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  • Vanillic Acid: A Comprehensive Review of its Chemistry, Biosynthesis, Biological Activities, Pharmacological Potential and Toxicological Profile

  • Photo Jainambu Beevi S.* 1 Photo Sakthi Abirami M. 1 Photo Gomathi V. 2 Photo Nithyapriya R. 1

  • 1Department of Pharmacology, College of Pharmacy, Madras Medical College, Chennai 600003, Tamil Nadu, India.
    2Department of Pharmacology, Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation (Deemed to be university), Ariyanoor, Salem 636008, Tamil Nadu, India
     

Abstract

Background: Vanillic acid (VA), a naturally occurring phenolic acid, is widely present in plants and food sources. Its diverse pharmacological effects have attracted growing attention in recent years. Objectives: This review aims to comprehensively analyze the chemical structure, biosynthetic pathways, pharmacological properties, formulation strategies, safety profile, and therapeutic potential of vanillic acid. Methods: Extensive literature was reviewed covering preclinical studies, mechanistic evaluations, and formulation innovations involving vanillic acid. Information was gathered on its bioactivities, including antioxidant, anti-inflammatory, antidiabetic, neuroprotective, and wound-healing effects. Findings: VA exhibits a broad spectrum of pharmacological actions, acting primarily through modulation of oxidative stress, inflammatory mediators, and molecular pathways such as PI3K/Akt, NF-?B, and AMPK. Formulations like nanoparticles and hydrogels have enhanced its bioavailability and therapeutic efficacy. Toxicological studies confirm its safety, and it is recognized as GRAS in food contexts. Conclusion: Vanillic acid is a promising bioactive compound with multifunctional therapeutic properties and excellent safety. While preclinical evidence is robust, clinical trials are needed to validate its efficacy in human health applications.

Keywords

Antioxidant, Biosynthesis, Hydrogels, Nanoparticles, Phenolic acid, Vanillic acid

Introduction

Phenolic acids are a widely distributed group of plant secondary metabolites known for their diverse biological and pharmacological activities. Among them, vanillic acid (4-hydroxy-3-methoxybenzoic acid) has gained significant attention due to its antioxidant, anti-inflammatory, antimicrobial, antidiabetic, neuroprotective, and anticancer properties [1-3]. Vanillic acid is a benzoic acid derivative and a key intermediate in the metabolism of other phenolic compounds such as vanillin and ferulic acid [4]. Vanillic acid is a naturally occurring phenolic acid and a major oxidative metabolite of vanillin, widely distributed in the plant kingdom and found in foods such as vanilla beans, green tea, wine, and fermented products [5,6]. It is produced biosynthetically from ferulic acid or vanillin and serves as an intermediate substance in the microbial breakdown of lignin. [7]. Given its wide array of bioactivities and natural occurrence, vanillic acid has been studied for its therapeutic potential in various disease models, including diabetes, cancer, neurodegenerative disorders, and cardiovascular diseases. Moreover, its low toxicity profile and chemical stability enhance its suitability for pharmaceutical and nutraceutical applications. This review aims to provide a comprehensive overview of vanillic acid, focusing on its chemical structure, biosynthesis, biological functions, pharmacological effects, toxicological safety, and therapeutic relevance. By compiling both preclinical and emerging clinical evidence, this review seeks to act as a point of reference for future research and drug development involving vanillic acid.

2. Chemical aspects

2.1 Structure and properties

Vanillic acid (4-hydroxy-3-methoxybenzoic acid) is a benzoic acid derivative with the molecular formula C?H?O? and a molecular weight of 168.15 g/mol [8]. It contains three functional groups: a hydroxyl (-OH) group at the para-position, a methoxy (-OCH?) group at the meta-position, and a carboxylic acid (-COOH) group on the benzene ring. (Figure 1)

Figure 1: Chemical structure of Vanillic acid

2.2. Chemical identification [8]

  • IUPAC name: 4-hydroxy-3-methoxybenzoic acid
  • Molecular formula: C8H8O4
  • Molecular weight: 168.15 g/mol
  • Synonym: p-Hydroxy-m-methoxy-benzoic Acid, Acide vanillique, p-Vanillic acid
  • CAS Registry number: 121-34-6

2.3. Chemical and physical properties

  • Description: White to beige powder or needle
  • Odor: vanilla like odour
  • Melting Point: 211.5°C
  • Vapour Pressure: 0.0000171 mmHg
  • Log P: 1.43
  • Dissociation constant (pKa): 4.51 at 25°C
  • Solubility: Slightly soluble in water, Soluble in ethanol and organic solvents

2.4. Chemical synthesis

Vanillic acid is typically synthesized via oxidation of vanillin, which is a common intermediate in the lignin degradation pathway. Chemical oxidants such as KMnO?, H?O?, or nitric acid can convert vanillin to vanillic acid through oxidation of the aldehyde group to a carboxylic acid [9]. (Figure 2)

Figure 2. Schematic representation of chemical synthesis of vanillic acid from vanillin.

