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Chebulagic acid is a naturally occurring COX-LOX dual inhibitor isolated from the Terminalia chebula Retz. It has antiviral activity and can inhibit SARS-CoV-2 viral replication with an EC50 of 9.76 μM.
| Targets |
Chebulagic acid targets cyclooxygenase-1 (COX-1) (IC50 = 0.8 μM) [3]
Chebulagic acid targets cyclooxygenase-2 (COX-2) (IC50 = 1.2 μM) [3] Chebulagic acid targets 5-lipoxygenase (5-LOX) (IC50 = 2.5 μM) [3] Chebulagic acid targets influenza A virus M2(S31N) ion channel (IC50 = 15.7 μM for inhibiting viral replication) [4] Chebulagic acid targets SARS-CoV-2 3CLpro (Ki = 1.8 μM, allosteric inhibition mode) [5] |
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| ln Vitro |
Autophagy is enhanced by chelagic acid. Chebulic acid possesses anti-infective and anti-inflammatory properties. Similar to the clinical symptoms of Parkinson's disease, 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity is another condition against which chelagic acid shows preventive properties. Chebulagic acid suppresses the elevation of TNF-α and IL-1β generated by LPS in a way that is dependent on both dose and time. Additionally, in EA.hy926 cells, chemilagic acid therapy reduced LPS-activated MAPK signaling.
- Neuroprotective activity: Chebulagic acid protected SH-SY5Y cells against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. At concentrations of 10 μM, 20 μM, and 40 μM, cell viability was increased by 22%, 41%, and 63% respectively, compared to 6-OHDA-treated cells (viability = 45% of normal control). It induced autophagy, as evidenced by increased LC3-II/LC3-I ratio and decreased p62 protein levels [1] - Anti-inflammatory activity: Chebulagic acid inhibited LPS-induced expression of TNF-α and IL-1β in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. At 50 μM, it reduced TNF-α and IL-1β mRNA levels by 72% and 68% respectively, and suppressed phosphorylation of ERK1/2, JNK, and p38 MAPK [2] - Anti-angiogenic activity: Chebulagic acid inhibited angiogenesis-related processes in HUVECs. It suppressed cell proliferation (IC50 = 32 μM), migration (inhibition rate = 58% at 50 μM), and tube formation (inhibition rate = 65% at 50 μM) by inhibiting COX-1, COX-2, and 5-LOX pathways [3] - Anti-influenza A virus activity: Chebulagic acid inhibited replication of influenza A virus (H1N1) carrying the M2(S31N) mutant ion channel, with an IC50 of 15.7 μM. It blocked M2 channel activity, reducing viral entry and release [4] - Anti-SARS-CoV-2 activity: Chebulagic acid inhibited SARS-CoV-2 3CLpro activity with a Ki of 1.8 μM, acting as an allosteric inhibitor. It reduced viral replication in Vero E6 cells, with an EC50 of 9.2 μM [5] |
| Enzyme Assay |
- COX-1/COX-2 inhibitory assay: Reaction mixtures containing COX enzyme (COX-1 or COX-2), arachidonic acid (substrate, 10 μM), and Chebulagic acid (0.1-10 μM) were incubated at 37°C for 30 minutes. Prostaglandin E2 (PGE2) production was measured using a colorimetric assay, and IC50 values were calculated [3]
- 5-LOX inhibitory assay: 5-LOX enzyme was mixed with arachidonic acid (10 μM) and Chebulagic acid (0.5-20 μM) in reaction buffer. The formation of leukotriene B4 (LTB4) was detected by fluorescence spectroscopy (excitation 400 nm/emission 460 nm), and IC50 was determined [3] - SARS-CoV-2 3CLpro activity assay: Recombinant SARS-CoV-2 3CLpro was mixed with a fluorescent resonance energy transfer (FRET) substrate and Chebulagic acid (0.1-10 μM) in assay buffer. Fluorescence intensity was measured at excitation 485 nm/emission 535 nm for 60 minutes. Kinetic analysis was performed to determine the inhibition mode and Ki value [5] - Influenza A virus M2(S31N) channel activity assay: M2(S31N) channel-expressing oocytes were incubated with Chebulagic acid (5-50 μM) for 30 minutes. Channel activity was measured using two-electrode voltage clamp, monitoring inward currents induced by low pH. Viral replication inhibition was assessed by plaque assay in MDCK cells [4] |
| Cell Assay |
- Neuroprotection and autophagy assay: SH-SY5Y cells were seeded at 1×10⁴ cells/well in 96-well plates, incubated overnight, pre-treated with Chebulagic acid (10-40 μM) for 2 hours, then exposed to 6-OHDA (100 μM) for 24 hours. Cell viability was measured by tetrazolium salt-based assay. For autophagy detection, cells were lysed after 24 hours of drug treatment, and LC3-I/LC3-II and p62 protein levels were analyzed by western blot [1]
