843663-66-1 Usage
Overview
Bedaquiline, formally called (1R, 2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol in chemistry and known as Sirturo in commercial, is a new anti-mycobacterial medicine of diarylquinolines. It impinges on the
ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of proton pump on the cell’s ATP synthetase, and thereby eliminates M. tuberculosis (TB). It’s used for adult multi-drug resistant tuberculosis (MDR-PTB).
Synthetic Methods
Fig: Synthetic route of Bedaquiline
Pharmacological Function
Bedaquinoline has the same bactericidal activity against both sensitive and resistant strains of mycobacterium tuberculosis as well as on dormant bacteria.
Pharmacology
The proton pump on the cell’s ATP synthetase, which is a crucial enzyme for M. tuberculosis (TB) to synthesize ATP, is the unique and specific locus of Bedaquinoline.
After the combination onto the oligomer and lipoprotein subunit c, Bedaquinoline can inhibit the synthesis of ATP and bring the death to the bacterium cell. Compared with those existing anti-TB medicines, it presents a novel pharmacology and no cross resistance effect was found between Bedaquinoline and other anti-TB medicines. The gene sequence of the subunit c of ATP synthetase is named as atpE, whose amino acid sequence is highly conservative. The resistance of TB to Bedaquinoline comes from its reduced combination onto subunit c of ATP synthetase due to the mutation of the 63rd or 66th on atpE.
Pharmacokinetics
Bedaquinoline is easy for oral assimilation. The bioavailability of Bedaquinoline taken with food is twice higher than when taken with an empty stomach. It reaches its blood concentration in 5 hours after taken and has a plasma protein binding rate of 99.9% as well as a plasma half-life of 173 hours. Bedaquinoline can be widely distributed in human body with a homeostasis distribution volume of 1000Ｌ. Its clearance rate is low enough and the elimination half-life is 5.5 months. Bedaquinoline is metabolize into metabolite 1~8 in the demethylation mainly through CYP3A4 and partly though CYP2C8 and CYP2C19. Metabolite 2 （M2）, the most important metabolite,? which has only 1/3-1/6 the activity of Bedaquinoline, yet present a more strong cytotoxicity and is more likely to cause the drug-induced phospholipidosis. Bedaquinoline and its metabolites are mostly excreted by feces, only 1% to 4% by urine.
Adverse Effect
Common adverse reactions are nausea, headache, arthralgia, loss of appetite, vomiting and rash, dizziness, elevated transaminase, increased hemodiastase, muscle pain, diarrhea and prolonged TQ interval.
Taboo
1.The allergic to this product;
2.Patients suffer serious dysfunction of heart, liver, kidney (relative contraindication);
3.Pregnant women, lactating women, children, the old and co-infected HIV sufferers (relative contraindication).
Description
Different sources of media describe the Description of 843663-66-1 differently. You can refer to the following data:
1. In December 2012, the US FDA approved bedaquiline as part of combination
therapy for the treatment of multi-drug resistant tuberculosis (MDRTB).
Bedaquiline is the first drug approved for MDR-TB and is the first
approval from a new class of antituberculosis agents in the past 40 years.
Due to the high unmetmedical need for treating MDR-TB, the FDA granted
bedaquiline accelerated approval based on Phase II results, providing patients access to the drug while additional clinical studies are carried out. Bedaquiline (also known as TMC207 and R207910) is a diarylquinoline
that was discovered from a high-throughput, whole-cell screening
strategy with Mycobacterium smegmatis used as a surrogate for
M. tuberculosis. Bedaquiline is a single enantiomer of an initial screening
hit. Bedaquiline has potent and selective activity against mycobacteria, and
is active against both drug-sensitive and drug-resistant M. tuberculosis. The mechanism of action of bedaquiline is unique amongst anti-TB drugs and
involves inhibition of mycobacterial ATP synthase; it is not active against
human ATP synthase. Bedaquiline has in vivo activity in numerous preclinical models of TB infection, alone and in combination with other anti-TB agents, and has bactericidal activity in established TB infection models. Bedaquiline is synthesized in five steps from 3-phenylpropionic acid
and para-bromoaniline. Following amide formation, treatment with POCl3
and DMF under Vilsmeier–Hack conditions gave a 2-chloroquinoline product.
