Synonym name: Azurechelin
Catalogue No.: BP1245
Cas No.: 69-72-7
Formula: C₇H₆O₃
Mol Weight: 138.122
Botanical Source: Present in willow bark (Salix sp.). Grindelia sp., Populus pseudo-simonii. Prod. by Pseudomonas cepacia

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.

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

HPLC of Salicylic acid

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

Introduction/Overview

Salicylic acid, also known as 2-hydroxybenzoic acid, is a simple phenolic acid compound widely found in plants in nature. Its CAS number is 69-72-7 and its molecular formula is C7H6O3. The application history of salicylic acid and its derivatives (the most famous of which is acetylsalicylic acid, also known as aspirin) dates back to ancient Sumerians and Egyptians using willow bark extract to relieve pain and fever. However, it was not until the mid-19th century that its active ingredients were isolated and purified, ushering in a new era of modern antipyretic, analgesic, and anti-inflammatory drugs. Although aspirin shines brighter, salicylic acid itself, as its active metabolite and precursor molecule, has always held a unique and fundamental position in the field of pharmacology. In recent years, with the deepening of molecular pharmacology research, the mechanism of action of salicylic acid has far exceeded the traditional scope of cyclooxygenase (COX) inhibition, and has been revealed to involve a complex network of multiple signaling pathways and molecular targets, exhibiting multifaceted effects in anti-inflammatory, analgesic, immune regulation, and even neuroprotection. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, multi-target mechanisms of action, pharmacological characteristics, and clinical application prospects of salicylic acid, in order to provide a comprehensive academic perspective for the deep development and innovative application of this classic natural product.

Chemical structure and physicochemical properties

Salicylic acid is a monohydroxybenzoic acid, whose chemical structure consists of a benzene ring, a carboxyl group (- COOH), and an adjacent phenolic hydroxyl group (- OH). This adjacent substituted hydroxybenzoic acid structure is the basis for its unique physicochemical properties and biological activity.

The basic physicochemical parameters are as follows: molecular weight of 138.1220 g/mol. The calculated lipid water partition coefficient (LogP) is approximately 1.88, indicating that salicylic acid has a certain degree of lipophilicity, but it is still an amphiphilic molecule as a whole. This is consistent with its ability to dissolve in organic solvents such as ethanol and ether, as well as being slightly soluble in hot water. Its water solubility value is about 1.997 mg/mL, which is slightly soluble. The topological polar surface area (TPSA) is 57.53 Å ², which is relatively small and conducive to transmembrane transport.

The phenolic hydroxyl group in salicylic acid molecules makes it weakly acidic (pKa ≈ 2.97), while the pKa of the carboxyl group is approximately 4.54. Under physiological pH conditions, salicylic acid mainly exists in the form of deprotonated anions. Its carboxyl and phenolic hydroxyl groups can participate in the formation of intramolecular hydrogen bonds, affecting its crystal structure and solubility. In addition, phenolic hydroxyl groups make it prone to oxidation reactions, which is also the structural basis for its antioxidant activity. This relatively simple structure endows salicylic acid with the ability to cross biological barriers, including the blood-brain barrier, providing the possibility for its application in central nervous system related diseases.

Plant sources and extraction methods

Salicylic acid is an important endogenous signaling molecule in plants, involved in defense responses such as systemic acquired resistance (SAR), and therefore widely present in various plants. Its natural sources mainly include:

1. Willow family plants The bark of Salix alba is the most classic source of salicylic acid glycosides, such as salidroside. Salicylic acid can be hydrolyzed and converted into salicylic acid by the human gut microbiota.
2. Rosaceae plants Plants such as Spiraea also contain salicylic acid and its derivatives.
3. Other plants Free or bound salicylic acid can also be detected in fruits (such as strawberries, grapes), vegetables, spices, and tea.

