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Purity: ≥98%
| Targets |
Anti-tuberculosis
mycobacterial ATP synthase TBAJ-587 targets M. tuberculosis ATP synthase, an essential enzyme for energy production in the bacterium. As a diarylquinoline analog of bedaquiline, it shares a similar mechanism of action by inhibiting the proton pump of ATP synthase, thereby disrupting the bacterium's energy metabolism and leading to cell death. TBAJ-587 demonstrates more potent anti-tubercular activity than bedaquiline, with greatly attenuated hERG blockade, indicating an improved safety profile. |
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| ln Vitro |
Bedaquiline belongs to the diarylquinoline class of drugs that have demonstrated clinical effectiveness in treating drug-resistant tuberculosis. However, because of its strong inhibition of the cardiac potassium channel protein hERG, bedaquiline has the potential to cause cardiac problems. An analogue of bedaquiline, TBAJ-587, exhibits significantly lessened hERG blockade and more powerful anti-tubercular action. TBAJ-587 has an IC50 of 13 μM for inhibiting the hERG channel[1].
MIC90 against M. tuberculosis H37Rv under replicating conditions (MABA assay): 0.006 µg/mL [1] MIC90 under non-replicating conditions (LORA assay): <0.02 µg/mL [1] hERG potassium channel inhibition IC50: 13 µM [1] Aqueous solubility at pH 7.4: <0.06 µM [1] In vitro, TBAJ-587 demonstrates potent anti-tubercular activity against M. tuberculosis H37Rv strain with MIC₉₀ values of 0.006 μg/mL in MABA assay and <0.02 μg/mL in LORA assay. It is a potent anti-tuberculosis agent that inhibits M. tuberculosis growth at very low concentrations. The compound inhibits hERG channel with an IC₅₀ of 13 μM, indicating greatly attenuated hERG blockade compared to bedaquiline. |
| ln Vivo |
In a mouse model of tuberculosis (aerosol inoculation of M.tb, treatment started 10 days post-infection), TBAJ-587 administered orally at 20 mg/kg daily for 12 days resulted in a 5.2 log reduction in lung CFU compared to vehicle control [1]
In vivo, TBAJ-587 has the potential to be an effective treatment for drug-resistant tuberculosis. As a diarylquinoline analog of bedaquiline with more potent activity and improved safety profile, it represents a promising candidate for further development. However, specific in vivo efficacy data in animal models are not extensively detailed in the available literature. |
| Enzyme Assay |
In vitro anti-tubercular activity assays for TBAJ-587 are performed using M. tuberculosis H37Rv strain. The MABA (Microplate Alamar Blue Assay) and LORA (Low Oxygen Recovery Assay) methods are used to determine the MIC₉₀ values. In the MABA assay, the compound is serially diluted in 96-well plates, and M. tuberculosis is added. After incubation, Alamar Blue is added, and fluorescence is measured to determine bacterial growth inhibition. The LORA assay is used to assess activity against non-replicating bacteria.
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| Cell Assay |
MABA (Microplate Alamar Blue Assay) was used to determine the minimum inhibitory concentration for 90% inhibition (MIC90) of growth of M. tuberculosis H37Rv under aerobic (replicating) conditions [1]
LORA (Low Oxygen Recovery Assay) was used to determine MIC90 under non-replicating conditions [1] Vero cell cytotoxicity assay was performed to determine IC50 in green monkey kidney epithelial cells, but specific data for TBAJ-587 was not reported (all tested compounds except compound 9 had IC50 >10 µg/mL) [1] In vitro cell-based assays for TBAJ-587 are not standard, as the compound's primary activity is against bacteria rather than mammalian cells. However, cytotoxicity assays may be performed using mammalian cell lines (e.g., HepG2 or Vero cells) to assess the compound's safety profile. Cells are cultured in appropriate media and treated with TBAJ-587 at various concentrations for 24-72 hours. Cell viability is measured by MTT or neutral red uptake assays to determine CC₅₀ values and selectivity index. |
| Animal Protocol |
For efficacy study: Female mice were infected with M. tuberculosis via aerosol route. Ten days post-infection, treatment with TBAJ-587 was initiated. The compound was administered orally once daily at a dose of 20 mg/kg for 12 days. At the end of treatment, lungs were harvested and colony-forming units (CFU) were enumerated [1]
For pharmacokinetic study: Mice received a single intravenous injection and a single oral dose of TBAJ-587. Blood samples were collected at various time points to determine plasma concentrations [1] In vivo animal studies for TBAJ-587 would typically involve mouse models of tuberculosis infection. Mice are infected with M. tuberculosis via aerosol or intravenous injection. TBAJ-587 is administered orally or intraperitoneally at doses determined from pharmacokinetic studies. After several weeks of treatment, bacterial load in the lungs and spleen is measured by colony counting. The compound's efficacy is compared to bedaquiline and other standard anti-tuberculosis drugs. |
