Product name: Isodemethylwedelolactone
Synonym name:
Catalogue No.: BP3117
Cas No.: 350681-33-3
Formula: C₁₅H₈O₇
Mol Weight: 300.222
Botanical Source:
Physical Description: Yellow powder
Type of Compound: Coumarins

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
The product could be supplied from milligrams to grams. Inquire for bulk scale.
We provide solution to improve the water-solubility of compounds, thereby facilitating the variety of activity tests and clinic uses.

For Reference Standard and R&D, Not for Human Use Directly.

HPLC of Isodemethylwedelolactone

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in the history of human disease treatment. Among them, the Asteraceae plant, Alternanthera philoxeroides（Eclipta alba In the traditional medical system, especially in Ayurveda and traditional Chinese medicine, it is commonly used to treat liver diseases, inflammation, and hemostasis. Its complex secondary metabolite library is a treasure trove of various bioactive components. Isodemethylwedelolactone (CAS: 350681-33-3) is a coumarin compound with significant biological activity isolated from this plant. Early studies labeled it as a coagulant and hemolytic component, suggesting that it may act on the blood system. However, with the deepening of modern pharmacological research, especially the development of network pharmacology and molecular docking technology, its pharmacological activity spectrum has been greatly expanded. Recent research has focused on its potential association with inflammatory bowel diseases such as colitis, regulating inflammation, cell apoptosis, and barrier function through multi-target mechanisms, demonstrating remarkable therapeutic prospects. This article aims to provide a systematic review of the chemical properties, plant sources, pharmacological activities, mechanisms of action, medicinal properties, and clinical application potential of isodemethylated pyrethroid, in order to provide comprehensive scientific references for the in-depth research and development of this compound.

Chemical structure and physicochemical properties

Isomethomyl is an organic compound belonging to the coumarin derivative class. Its core structure is benzo [a] - pyranone, and multiple hydroxyl, methoxy, and other substituents are attached to the parent nucleus. It is an isomer of its homologue Demethylwedelolactone. This subtle difference in structure determines its unique physicochemical properties and biological activity.

From the perspective of pharmacological parameters, the molecular weight of this compound is 300.220, belonging to the category of small molecule compounds and possessing good cell membrane permeability potential. Its lipid water partition coefficient (LogP) is 2.1335, indicating that the molecule has moderate lipophilicity, which facilitates its passage through biological membranes. However, excessively high LogP may also lead to solubility and metabolic issues. The calculated topological polar surface area (TPSA) is 124.2700 Å ², which is relatively high. This is mainly attributed to multiple hydrogen bond donors and acceptors (such as hydroxyl and carbonyl groups) in the molecular structure, suggesting that it may have moderate membrane permeability and may affect its oral bioavailability. The water solubility data (0.0198 mg/mL) confirms that it is a poorly soluble compound, which will be one of the key challenges to overcome in formulation development. In addition, preliminary drug risk assessment shows that its ability to cross the blood-brain barrier is low, indicating that the risk of central nervous system related side effects may be relatively low; The hERG channel inhibition experiment showed negative results, reducing the potential risk of inducing QT interval prolongation and apical torsion type ventricular tachycardia in the heart; The Ames test result is 1.2 (usually considered negative if the ratio is less than 2), indicating that there is no significant genetic toxicity. These physicochemical and early safety parameters laid the foundation for further pharmacological development and structural optimization.

Plant sources and extraction methods

Isodemethylated pyrethroid is mainly derived from its original plant, Alternanthera philoxeroides（Eclipta alba Obtained by separation from (L.) Hassk. Dryland is an annual herbaceous plant widely distributed in tropical and subtropical regions, growing in China, India, Southeast Asia, and South America. In traditional medicine, its whole herb is considered to have the effects of nourishing the liver and kidneys, cooling blood and stopping bleeding, clearing heat and detoxifying.