The traditional method of extracting salicylic acid from plant materials is mainly based on its acidity and solubility:

• Solvent extraction method Organic solvents such as methanol, ethanol, or acetone are commonly used for leaching or reflux extraction. This method is easy to operate, but has poor selectivity and can simultaneously extract a large amount of other phenolic acids and impurities.
• Alkali extraction and acid precipitation method Using the acidity of salicylic acid, plant materials are first soaked in dilute alkaline solution (such as sodium bicarbonate solution) to convert them into water-soluble salts and dissolve them. Then, the filtrate is acidified with inorganic acid (such as hydrochloric acid) to allow salicylic acid to precipitate again in the form of free acid. This method can obtain crude products with high purity.
• Modern Separation Technology To further purify, column chromatography (such as silica gel column, macroporous adsorption resin column), preparative high-performance liquid chromatography (HPLC) and other techniques are often combined. Green technologies such as supercritical fluid extraction (SFE) have also been applied in research.

At present, the large-scale production of salicylic acid in industry mainly adopts chemical synthesis methods (such as Kolbe Schmidt reaction), but naturally extracted salicylic acid still has demand in specific fields such as cosmetics and food additives.

Pharmacological activity research

The core pharmacological activities of salicylic acid are anti-inflammatory, antipyretic, and analgesic, which are in line with the effects of aspirin. However, in-depth research reveals a broader spectrum of pharmacological effects.

1. anti-inflammatory activity This is the core pharmacological effect of salicylic acid. It can effectively inhibit redness, exudation, and tissue damage in various acute and chronic inflammation models. Its anti-inflammatory effect is not limited to the periphery, as it can penetrate the blood-brain barrier and also has the potential to regulate central nervous system inflammation.
2. Analgesic effect Salicylic acid has inhibitory effects on various pain models, such as pain caused by chemical and thermal stimuli. Its analgesic mechanism is partly derived from peripheral anti-inflammatory effects, reducing the production of pain inducing substances such as prostaglandins and bradykinin; It is also related to ion channels that directly act on sensory neurons, such as TRPV1 and TRPA1.
3. Antipyretic effect Salicylic acid acts on the hypothalamic thermoregulatory center, promoting heat dissipation and inhibiting thermogenesis, thereby reducing the body temperature of individuals with fever, with minimal impact on normal body temperature.
4. Keratin regulation and anti proliferative effects In dermatology, salicylic acid, due to its lipophilicity and keratin solubility, can penetrate hair follicles, loosen the connections between keratinocytes, promote epidermal shedding, and is commonly used to treat keratinization disorders such as acne, psoriasis, and ichthyosis.
5. Antioxidant and Cellular Protective Effects The phenolic hydroxyl structure of salicylic acid enables it to scavenge free radicals and inhibit lipid peroxidation. Research has also shown that salicylic acid can regulate cell apoptosis under certain conditions and has the potential for cell protection.
6. Other potential activities: Recent studies suggest that salicylic acid may have a positive impact on metabolic diseases (such as diabetes), cardiovascular protection and chemoprevention of some cancers, but its mechanism and clinical significance are still under exploration.

Mechanism of action and molecular targets

The traditional view is that salicylic acid and its derivatives mainly block the synthesis of prostaglandins (PGs) by irreversible acetylation and inhibition of cyclooxygenase (COX, especially COX-1). However, salicylic acid itself has weak acetylation ability towards COX, and its mechanism of action is more diverse and complex, involving the regulation of multiple key signaling molecules and pathways. Based on the provided target information, its functional network can be summarized as follows:

1. Dual effects on cyclooxygenase (COX)Salicylic acid is COX active Competitive inhibitors Instead of covalent modification inhibitors like aspirin. It can directly compete with arachidonic acid for the active site of COX, thereby inhibiting the production of prostaglandins (such as PGE2). It is worth noting that salicylic acid has a relatively stronger inhibitory activity on inducible COX-2, and this inhibition is not related to its impact on NF - κ B transcriptional activation, indicating its direct enzyme activity inhibition.

2. Regulating the nuclear factor kappa B (NF - κ B) signaling pathway NF - κ B is the core transcription factor of inflammatory response. Salicylic acid can inhibit the activation of NF - κ B in a dose-dependent manner. Its mechanism does not directly act on the NFKB1 gene product p50 protein, but rather inhibits the activity of I κ B kinase (IKK), preventing its phosphorylation and degradation, thereby retaining NF - κ B in the cytoplasm and reducing the transcription of pro-inflammatory factors (such as TNF - α, IL-6) genes.