| ADME/Pharmacokinetics |
Human microsomal CLint: 2 µL/min/mg [1]
Mouse microsomal CLint: 18 µL/min/mg [1] IV clearance (mouse): 48 mL/min/kg [1] Volume of distribution (Vz, mouse): 95 L/kg [1] Oral AUC0-inf (mouse): 1.72 µg*h/mL [1] Oral bioavailability (mouse): 48% [1] Aqueous solubility at pH 7.4: <0.06 µM [1] clogP: 5.80 [1] Specific pharmacokinetic properties of TBAJ-587 are not extensively detailed in the available literature. As a diarylquinoline analog with a molecular weight of 614.5 g/mol, it is expected to have good oral bioavailability and tissue distribution. The compound is likely metabolized in the liver and excreted primarily in feces. Its improved safety profile, with attenuated hERG blockade, suggests favorable pharmacokinetic and safety properties. |
| Toxicity/Toxicokinetics |
hERG channel inhibition IC50: 13 µM (attenuated compared to bedaquiline IC50 1.6 µM) [1]
No significant cytotoxicity in Vero cells? (compound 8 not specifically listed, but most compounds had IC50 >10 µg/mL) [1] Comprehensive toxicological data for TBAJ-587 are not widely available in public literature. The compound demonstrates greatly attenuated hERG blockade (IC₅₀ = 13 μM) compared to bedaquiline, indicating a reduced risk of cardiac toxicity. As a research compound, it is intended for laboratory use only and is not for human therapeutic use. Standard safety precautions should be followed when handling this compound. |
| References | |
| Additional Infomation |
TBAJ-587 (compound 8) is a 3,5-dialkoxy-4-pyridyl analogue of bedaquiline with potent antituberculosis activity and reduced hERG inhibition. It was selected for preclinical development along with TBAJ-876 [1]
CAS number: 2252316-16-6 [1] Indication: drug-resistant tuberculosis [1] Mechanism of action: selective inhibition of mycobacterial ATP synthase (inferred from bedaquiline) [1] TBAJ-587 is a diarylquinoline analog of bedaquiline that demonstrates potent anti-tubercular activity. It inhibits M. tuberculosis H37Rv growth with MIC₉₀ values of 0.006 μg/mL in MABA assay. The compound exhibits more potent activity than bedaquiline with greatly attenuated hERG blockade (IC₅₀ = 13 μM). TBAJ-587 is a promising candidate for the treatment of drug-resistant tuberculosis. This product is for research use only. |
| Molecular Formula |
C30H33BRFN3O5
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|---|---|
| Molecular Weight |
614.502530813217
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| Exact Mass |
613.16
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| Elemental Analysis |
C, 58.64; H, 5.41; Br, 13.00; F, 3.09; N, 6.84; O, 13.02
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| CAS # |
2252316-16-6
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| Related CAS # |
2252316-16-6;TBAJ-587 HCl;
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| PubChem CID |
138319677
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| Appearance |
Solid powder
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| LogP |
5.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
40
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| Complexity |
774
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CN(C)CC[C@@](C1=CC(=NC(=C1)OC)OC)([C@H](C2=C(C(=CC=C2)OC)F)C3=C(N=C4C=CC(=CC4=C3)Br)OC)O
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| InChi Key |
JJEGOJPMKLRSPJ-POURPWNDSA-N
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| InChi Code |
InChI=1S/C30H33BrFN3O5/c1-35(2)13-12-30(36,19-16-25(38-4)34-26(17-19)39-5)27(21-8-7-9-24(37-3)28(21)32)22-15-18-14-20(31)10-11-23(18)33-29(22)40-6/h7-11,14-17,27,36H,12-13H2,1-6H3/t27-,30-/m1/s1
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| Chemical Name |
(1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol
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| Synonyms |
TBAJ-587; TBAJ 587; TBAJ587
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~43.33 mg/mL (~70.51 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (3.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.17 mg/mL (3.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.17 mg/mL (3.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.17 mg/mL (3.53 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6273 mL | 8.1367 mL | 16.2734 mL | |
| 5 mM | 0.3255 mL | 1.6273 mL | 3.2547 mL | |
| 10 mM | 0.1627 mL | 0.8137 mL | 1.6273 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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