Alternatively, biotransformation methods using microbial or enzymatic catalysis provide greener and more sustainable options for production. For example, Pseudomonas putida and Amycolatopsis species are known to oxidize ferulic acid into vanillic acid under aerobic conditions [4,6].

2.5. Analytical Techniques [10-13]

 Several analytical methods are employed for identification and quantification of vanillic acid in plant extracts, biological samples, or pharmaceutical formulations. Each method offers specific advantages based on sample complexity, sensitivity, and selectivity represented in Table 1

Table 1. Analytical techniques used for vanillic acid identification and quantification.

Technique

Application

Advantages

HPLC-UV/MS

Quantification in biological/plant samples

High sensitivity and selectivity

GC–MS

Detection in volatile/derivatized samples

Excellent for complex matrices

NMR Spectroscopy

Structural elucidation

Detailed functional group information

FTIR

Functional group identification

Quick and non-destructive

UV-Vis Spectroscopy

Antioxidant activity assays

Simple and rapid

3. Biosynthesis of vanillic acid

Vanillic acid is a naturally occurring phenolic acid found in a broad variety of plant species and fermented products. It is primarily derived from the phenylpropanoid pathway, which originates from L-phenylalanine and L-tyrosine, two aromatic amino acids formed via the shikimate pathway in plants and microorganisms [14,15].

3.1 Plant Biosynthesis Pathway

In plants, vanillic acid is biosynthesized as part of the lignin degradation pathway or as a secondary metabolite of ferulic acid and vanillin.

Figure 3: Biosynthesis of vanillic acid from phenylalanine in plants.

3.2. Microbial Biosynthesis

Several soil and lignin-degrading microorganisms can biosynthesize vanillic acid from ferulic acid or vanillin. Microbial pathways are often used in industrial biotechnology for vanillic acid production using renewable biomass sources. Ferulic acid is first converted to vanillin by feruloyl-CoA synthetase and enoyl-CoA hydratase. Vanillin is then oxidized to vanillic acid by vanillin dehydrogenase or aldehyde oxidase enzymes [4]. Organisms known to produce Vanillic Acid such as Pseudomonas fluorescens, Amycolatopsis sp., Streptomyces setonii, Bacillus subtilis, Aspergillus niger. These organisms are capable of biotransforming lignin-derived aromatics into value-added products like vanillic acid, especially under aerobic fermentation conditions [9,16].

3.3. Enzymes Involved

Table 2: Enzymes involved in the biosynthesis of Vanillic acid

Enzyme

Reaction Catalyzed

Phenylalanine ammonia lyase (PAL)

Phenylalanine → Cinnamic acid

Cinnamate 4-hydroxylase

Cinnamic acid → p-Coumaric acid

O-Methyltransferase

Hydroxycinnamic acids → Methoxy derivatives

Feruloyl-CoA synthetase

Ferulic acid activation to CoA ester

Vanillin dehydrogenase

Vanillin → Vanillic acid

Aldehyde oxidase

Vanillin → Vanillic acid (alternative pathway)

3.4. Industrial Production

Biotechnological production of vanillic acid through ferulic acid biotransformation is considered sustainable and scalable. Agricultural waste (e.g., rice bran, wheat bran, sugar beet pulp) rich in lignin and ferulic acid serves as an ideal substrate [17].

4. Biological and pharmacological activities of vanillic acid

Vanillic acid (VA), a phenolic acid commonly found in edible plants, fruits, and medicinal herbs, exhibits a wide spectrum of biological activities relevant to human health. These effects are attributed to its antioxidant phenolic structure and its ability to modulate various signaling pathways. Vanillic acid, a phenolic compound derived from lignin, has been widely studied for its diverse pharmacological properties. Below is a detailed overview of its various activities, mechanisms of action, and potential therapeutic applications:

Table 3: Pharmacological activities, Mechanism of action and Therapeutic applications of Vanillic acid

Pharmacological activity

Mechanism of action

Therapeutic applications

Anti-inflammatory [18,19]

Vanillic acid inhibits the production of pro-inflammatory cytokines (TNF-α, IL-1β) and enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), reducing inflammation.

Vanillic acid has shown potential for managing chronic inflammation, such as in diabetic foot ulcers, and other inflammatory diseases like arthritis.

Antioxidant [20,21]

Scavenging free radicals and reducing oxidative stress is one of the key mechanisms by which vanillic acid exerts its therapeutic effects. It enhances antioxidant enzyme activity and reduces lipid peroxidation.

