GALLIC ACID: PHARMACOLOGICAL PROMISING LEAD MOLECULE: A REVIEW

Abstract

Gallic acid is a naturally occurring polyphenolic compound found in processed beverages such as red wines and green teas. It occurs in plants in the form of free acids, esters, catechin derivatives and hydrolysable tannins. The interest in these compounds is due to its pharmacological activity as radical scavengers. It has been proved to have potential preventive and therapeutic effects in many diseases, where the oxidative stress has been implicated, including cardiovascular diseases, cancer, neurodegenerative disorders and in aging. Thus, it is imperative to promote more credible research on exploring medicinal properties of gallic acid and its congeners. The present review is an attempt to summarize the medicinal and toxicological properties of the gallic acid and its derivatives in various forms for different purpose.

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International Journal of Pharmacognosy and Phytochemical Research 2018; 10(4); 132-138
ISSN: 0975-4873
Review Article
*Author for Correspondence: manish_bn@yahoo.co.in
Gallic Acid: Pharmacogical Promising Lead Molecule: A Review
Singh Manish Pal*, Gupta Avneet, Sisodia S Siddhraj
Department of pharmacology, Bhupal Nobles College of Pharmacy, Bhupal Nobles University, Udaipur, Rajasthan,
India
Received: 30th Jan 18; Revised 2nd Mar, 18, Accepted: 25th Mar, 18; Available Online:25th Apr, 18
ABSTRACT
Gallic acid is a naturally occurring polyphenolic compound found in processed beverages such as red wines and green teas.
It occurs in plants in the form of free acids, esters, catechin derivatives and hydrolysable tannins. The interest in these
compounds is due to its pharmacological activity as radical scavengers. It has been proved to have potential preventive and
therapeutic effects in many diseases, where the oxidative stress has been implicated, including cardiovascular diseases,
cancer, neurodegenerative disorders and in aging. Thus, it is imperative to promote more credible research on exploring
medicinal properties of gallic acid and its congeners. The present review is an attempt to summarize the medicinal and
toxicological properties of the gallic acid and its derivatives in various forms for different purpose.
Keywords: Gallic acid, Antioxidants, Antidiabetic, Toxicology, Polyphenols.
INTRODUCTION
Gallic acid (3, 4, 5-trihydroxybenzoic acid) is a naturally
occurring polyphenolic compound found in processed
beverages such as red wines and green teas. It occurs in
plants in the form of free acids, esters, catechin derivatives
and hydrolysable tannins1-2. The interest in these
compounds is due to its pharmacological activity as radical
scavengers. It has been proved to have potential preventive
and therapeutic effects in many diseases, where the
oxidative stress has been implicated, including
cardiovascular diseases, cancer, neurodegenerative
disorders and in aging3-5. Gallic acid has been reported to
occur in a number of plants, some of them are Allan
blackia floribunda, Garcinia densivenia, Bridelia
micrantha, Caesalpinia sappan, Dillenia indica,
Diospyros cinnabarina, Paratecoma peroba, Terminalia
bellerica, etc. Many gallic acid derivatives occur naturally
in plant, these include from Frankenia laevis and Tamarix
amplexicaulis, 3-methyl-4-O-[3,4-dihydroxy-5-
methoxybenzoyl-(→6)- β-D-glucopyranoside], Rhus
glabra, 3-ethyl ether from Phyllanthus emblica, and 4-
ethyl ether from Eucalyptus gunnii, Terminalia chebula
and Elephantorrhiza elephantine 6. A recent study
indicated presence of antioxidant gallic acid esters
(gallates) in dust from homes and microenvironments7.
The purpose of this review summarized the medicinal and
toxicological properties of gallic acid, present in active
phystoconstitutent in various herbal polyherbal plant
preparations.
Physiochemical Profile of Gallic Acid8
Chemical formula: C7H6O5
Molar mass: 170.12 g/mol
Appearance: White, yellowish-white, or pale fawn-colored
crystals
Density: 1.694 g/cm3 (anhydrous)
Melting point: 260 °C (500 °F; 533 K)
Pharmacological Profile of Gallic Acid
Antidiabetic Activity
Prince et al (2011) have reported the antihyperglycaemic,
antilipid peroxidative and antioxidant effects of gallic acid
on streptozotocin induced diabetic male wister rats.
Further, histopathology of pancreas confirmed the
protective effects of gallic acid in diabetic rats. In vitro
study also revealed the potent antioxidant effect of gallic
acid9. Khanh et al (2015) have reported the gallic acid
plays its role through the activation of AMP-activated
protein kinase (AMPK) and by regulating mitochondrial
function via the activation of peroxisome proliferator-
activated receptor-alpha coactivator1 alpha (PGC1 alpha).
In addition, the administration of GA protected diet-
induced body weight gain without a change in food
intake10. Kyriakis et al (2015) have reported the binding of
gallic acid and its dimer ellagic acid to glycogen
phosphorylase (GP). The authors suggested both
compounds are competitive inhibitors with respect to the
substrate, glucose-1-phoshate, and non-competitive to the
allosteric activator, AMP11.
Other investigators reported that gallic acid can increase
GLUT4 translocation and glucose uptake activity in an
Akt-independent but wortmannin-sensitive manner.
Further analysis suggested the role of atypical protein
kinase Cf/k in gallic acid mediated GLUT4 translocation
and glucose uptake12. Oliveria et al (2016) have reported
the effect of gallic acid on the biochemical, histological
and oxidative stress parameters in the liver and kidney of
diabetic rats. This study indicates that gallic acid can
protect against oxidative stress-induced damage in the
diabetic state13. Huang et al (2005) have reported the
mechanism of antidiabetic action of gallic acid, which is
the active phytoconstituents of Punica granatum flower

