+86-28-82633987
Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃
75.8500
1.0600
.7700
Low
No
No
No
Unknown
No
Unknown
Gallic acid trimethyl ether (3,4,5-trimethoxybenzoic acid, CAS number 118-41-2), also known as Eudesmic acid or Trimethylgallic acid, is an important benzoic acid derivative. As a typical representative among natural products and their derivatives, trimethyl gallate has attracted widespread attention in recent years in the fields of medicinal chemistry and natural product pharmacology due to its unique chemical structure and diverse bioactivity. This compound not only exhibits significant antibacterial activity, especially against Staphylococcus aureus, but also shows a minimum inhibitory concentration (MIC) as low as 0.97 μg/mL, while also showing potential therapeutic value in various pathological conditions such as antioxidant and anti-inflammatory conditions. This paper aims to systematically review the chemical structure and physicochemical properties of trimethyl gallate ether, plant origin and extraction methods, pharmacological activity and mechanism of action, druggability evaluation and pharmacokinetic characteristics, and to explore its clinical application prospects and development directions, providing theoretical basis and practical guidance for related research.
The chemical formula of trimethyl gallate is C11H14O5, with a molecular weight of 212.20. Its structure is based on the benzoic acid framework, with the hydroxyl group at positions 3, 4, and 5 replaced by methoxy groups, forming a trimethyl ether structure, chemically named 3,4,5-trimethoxybenzoic acid. This structure imparts strong stability and moderate polarity, with a LogP value of 1.06, indicating moderate lipid solubility, which facilitates membrane permeability without being overly hydrophobic. The molecular surface area (TPSA) is 75.85 Ų, and the number of hydrogen bond acceptors is 5, indicating that it possesses certain hydrophilicity and is conducive to hydrogen bonding with biomacromolecules.
The physicochemical properties of trimethyl gallate give it excellent pharmacokinetic potential in drug design. Its low blood-brain barrier penetration suggests a low risk of side effects in the central nervous system. Both hepatotoxicity and cardiotoxicity are low-risk, and there is no hERG channel inhibitory activity, indicating good cardiac safety. Although Ames mutagenicity test results are not yet clear, existing data support its status as a highly safe drug candidate.
Gallic acid trimethyl ether is widely found in various plants, especially in plant groups rich in benzoic acid derivatives. Its natural sources mainly include gallophiles (such as Rhus spp.), some woody plants, and medicinal herbs. Trimethyl gallate in plants usually exists in its free form or in combination with other phenolic compounds.
Common extraction techniques include solvent extraction, ultrasound-assisted extraction, and liquid-liquid extraction. Reflux extraction using methanol, ethanol, or ethyl acetate as solvents is the most common method, and combining ultrasound assistance can significantly improve extraction efficiency. After concentration and separation purification (such as silica gel column chromatography and reversed-phase high-performance liquid chromatography), high-purity trimethyl gallate ether can be obtained. In recent years, green extraction technologies such as supercritical CO2 extraction and microwave-assisted extraction have also been used to improve extraction efficiency and environmental friendliness.
Trimethyl gallate exhibits inhibitory effects on various bacteria, especially against Gram-positive bacteria such as Staphylococcus aureus (S. aureus) has significant activity. Its minimum inhibitory concentration (MIC) is 0.97 μg/mL, demonstrating strong antibacterial activity. This activity gives it potential application value in anti-infective drug development, especially amid the increasing number of resistant strains, where the prospects of trimethyl gallate as a natural antimicrobial agent are attracting significant attention.
Trimethyl gallate has significant antioxidant activity, scavenging free radicals and reducing cell damage caused by oxidative stress. Its antioxidant mechanism mainly works by activating the nuclear factor 2-related factor 2 (NRF2) signaling pathway, inducing the expression of downstream antioxidant enzymes such as heme oxygenase 1 (HMOX1), thereby enhancing the cell's antioxidant defense capacity.
Additionally, gallic trimethyl ether exhibits good anti-inflammatory activity. It can inhibit the expression of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (PTGS2, COX-2), thereby reducing inflammatory responses. Both related in vitro and in vivo experiments have confirmed its efficacy in various inflammatory models, suggesting its potential therapeutic value in inflammatory diseases such as arthritis and inflammatory bowel disease.
Although there are currently few reports on other pharmacological effects of gallate trimethyl ether, its structure resembles various bioactive benzoic acid derivatives, and future research is expected to reveal its potential in anti-tumor, neuroprotection, and metabolic regulation.