It can be used to protect against oxidative damage associated with diabetic complications, wound healing, and aging.

Antibacterial [22,23]

Vanillic acid exhibits antibacterial activity by disrupting bacterial cell membrane integrity and inhibiting biofilm formation, which is essential in chronic infections.

Vanillic acid's antibacterial properties make it a potential candidate for treating infections in diabetic foot ulcers and preventing wound infections.

Wound Healing [24,25]

Vanillic acid promotes collagen synthesis, fibroblast proliferation, and re-epithelialization, all critical processes in wound healing.

It can enhance wound healing in diabetic ulcers, facilitating faster recovery and reducing complications.

Antidiabetic [26,27]

Vanillic acid improves insulin sensitivity and reduces blood glucose levels by enhancing glucose metabolism and modulating key enzymes.

It holds promise as an adjunct therapy for managing diabetes, improving glycemic control and reducing complications like diabetic foot ulcers.

Anticancer [28,29]

Vanillic acid induces apoptosis in cancer cells and inhibits the proliferation of tumor cells by modulating key signaling pathways like the PI3K/Akt pathway.

Vanillic acid may have potential for cancer therapy or prevention, especially in cancers related to oxidative stress or chronic inflammation.

Neuroprotective [30,31]

It reduces neuroinflammation, inhibits oxidative stress, and alleviates pain by modulating inflammatory pathways, making it protective against neurodegenerative diseases.

Vanillic acid is a candidate for the treatment of diabetic neuropathy and neurodegenerative disorders such as Alzheimer’s or Parkinson's disease.

Cardioprotective [32,33]

Vanillic acid reduces lipid peroxidation, modulates lipid metabolism, and improves heart function, protecting against cardiovascular damage.

It may be beneficial in managing cardiovascular diseases associated with diabetes, such as atherosclerosis and heart failure.

Antiviral [34]

Vanillic acid inhibits viral replication and modulates immune responses, suggesting potential antiviral activity.

It may be useful for managing viral infections, particularly in immunocompromised individuals like those with diabetes.

Hepatoprotective [35,36]

By protecting liver cells from oxidative damage and modulating liver enzymes (such as ALT and AST), vanillic acid helps maintain liver health.

It could aid in managing liver diseases like non-alcoholic fatty liver disease (NAFLD) that often co-exist with diabetes.

Anticoagulant [37]

Vanillic acid inhibits platelet aggregation and thrombus formation, potentially reducing the risk of blood clots.

This activity may be useful in preventing thrombosis, a common risk for diabetic patients, especially those with vascular complications.

Antidepressant [38]

Vanillic acid modulates neurotransmitter levels (serotonin and dopamine) in the brain, reducing anxiety-like behaviors and depression.

It may provide therapeutic benefits for mood disorders, such as depression and anxiety, which are common in diabetic patients.

Anti-ulcer [39,40]

Vanillic acid protects gastric mucosa by inhibiting acid secretion and reducing ulceration, a common issue in diabetic patients.

It can be used to manage gastrointestinal ulcers, particularly in individuals with diabetes, who are prone to such complications.

Anti-hyperlipidemic [41]

Vanillic acid reduces cholesterol and triglyceride levels by modulating lipid metabolism and improving lipid profile.

It has potential use in managing dyslipidemia in diabetic patients, helping prevent cardiovascular diseases.

Anti-obesity [42]

Vanillic acid inhibits adipogenesis (fat cell formation) and promotes fat oxidation, supporting weight loss and metabolic health.

It may assist in the management of obesity, which is often associated with metabolic syndrome and diabetes.

5. Formulations of vanillic acid

5.1. Drug Formulations and Delivery Systems

Due to its water solubility and phenolic structure, vanillic acid is suitable for incorporation into various advanced delivery systems:

  • Nanoparticles:

VA-loaded chitosan nanoparticles have demonstrated improved bioavailability and sustained antioxidant delivery in oxidative stress models [27].

  • Hydrogels:

VA has been incorporated into carbopol- or alginate-based hydrogels for topical applications, especially in wound healing and anti-inflammatory formulations [43].

  • Topical Use:

VA-rich plant extracts and formulations have shown efficacy in eczema, ulcers, and microbial infections, though further dermatological studies are needed [44].

6. Pharmacokinetics of vanillic acid [45]

Absorption: Rapidly absorbed in the small intestine; peak plasma concentration (Cmax) reached within 1–2 hours post-oral administration.

Distribution: Moderately binds plasma proteins; distributes to liver, kidneys, brain, and plasma; limited blood-brain barrier penetration.

Metabolism: Primarily undergoes Phase II metabolism (glucuronidation and sulfation); minimal Phase I metabolism; gut microbiota may further transform VA.