Extracting and purifying a single active ingredient from such a complex plant matrix is a delicate task. The conventional extraction process begins with the crushing of dried plant materials (usually whole grass or aboveground parts). Initial extraction is often carried out using solvent extraction methods, with commonly used solvents including methanol, ethanol, or ethanol water mixed solutions. Extraction efficiency is improved through immersion, reflux, or ultrasound assisted extraction. The crude extract obtained needs to be purified through a series of chromatographic separation techniques after vacuum concentration. The commonly used normal or reverse phase silica gel column chromatography is an effective means of preliminary separation, which can be grouped according to the different polarities of the compounds. Subsequently, more precise separation was performed using preparative high performance liquid chromatography (HPLC) or medium pressure liquid chromatography (MPLC) to obtain high-purity isodemethylated pyrethroid. Modern technologies such as high-speed countercurrent chromatography (HSCCC) have also been applied to the separation of such natural products due to their advantages of irreversible adsorption and high recovery rate. The optimization of extraction processes, such as solvent ratio, temperature, and time control, as well as the application of green extraction techniques (such as supercritical fluid extraction), are crucial for improving the yield of target compounds and maintaining their biological activity. In addition, chemical synthesis and biosynthetic pathways are also being explored, aiming to solve the problems of limited plant sources and low content, and provide alternative solutions for their large-scale supply.

Pharmacological activity research

The pharmacological activity research of isoleuclide has expanded from early blood system effects to a wider range of fields, especially in anti-inflammatory and immune regulation.

1. The effect on the blood system Early studies defined it as a coagulant and hemolytic component. Its procoagulant activity may be achieved by affecting coagulation factors or platelet function, but the specific mechanism remains to be elucidated. The hemolytic activity suggests that it may have a destructive effect on the red blood cell membrane at high concentrations, which is not only a potential toxicity aspect, but also may be related to certain specific pathological processes (such as clearing damaged red blood cells), and should be carefully balanced between therapeutic and toxic doses.

2. Anti inflammatory and immune regulatory activity This is the core focus of current research. In various chemically induced colitis models in rodents (such as DSS, TNBS), isodemethylated pyrethroid showed significant improvement effects. It can effectively alleviate pathological damage to colon tissue, including reducing mucosal ulcers, inflammatory cell infiltration, and crypt structure destruction. At the same time, it can reduce the levels of pro-inflammatory cytokines (such as TNF - α, IL-1 β, IL-6) in serum and colon tissue, and promote the expression of anti-inflammatory factors (such as IL-10). This extensive anti-inflammatory effect indicates its ability to regulate immune responses with multiple targets.

3. Antioxidant and anti apoptotic activity Oxidative stress is an important driving factor for inflammatory diseases such as colitis. Research has shown that isodemethylated pyrethroid can enhance the antioxidant defense ability of colon tissue, such as increasing the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH Px), and reducing the level of lipid peroxidation product malondialdehyde (MDA). In addition, it can also inhibit excessive apoptosis of colonic epithelial cells by regulating the expression of apoptosis related proteins (such as Bcl-2/Bax, Caspase family), maintaining the integrity of the intestinal epithelial barrier.

4. Other potential activities Based on the similarity between its core structure and homologs (such as Scutellaria baicalensis lactone), it is speculated that it may also have activities such as hepatoprotective, antiviral (such as anti hepatitis virus), and anti osteoporosis, but these still need further experimental verification.

Mechanism of action and molecular targets

Modern systems pharmacology analysis has revealed that the use of isodemethylated pyrethroid in the treatment of colitis may involve a complex multi-target and multi pathway network. Its function is not through a single target, but through the coordinated regulation of multiple key signaling nodes:

1. Regulating inflammatory signaling pathways：

   • TLR4/NF - κ B pathway Toll like receptor 4 (TLR4) is a key receptor that recognizes bacterial lipopolysaccharides (LPS) and initiates innate immunity. Isomethomyl may block the downstream nuclear factor kappa B (NF - κ B) signaling pathway by inhibiting the activation of TLR4. After the nuclear translocation and transcriptional activity of NF - κ B (involving the key subunit RELA/p65) are inhibited, it leads to the downregulation of gene expression of a large number of pro-inflammatory factors (such as TNF - α, IL-1 β, IL-6) and inflammatory mediators, which is one of the core mechanisms of its anti-inflammatory effect.
   • MAPK pathway The mitogen activated protein kinase (MAPK) pathway, particularly the extracellular signal regulated kinase (MAPK1/ERK), is another important pathway for inflammation and stress response. This compound may synergistically inhibit inflammatory responses by regulating the phosphorylation level of MAPK1, affecting the activity of transcription factors such as AP-1.