- Anti-inflammatory assay: HUVECs were seeded at 5×10⁴ cells/well in 24-well plates, incubated overnight, pre-treated with Chebulagic acid (10-50 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours. TNF-α and IL-1β mRNA levels were detected by RT-PCR. Phosphorylated ERK1/2, JNK, and p38 were analyzed by western blot [2] - Anti-angiogenic assay: HUVECs were seeded at 5×10³ cells/well (proliferation assay) or 1×10⁵ cells/well (migration assay), pre-treated with Chebulagic acid (10-50 μM) for 1 hour. Proliferation was measured after 48 hours by tetrazolium salt assay. Migration was assessed by scratch assay, measuring wound closure after 24 hours. Tube formation was evaluated by seeding cells on Matrigel-coated plates with drug treatment, counting tube-like structures after 6 hours [3] - Anti-SARS-CoV-2 assay: Vero E6 cells were seeded at 2×10⁴ cells/well, incubated overnight, infected with SARS-CoV-2 (MOI = 0.01) for 1 hour, then treated with Chebulagic acid (1-50 μM) for 48 hours. Viral replication was quantified by qRT-PCR targeting viral N gene, and EC50 was calculated [5] |
| References |
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| Additional Infomation |
Phyllanthic acid has been reported to exist in Phyllanthus emblica, Acalypha indica, and Terminalia chebula, and relevant data are available. See also: Terminalia chebula (note moved here).
- Natural source: Terminalia chebula is a natural ellagic tannin isolated from the fruit of Terminalia chebula Retz. (Combretaceae family)[1][3] - Chemical classification: It belongs to the ellagic tannin polyphenol compound class, characterized by having a galloyl glucose core and an ellagic acid moiety[1][3] - Mechanism of action: Terminalia chebula exerts multi-target activity through different pathways: inducing autophagy to exert neuroprotective effects[1]; inhibiting the MAPK signaling pathway to exert anti-inflammatory effects[2]; inhibiting the COX-LOX pathway to exert anti-angiogenic effects[3]; exerting antiviral effects by blocking viral ion channel (M2) or protease (3CLpro) activity[4][5] - Selectivity: At therapeutic concentrations, it can simultaneously inhibit COX and LOX enzymes and has no significant cytotoxicity to normal cells[3] - Antiviral specificity: It targets SARS-CoV-2 The allosteric site of 3CLpro avoids cross-reaction with human proteases [5] |
| Molecular Formula |
C41H30O27
|
|---|---|
| Molecular Weight |
954.6607
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| Exact Mass |
954.097
|
| CAS # |
23094-71-5
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| PubChem CID |
250397
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| Appearance |
Off-white to light yellow solid powder
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| Density |
2.1±0.1 g/cm3
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| Boiling Point |
1610.6±65.0 °C at 760 mmHg
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| Melting Point |
>300℃
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| Flash Point |
480.0±27.8 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.876
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| LogP |
2.25
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| Hydrogen Bond Donor Count |
13
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| Hydrogen Bond Acceptor Count |
27
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
68
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| Complexity |
1970
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HGJXAVROWQLCTP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C41H30O27/c42-13-1-8(2-14(43)24(13)49)35(56)68-41-34-33-31(64-39(60)12(6-19(47)48)22-23-11(38(59)67-34)5-17(46)27(52)32(23)65-40(61)30(22)55)18(63-41)7-62-36(57)9-3-15(44)25(50)28(53)20(9)21-10(37(58)66-33)4-16(45)26(51)29(21)54/h1-5,12,18,22,30-31,33-34,41-46,49-55H,6-7H2,(H,47,48)
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| Chemical Name |
2-[13,14,15,18,19,20,31,35,36-nonahydroxy-2,10,23,28,32-pentaoxo-5-(3,4,5-trihydroxybenzoyl)oxy-3,6,9,24,27,33-hexaoxaheptacyclo[28.7.1.04,25.07,26.011,16.017,22.034,38]octatriaconta-1(37),11,13,15,17,19,21,34(38),35-nonaen-29-yl]acetic acid
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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 : ~100 mg/mL (~104.75 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (0.87 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (0.87 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 8.3 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: ≥ 0.83 mg/mL (0.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0475 mL | 5.2375 mL | 10.4749 mL | |
| 5 mM | 0.2095 mL | 1.0475 mL | 2.0950 mL | |
| 10 mM | 0.1047 mL | 0.5237 mL | 1.0475 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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