Excretion: Mainly excreted in urine as conjugated metabolites; minor fecal elimination; half-life ranges from 2 to 6 hours; some biliary excretion with potential enterohepatic recirculation.

7. Toxicological and safety profile of vanillic acid

Vanillic acid (VA) is generally considered a safe phenolic compound, especially due to its natural occurrence in common dietary sources like vanilla beans, wine, and whole grains. However, systematic toxicological evaluations are essential to assess its safety for therapeutic and long-term use.

7.1. Subacute Toxicity Studies [46]

  • Rodents: In oral toxicity studies in mice and rats, vanillic acid showed a high LD?? (>2000 mg/kg), suggesting low acute toxicity.
  • Subacute studies (28-day exposure) in rats reported: No significant changes in body weight, organ weight, hematological parameters, or serum biochemical markers at doses up to 500 mg/kg/day. No histopathological alterations in liver, kidney, or heart tissues.
  • No mortality or adverse effects were observed in mice treated orally with 100–200 mg/kg for 14 days in antioxidant and hepatoprotective models.

7.2. Safety in Food and Nutraceutical Contexts

  • Vanillic acid is classified as Generally Recognized as Safe (GRAS) by the US FDA when present as a natural constituent of vanilla flavoring [47].
  • Estimated daily dietary intake is low (~1–2 mg/day), and no adverse events have been reported from natural consumption in foods.

CONCLUSION

Vanillic acid, a naturally occurring phenolic compound, exhibits a promising pharmacological profile supported by substantial preclinical evidence. Its chemical simplicity, ease of biosynthesis via both plant and microbial routes, and favourable physicochemical properties make it a versatile candidate for pharmaceutical applications. VA demonstrates potent antioxidant, anti-inflammatory, antidiabetic, neuroprotective, and anticancer activities, acting through well-characterized molecular pathways including modulation of oxidative stress, inflammatory cytokines, and apoptotic regulators. Furthermore, its low toxicity profile, high biocompatibility, and safety in both in vitro and in vivo models enhance its therapeutic appeal. Innovative drug delivery systems such as nanoparticles and hydrogels have further improved its bioavailability and target specificity. However, despite encouraging results from animal models and formulation advancements, clinical studies on vanillic acid remain scarce. Future research should focus on well-designed clinical trials, and detailed toxicity evaluations to validate its efficacy and safety in humans. In conclusion, vanillic acid holds significant potential as a multifunctional bioactive agent for the prevention and treatment of various chronic diseases. With continued research and development, it may become an integral component of future therapeutic strategies in modern medicine.

ACKNOWLEDGEMENT

The authors sincerely thank the faculty and staff of Department of Pharmacology [College of Pharmacy], for their continuous support and guidance during the preparation of this review.

CONFLICT OF INTEREST

The authors declare no conflict of interest related to this review article. The content and conclusions presented herein are based on independent research and interpretation of the existing scientific literature.

AUTHOR CONTRIBUTION

Jainambu beevi S: Conceptualized the study, performed literature review on chemistry, biosynthesis, and drafted the manuscript.

Sakthi abirami M: Analyzed pharmacological data, compiled therapeutic applications and created summary tables.

Gomathi V: Supervised the study, revised the manuscript for scientific content, and ensured overall coherence.

Nithyapriya R: Managed references, formatted the manuscript, and assisted in proofreading and figure preparation.

All authors read and approved the final manuscript.

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Reference

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  2. Ingole A, Kadam MP, Dalu AP, Kute SM, Mange PR, Theng VD, et al. A Review of the Pharmacological Characteristics of Vanillic Acid. J. Drug Delivery Ther. [Internet]. 2021 Apr. 15 [cited 2025 Apr. 4];11(2-S):200-4. Available from: https://jddtonline.info/index.php/jddt/article/view/4823
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Jainambu Beevi S.
Corresponding author

Department of Pharmacology, College of Pharmacy, Madras Medical College, Chennai 600003, Tamil Nadu, India.

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Sakthi Abirami M.
Co-author

Department of Pharmacology, College of Pharmacy, Madras Medical College, Chennai 600003, Tamil Nadu, India.

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Gomathi V.
Co-author

Department of Pharmacology, Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation (Deemed to be university), Ariyanoor, Salem 636008, Tamil Nadu, India.

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Nithyapriya R.
Co-author

Department of Pharmacology, College of Pharmacy, Madras Medical College, Chennai 600003, Tamil Nadu, India.

Jainambu Beevi S.*, Sakthi Abirami M., Gomathi V., Nithyapriya R., Vanillic Acid: A Comprehensive Review of its Chemistry, Biosynthesis, Biological Activities, Pharmacological Potential and Toxicological Profile, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 3789-3799. https://doi.org/10.5281/zenodo.15726577

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