2. Regulating lipid metabolism and signaling：

   • Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) axis SPHK1 catalyzes the generation of S1P from sphingosine, which is an important lipid signaling molecule involved in cell proliferation, migration, and inflammation regulation. Inhibiting SPHK1 can reduce the generation of S1P, which may inhibit its mediated pro-inflammatory and fibrotic signals.
   • Lysophosphatidic acid receptor 2 (LPAR2)LPAR2 is one of the receptors for lysophosphatidic acid (LPA), involved in intestinal barrier function, inflammation, and pain perception. Regulating LPAR2 signaling may help stabilize the intestinal barrier and alleviate inflammation.
   • Fatty acid amide hydrolase (FAAH)FAAH is a key enzyme for degrading endogenous cannabinoids such as arachidylethanolamine (AEA). Inhibition of FAAH can increase endogenous cannabinoid levels and exert anti-inflammatory, analgesic, and intestinal motility regulatory effects by activating cannabinoid receptors (CB1/CB2).

3. Affects cellular stress and death：

   • Protein kinase C alpha (PRKCA)PKC α is involved in various cellular processes, including inflammatory signal transduction and cell apoptosis. Regulating its activity may affect downstream NF - κ B and MAPK pathways.
   • Cystatine-1 (CASP1)CASP1 is a key effector protein for inflammasome activation, responsible for cleaving IL-1 β and IL-18 precursors into mature forms. Inhibiting the activity of CASP1 can directly block the release of IL-1 β, thereby inhibiting pyroptosis and inflammation.

4. Drug metabolism and activity regulation：

   • Carboxyesterase 1 (CES1)CES1 is an important hydrolytic enzyme in the body, involved in the metabolism of various esters and prodrugs. Isomethomyl may interact with CES1, affecting its own or other drug metabolism processes, and may also affect the level of endogenous lipid mediators by regulating CES1 function.

In summary, isoleuclide forms a synergistic network by simultaneously acting on multiple targets such as CES1, TLR4, PRKCA, CASP1, LPAR2, RELA, FAAH, SPHK1, MAPK1, TNF, etc. It intervenes in the pathological process of colitis in multiple dimensions and levels, from inhibiting inflammation initiation (TLR4), blocking inflammation signaling (NF - κ B, MAPK), regulating lipid inflammatory mediators (S1P, LPA, endogenous cannabinoids) to inhibiting inflammatory cell death (CASP1).

Evaluation of drug properties and pharmacokinetics

Despite exhibiting good pharmacological activity, the drug affinity of isodemethylated pyrethroid remains to be comprehensively evaluated.

1. Prediction and Challenges of Absorption, Distribution, Metabolism, and Excretion (ADME)：

   • absorb Moderate LogP value (2.13) is beneficial for passive diffusion absorption, but higher TPSA (124) and lower water solubility (0.0198 mg/mL) may limit its gastrointestinal absorption rate and degree, resulting in suboptimal oral bioavailability. The formulation strategy, such as making nanocrystals, solid dispersions, liposomes, or cyclodextrin inclusion complexes, is the key to improving their solubility and dissolution.
   • distribution Low molecular weight, conducive to distribution. Predicting low blood-brain barrier permeability may be an advantage for treating peripheral diseases such as colitis, reducing central side effects. However, its specific distribution and accumulation ability in inflamed colon tissue still need to be confirmed by in vivo studies.
   • Metabolism As a derivative of coumarin, it is likely to undergo oxidative metabolism through the liver cytochrome P450 (CYP) enzyme system (such as CYP3A4, CYP2C9), and may also undergo glucuronic acid binding or sulfation reactions. The interaction with CES1 suggests that its metabolic pathway may be more complex. Clear metabolic profiles and studies on the activity/toxicity of major metabolites are necessary.
   • excretion It is speculated that its metabolites are mainly excreted through the kidneys or bile. The excretion pathway of the prototype drug needs to be clarified.

