that these two compounds may interfere with the endocytosis process. Thus, we have identified two FDA-approved antihistamine drugs, CAM and SCM, which can be repurposed for inhibiting infection by divergent influenza A strains and one influenza B strain with potential to be used for treatment and prevention of influenza virus infection.
| S-EPMC6232386 | biostudies-literature
Project description:The title organic salt, C(4)H(6)N(3)O(+)·C(4)H(3)O(4) (-)·C(4)H(5)N(3)O, was synthesized from cytosine base and maleic acid. An intra-molecular O-H?O hydrogen bond occurs in the hydrogen maleate anion. The crystal packing is stabilized by inter-molecular N-H?O, N-H?N and C-H?O hydrogen bonds, giving rise to a nearly planar two-dimensional network parallel to (101).
| S-EPMC2972138 | biostudies-literature