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extract (PGF). Authors were concluded that PPAR is a
molecular target for PGF extract and its prominent
component gallic acid, and provide a better understanding
of the potential mechanism of the anti-diabetic action of
PGF14.
Neuroprotective Activity
Lu et al (2006) have reported the relationship between the
structures of gallic acid derivatives, their antioxidant
activities, and neuroprotective effects; they examined their
free radical scavenging effects in liposome and anti-
apoptotic activities in human SH-SY5-Y cell induced by
6-hydrodopamine auto oxidation. The authors reveal that
compounds with high antioxidant activity and appropriate
hydrophobicity are generally more effective in preventing
the injury of oxidative stress in neurodegenerative
diseases15. Korani et al (2014) have reported the
neuroprotective role of gallic acid in CNS. They studied
the effect of gallic acid (GA; 100 mg/kg, p.o. for 10days)
on cognitive deficit and cerebral oxidative stress induced
by permanent bilateral common carotid artery occlusion
(2VO) as an animal model of vascular dementia (VD).
Furthermore, chronic administration of GA significantly
restored the spatial memory, totalthiol and GPx contents
and also decreased MDA levels in these tissues16.
Mansouri et al (2014) have explored the possible
mechanisms involved in the anxiolytic like activity of
gallic acid (GA) in the rat elevated plus maze (EPM) test.
Authors reported that the treatment with GA markedly
produced an increase in the time spent and entries in the
open arms of EPM at doses of 30 and 300 mg/kg,
respectively. Also this study suggests that the anxiolytic-
like activity of GA is primarily mediated by the 5-HT1A but
not benzodiazepine receptors17. Mansouri et al (2012) have
investigated the neuroprotective role of gallic acid against
cerebral oxidative stress induced by 6-hydroxydopamine
in rats. The study results suggest that GA has
neuroprotective activity against 6-OHDAinduced
oxidative stress via enhancement of cerebral antioxidant
defense18.
Gallic acid, founded by investigators to antioxidant
properties of polyphenols have been exploited in the
inhibition of fibrillar protein deposits that lead to disorders
like Alzheimer’s and Parkinson’s disease19.
Antioxidant Activity
Chou et al (2016) have reported the role of grafting amount
of antioxidant gallic acid (GA) on to GN in situ gelling
copolymers made of biodegradable gelatin and thermo-
responsive poly (N-isopropylacrylamide) for intracameral
delivery of pilocarpine in antiglaucoma treatment. Further
reported that increasing GA content increased total
antioxidant level and decreased nitrite level in the aqueous
humor, suggesting a much improved antioxidant status in
glaucomatous eyes20. Kim (2007) has investigated the
melanogenesis inhibitory action of gallic acid (GA). In this
current study, the effects of GA on mushroom tyrosinase,
tyrosinase inhibitory activity, and melanin content were
assessed in B16 melanoma cells (B16 cells). This study
suggested that GA exerts antimelanogenic activity coupled
with antioxidant properties by suppressing RS generation
and maintaining a higher GSH/GSSG ratio21. Naksuriya et
al (2015) have reported the antioxidant power of curcumin
in comparison with three important natural antioxidants;
gallic acid, ascorbic acid, and xanthone on free radical
scavenging action and their combination effects on this
activity. Authors have suggest that curcumin-gallic acid
combination is the potential antioxidant mixture to be used
in place of the individual substance whereas using of
curcumin in combination with ascorbic acid or xanthone
should be avoid22. Bajpai et al (2005) have reported that
the phenolic contents of medicinal plants responsible for
antioxidants activity. Further they have reported
T.bellerica fruit contain rich source of gallic acid (2290
Gallic acid
Methyl gallate
Phenyl gallate
Ethyl gallate
Figure 1: Chemical structure of gallic acid (3, 4, 5-trihydroxybenzoic acid) and some of its D Derivatives