The pharmacological effects of trimethyl gallate are mainly realized by regulating key molecular targets. Its antioxidant and anti-inflammatory effects involve the following main targets:
TNF (tumor necrosis factor α): As an important pro-inflammatory cytokine, TNF plays a central role in various inflammatory and immune responses. Trimethyl gallate can inhibit TNF expression and signaling, reducing inflammatory responses.
PTGS2 (cyclooxygenase-2, COX-2) :P TGS2 are key enzymes that catalyze prostaglandin synthesis during inflammatory processes. Trimethyl gallate exerts anti-inflammatory effects by inhibiting PTGS2 expression, reducing the formation of inflammatory mediators.
IL-6 (Interleukin 6): IL-6 is a multifunctional pro-inflammatory cytokine involved in immune regulation and inflammatory responses. Trimethyl gallate can inhibit IL-6 secretion and regulate the inflammatory microenvironment.
NRF2 (nuclear factor 2-related to red blood cell 2): NRF2 is a transcription factor that regulates cellular antioxidant responses. Trimethyl gallate activates the NRF2 signaling pathway, promotes the expression of antioxidant enzymes such as HMOX1, and enhances cellular antioxidant capacity.
HMOX1 (Heme Oxygenase 1): As a key antioxidant enzyme downstream of NRF2, HMOX1 is involved in relieving oxidative stress. Trimethyl gallate protects cells from oxidative damage by upregulating HMOX1 expression.
The synergistic regulation of these targets forms the molecular basis for the multiple pharmacological effects of trimethyl gallate ether, providing theoretical support for its application in antibacterial, anti-inflammatory, and antioxidant therapies.
The druggability parameters of trimethyl gallate indicate that it has promising potential for drug development. Moderate molecular weight (212.20), within the ideal range of Lipinski's rules. A LogP value of 1.06 indicates good lipophilus, making it easy for oral absorption. TPSA is 75.85 Ų, suitable for cell membrane permeability but resistance to crossing the blood-brain barrier, reducing the risk of central nervous system side effects.
In terms of safety, trimethyl gallate carries relatively low hepatotoxicity and cardiotoxicity risks, with no hERG channel suppression, indicating good cardiac safety. Although the results of Ames' mutagenicity tests are not yet clear, existing data do not show a significant genotoxicity risk.
Pharmacokinetic studies show that trimethyl gallate is well absorbed orally, has high bioavailability, is mainly confined to peripheral tissues, and has low blood-brain barrier permeability. The metabolic pathway mainly involves demethylation and carboxylation modification of methoxy groups through the hepatic enzyme system, and the metabolites have relatively low toxicity. Excretion is mainly completed through the kidneys and bile pathways.
In-depth pharmacokinetic and toxicological evaluations in the future, especially long-term toxicity and mutagenicity studies, will provide more comprehensive safety data support for the clinical development of gallic trimethyl ether.
Trimethyl gallate has broad clinical application potential due to its remarkable antibacterial, antioxidant, and anti-inflammatory activities. Its potent inhibitory effect against Staphylococcus aureus makes it an important candidate for the development of novel antimicrobial drugs, especially in the context of increasingly severe resistance strains, where natural product-based antibiotics offer irreplaceable advantages.
Its antioxidant and anti-inflammatory properties give gallic trimethyl ether potential therapeutic value in chronic inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, and other fields. By regulating the NRF2-HMOX1 signaling pathway, trimethyl gallate can alleviate oxidative stress and inflammatory responses, improving the pathological status of related diseases.
Additionally, as an important building block in organic synthesis, trimethyl gallate provides an ideal chemical foundation for structural modification and new drug design. By combining structural optimization with drug carrier technology, its bioavailability and targeting are expected to be enhanced, expanding its clinical application scope.
However, clinical research on gallic trimethyl ether is still in its early stages, and future pharmacodynamics, pharmacokinetics, and safety evaluations are needed, combined with clinical trials to verify its efficacy and safety. At the same time, in-depth analysis of its molecular mechanisms and multi-target mode of action will provide theoretical support for precision therapy.
As a structurally unique benzoic acid derivative, trimethyl gallate demonstrates broad research and application prospects in the field of natural product pharmacology due to its remarkable antibacterial, antioxidant, and anti-inflammatory activities. Its excellent druggability parameters and safety characteristics lay a solid foundation for new drug development. In the future, through interdisciplinary in-depth research, it is expected to promote the clinical translation of gallate trimethyl ether into a novel drug for treating infectious and inflammatory-related diseases. Ongoing attention to its mechanisms of action, pharmacokinetics, and clinical applications will inject new vitality into the development of natural product pharmacology.
Shenshuai
Wenjing
Hedandan