3. Intervention in Janus kinase/signal transduction and transcriptional activator (JAK/STAT) pathway Salicylic acid can inhibit the activation of key inflammatory factor interleukin-6 (IL-6) and its downstream signaling molecule STAT3. The sustained activation of STAT3 is closely related to chronic inflammation and tumorigenesis. Salicylic acid may exert anti-inflammatory and potential anti-tumor effects by inhibiting IL-6 production upstream or directly affecting the JAK/STAT phosphorylation cascade.

4. Affects the synthesis of nitric oxide (NO)Salicylic acid can inhibit the expression and activity of inducible nitric oxide synthase (iNOS, NOS2), reduce excessive NO production under inflammatory conditions, and thus alleviate NO mediated cytotoxicity and vasodilation.

5. Regulating transient receptor potential (TRP) channels Salicylic acid is an agonist or modulator of certain TRP channels. It can activate TRPV1 and TRPA1 channels, which may initially cause a burning or stinging sensation (a common feeling when applied topically), but over time or under specific conditions, this activation may lead to desensitization of the channels or inhibition of the transmission of nociceptive signals, participating in their peripheral analgesic mechanisms.

6. Regulating Pyroptosis Salicylic acid has been reported to inhibit the activation of Caspase-1 (CASP1). Caspase-1 is a key effector protein of inflammasomes, responsible for cleaving the precursors of IL-1 β and IL-18, and mediating cell apoptosis. By inhibiting Caspase-1, salicylic acid may alleviate excessive inflammatory response and tissue damage.

7. Regulation of tumor necrosis factor - α (TNF - α)Salicylic acid can inhibit the production and signaling of TNF - α. TNF - α is another core pro-inflammatory cytokine, and salicylic acid may reduce its synthesis by affecting its mRNA stability or translation process.

In summary, the mechanism of action of salicylic acid is a multi-target, multi-level network system, and its anti-inflammatory effect is the comprehensive result of synergistically inhibiting prostaglandin synthesis, cytokine production, transcription factor activity, and inflammatory mediator release.

Evaluation of drug properties and pharmacokinetics

From the perspective of medicinal properties, salicylic acid has distinct characteristics:

• Absorption and distribution Oral salicylic acid is rapidly absorbed in the stomach and small intestine. The degree and rate of absorption are affected by the dosage form and pH value. Due to its pKa value, it mainly exists in molecular form in the acidic environment of the stomach, which is conducive to passive diffusion absorption. After absorption, it is widely distributed in tissues and body fluids throughout the body, and can penetrate joint cavities, cerebrospinal fluid (confirming its blood-brain barrier permeability), and placenta.
• Metabolism and excretion Salicylic acid is mainly metabolized in the liver, and its main pathways include binding with glycine to form salicylic acid (main pathway), binding with glucuronic acid to form ether or ester glucuronides, and a small amount of oxidative metabolism. These metabolites and prototype drugs are mainly excreted through the kidneys. Its metabolism is saturable, that is, when the dose increases, the metabolic pathway tends to saturate and the half-life is significantly prolonged, which can easily lead to accumulation poisoning.
• Analysis of drug properties parameters：
  • Molecular weight (138.12)Far less than 500, meeting the requirements for small molecule drugs.
  • LogP（~1.88）The ideal lipid water partition coefficient balances membrane permeability and water solubility.
  • TPSA（57.53 Ų）Smaller, conducive to cell infiltration and oral absorption.
  • Water solubility (slightly soluble)One of the main factors limiting its high-dose dosing design is the need to produce sodium salts to increase solubility.
  • Blood-brain barrier permeability The clear ability to penetrate is a potential advantage that distinguishes it from many nonsteroidal anti-inflammatory drugs (NSAIDs), providing possibilities for the treatment of central nervous system diseases.
  • HERG inhibition (No)The risk of cardiac toxicity (QT interval prolongation) is low.
  • Ames test (0.0)Preliminary results indicate that there is no mutagenicity under the conditions of this experiment, but it needs to be comprehensively evaluated in conjunction with other genetic toxicity tests.
• security issue The main adverse reactions of salicylic acid include gastrointestinal irritation (nausea, vomiting, ulcers), dose-dependent tinnitus, dizziness (salicylic acid reaction), as well as respiratory alkalosis and metabolic acidosis that may occur at high doses. Its antiplatelet aggregation effect is weaker than aspirin.