Treatment with sodium methoxide, followed by condensation with
3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one, and separation of isomers
gave bedaquiline.
2. TMC207 is a diarylquinoline that selectively inhibits the proton pump of the mycobacterial ATP synthase. It demonstrates potent activity against both drug-sensitive and drug-resistant M. tuberculosis and other mycobacterial species with MIC50 values of ~0.03 μg/ml.
Uses
Different sources of media describe the Uses of 843663-66-1 differently. You can refer to the following data:
1. (αS,βR)-Bedaquiline is a diarylquinoline derivative that acts as a mycobacterial inhibitor. Bedaquiline shows promise as potential drug in the treatment of tuberculosis.
2. Labeled Bedaquiline, intended for use as an internal standard for the quantification of Bedaquiline by GC- or LC-mass spectrometry.
Brand name
Sirturo
References
Andries et al. (2005), A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis; Science, 307 223
Koul et al. (2007), Diarylquinolines target subunit c of mycobacterial ATP synthase; Nat. Chem. Biol., 3 323
Biukovic et al. (2013), Variations of subunit {varepsilon} of the Mycobacterium tuberculosis F1F0 ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207; Antimicrob. Agents Chemother., 57 168
Sarathy et al. (2019), Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline; Antibiotics (Basel), 8 261
Ghahremanpour et al. (2020), Identification of 14 Known Drugs as Inhibitors of the Main Protease of SARS-CoV-2; ACS Med. Chem. Lett., 11 2526
Check Digit Verification of cas no
The CAS Registry Mumber 843663-66-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,4,3,6,6 and 3 respectively; the second part has 2 digits, 6 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 843663-66:
(8*8)+(7*4)+(6*3)+(5*6)+(4*6)+(3*3)+(2*6)+(1*6)=191
191 % 10 = 1
So 843663-66-1 is a valid CAS Registry Number.
843663-66-1Relevant articles and documents
Crystal structures of salts of bedaquiline
Bogandowich-Knipp, Susan,Byrn, Stephen R.,Clase, Kari L.,Okezue, Mercy,Purcell, Dale K.,Smith, Daniel,Smith, Pamela,Zeller, Matthias
, p. 1010 - 1023 (2020/11/13)
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.
Method for preparing bisarylquinoline antibiotics by optical resolution (by machine translation)
-
Paragraph 0084-0085, (2020/02/27)
The present invention provides a method, for preparing bisarylquinoline antibiotics using optical resolution comprising separating optically pure, bromine - (αS,βR) - 6 - from)-(dimethylamino] - 2 - ethyl 6 - methoxy -S :phenyl - 3 3-quinolinolaquindox) in the three-dimensional isomer mixture of-phenyl - 3 3-quinolinolathanol in a high yield)% yield of the optically pure isomer mixture of the optically active agents] - 2 -yl-phenyl-3-quinolinolaquinola. (dimethylamino-methoxy-S :phenyl-3-quindox. (by machine translation)
Beda quinoline preparation method
-
Paragraph 0102; 0103; 0104; 0105, (2017/10/13)
The invention discloses a preparation method for bedaquiline. The preparation method comprises the following steps: enabling a compound (9) to be reacted with a reducing agent in a solvent; and then collecting racemate of bedaquiline from a reaction product. The preparation method has the advantages that the compound (9) is a novel compound which has not been reported in literature; the racemate of bedaquiline is prepared from a compound (8) and the compound (9); the obtained product is greatly increased in yield (greater than 47%) which is remarkably greater than the yield (26%) in the original patent; and the obtained racemate of bedaquiline is high in purity, stable and controllable in quality, and beneficial for subsequent resolution reaction, and has relatively great positive effects and relatively high practical application value. The reaction formula is shown as follows: a FORMULA as shown in the description.