2. Preliminary Safety Assessment：

   • Early data showed no hERG inhibition and genotoxicity (Ames test negative), which are two important preclinical safety signals. However, its procoagulant and hemolytic activities suggest that close attention should be paid to its effects on coagulation function and red blood cells when administered systemically, in order to determine a safe window. Comprehensive preclinical toxicology research, including acute toxicity, subchronic toxicity, reproductive toxicity, etc., is a necessary path to promote its development.

3. Current status of pharmacokinetic research：
   At present, there is still a significant lack of pharmacokinetic studies on the isodemethylated pyrethroid system, such as blood concentration time curves, absolute bioavailability, tissue distribution, plasma protein binding rate, etc. in rats or beagle dogs. Establishing sensitive and accurate analytical methods (such as LC-MS/MS) for quantitative analysis of the compound and its metabolites in biological samples is a prerequisite for conducting such research.

Clinical application prospects and prospects

The multi-target anti-inflammatory properties of isoleuclide have brought broad application prospects in the treatment of inflammatory bowel disease (IBD), especially ulcerative colitis.

1. therapeutic potential：

   • Inflammatory bowel disease (IBD)As one of the effective ingredients of traditional anti IBD herbal medicine, Alternanthera philoxeroides, its development is expected to provide a novel treatment option with multiple mechanisms for IBD patients, which may be suitable for patients who have insufficient response or intolerance to existing aminosalicylic acids, glucocorticoids, or biologics.
   • Other inflammation related diseases Its mechanism of action suggests that it may also have potential therapeutic effects on other diseases associated with excessive activation of the TLR4/NF - κ B pathway, such as arthritis, dermatitis, hepatitis, acute lung injury, etc., which is worth exploring.

2. Development Strategy and Challenges：

   • structural optimization The core task of pharmaceutical chemists is to carry out reasonable structural modifications based on its parent nucleus, aiming to improve water solubility, enhance metabolic stability, enhance target selectivity, or reduce potential toxicity such as hemolysis.
   • New delivery system Developing colon targeted delivery systems (such as pH dependent, time-dependent, or enzyme triggered formulations) is highly valuable in addressing the issues of low solubility and potential irritation to the stomach. This strategy can increase the concentration of drugs at the lesion site while reducing systemic exposure and side effects.
   • combination therapy Considering its multi-target characteristics, when combined with existing drugs with a single mechanism of action (such as 5-ASA, specific cytokine inhibitors), it may produce synergistic effects, reduce their respective dosages, improve efficacy, and reduce drug resistance.
   • Clinical conversion bottleneck From in vitro and animal model data to human clinical trials, it is necessary to complete systematic preclinical pharmacological, pharmacokinetic, and toxicological studies, and solve the problem of large-scale and compliant raw material supply (extraction or synthesis).

Conclusion

As a coumarin compound discovered from the traditional medicinal plant Alternanthera philoxeroides, the research process of isodemethylated pyrethroid reflects the deepening from traditional experience to modern molecular pharmacology. The early understanding of its procoagulant and hemolytic activities has gradually been expanded by its powerful multi-target anti-inflammatory, antioxidant, and anti apoptotic activities, especially its remarkable therapeutic effects in colitis models. Its mechanism of synergistic therapeutic effect by regulating multiple key signaling nodes such as TLR4/NF - κ B, MAPK, SPHK1/S1P, and endogenous cannabinoid system is in line with the concept of modern networked therapy for complex diseases. However, its poor solubility and unclear pharmacokinetic and safety characteristics are the main obstacles on its drug development path. Future research should focus on in-depth mechanism validation, systematic drug efficacy optimization, and the application of innovative formulation technologies. Through interdisciplinary collaboration, isodesmopyrolactone is expected to be successfully transformed from a promising natural active molecule into a novel candidate drug for the treatment of inflammatory bowel disease and other inflammatory diseases, continuing the glorious chapter of natural products in drug discovery.