Clinical application prospects and prospects

At present, the direct application of salicylic acid and its salts in clinical practice mainly focuses on the following aspects:

1. External Dermatology Medication As a keratolytic agent, anti-inflammatory agent, and antibacterial agent, it is widely used to treat acne vulgaris, psoriasis, seborrheic dermatitis, corns, calluses, and certain skin fungal infections. Different concentrations (0.5% -30%) correspond to different indications.
2. Rheumatic diseases Sodium salicylate and other preparations have been used for the treatment of rheumatic fever and rheumatoid arthritis, but due to their inferior efficacy and tolerability compared to other NSAIDs, they are now less commonly used as first-line oral systemic drugs.
3. Local analgesia and anti-inflammatory effects Some topical ointments or patches contain methyl salicylate (wintergreen oil) or salicylates, which are used to relieve muscle and joint pain.

Looking ahead to the future, based on a new understanding of its multi-target mechanism of action, the clinical application of salicylic acid may expand in the following directions:

• Inflammatory diseases of the nervous system Exploring its adjuvant therapeutic value in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuroinflammatory related diseases by utilizing its blood-brain barrier permeability, inhibition of microglial activation, and regulation of central inflammatory factors (such as inhibition of NF - κ B and STAT3).
• Intervention of Metabolic Inflammation Chronic low-grade inflammation is the core feature of metabolic diseases such as obesity, type 2 diabetes, nonalcoholic fatty liver. Salicylic acid may improve insulin resistance and metabolic disorders by inhibiting pathways such as IKK β/NF - κ B. There have been studies to explore the therapeutic effect of high-dose salicylic acid preparations (such as bissalicylate) on diabetes.
• Chemotherapy prevention and adjuvant therapy for cancer Long term use of aspirin can reduce the risk of colorectal cancer and other diseases. Salicylic acid, as its active metabolite, may play a role in its anti proliferative, pro apoptotic, and anti-inflammatory effects (especially in inhibiting COX-2 and STAT3). The potential of studying it as a low-cost chemopreventive agent or in combination with radiotherapy and chemotherapy deserves attention.
• Development of new formulations To address its shortcomings such as poor water solubility and strong gastrointestinal irritation, new delivery systems such as nanoparticles, liposomes, microneedle patches, etc. have been developed to improve their targeting, bioavailability, and local drug efficacy, while reducing systemic side effects. For example, nanocarriers targeting hair follicles for acne treatment.
• Structural optimization as a lead compound Salicylic acid has a simple structure and is an ideal lead compound for chemical modification. By modifying its carboxyl and phenolic hydroxyl groups, it is possible to develop new anti-inflammatory and analgesic drugs with stronger activity, higher selectivity, and fewer side effects.

Conclusion

Salicylic acid, a natural product derived from ancient willow bark, has undergone hundreds of years of application and decades of in-depth research. Its image has evolved from a simple antipyretic and analgesic precursor to a versatile agent with a complex mechanism of action and diverse targets. It is not only a signaling molecule for plant defense, but also an important tool for humans to combat inflammation and related diseases. From directly inhibiting COX enzyme activity, to upstream regulation of key signaling pathways such as NF - κ B and JAK/STAT, to affecting TRP channels and cell apoptosis, salicylic acid, with its unique chemical structure, weaves a fine network of action in the body. Although it has certain limitations as a systemic oral drug, its excellent pharmacological basis (such as appropriate LogP, blood-brain barrier permeability, low cardiac toxicity) and clear multi-target effects provide broad space for its "new use of old drugs" and "structural redevelopment" in modern medicine. In the future, by combining systems pharmacology, structural biology, and new formulation technologies, we will deeply explore the potential of salicylic acid in the fields of neuroinflammation, metabolic diseases, tumor prevention, etc., which is expected to give this classic molecule new vitality in the era of precision medicine and continue to contribute to human health. The continuous research on salicylic acid is also a vivid confirmation of the value of natural products as a source of drug discovery.