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IJPPR, Volume 10, Issue 4: April 2018 Page 134
µg/g plant material dry weight)23. Gaulejac et al (1999)
have reported antioxidant activity of polyphenol.
Plyphenol compounds were found to be efficient free
radical scavengers even for the weak concentrations in
wines. Their activity in grapes or wines was much stronger
than that of other commercially available natural
antioxidants (such as ascorbic acid and gallic acid)24.
Traditional use of gallic acid as an anti-oxidant agent25.
Gallic acid has high oxygen derived free radical
scavenging activity due to the presence of polyphenolic
functionality26.
It prevents the rancidity and spoilage of fats and oils due
to its antioxidant nature facilitating its application as food
additives in various eatable materials like baked goods,
candy and chewing gums27. It can be used as an antioxidant
to protect human cells against oxidative damage, to treat
albuminuria and diabetes and as a remote astringent in case
of internal hemorrhage28. Another investigators have been
reported the different vascular protective effects of gallic
acid, like- gallic acid non-enzymatically oxidized in
physiological solutions by generating superoxide anions,
the low level of H2O2 levels and the cyclooxygenase
activation, endothelium-independent relaxation with
respect to levels of H2O2 and the activation of smooth
muscle K+ channels; an irreversible, slow-developing
endothelium-independent relaxation due to high H2O2
levels and quinines, which cause cellular damage29.
Anti-inflammatory Activity
Pandurangan et al (2015) have reported the effects of a
naturally occurring polyphenol, gallic acid (GA), in an
experimental murine model of UC. A significant blunting
of weight loss and clinical symptoms was observed in
dextran sodiumsulfate (DSS)-exposed, GA-treated mice
compared with control mice. Investigators suggest that GA
exerts potentially clinically useful anti-inflammatory
effects mediated through the suppression of p65-NF-κB
and IL-6/p-STAT3Y705 activation30. Piana et al (2016) have
reported the extract from S. corymbiflorum leaves the
crotonoil-induced ear edema and myeloperoxidase (MPO)
activity with maximum inhibition of 87±3% and 45±7%,
respectively in the dose of 1 mg/ear. Authors have been
reported their activity at least in part, the presence of
polyphenols (195.28 mg GAE/g) and flavonoids, as
chlorogenicacid (59.27 mg/g), rutin (12.72 mg/g),
rosmarinic acid, caffeic acid and gallic acid found by high
performance liquid chromatography (HPLC) analysis31.
Abarikwu et al (2014) have reported the effects of
administration of gallic acid (Gal) with or without
curcumin (Cur) on the sperm output, steroid level and
antioxidant defenses in rat testis in vivo and the expression
of inflammatory responsive genes in vitro. Further, they
have been reported that the level of testosterone and the
activities of the steroidogenic enzymes were significantly
increased after treatment with Cur alone. Malondialdehyde
concentration was unchanged following Gal treatment,
while a significant decrease in malondialdehyde level was
observed following treatment with Cur alone or in
combination with Gal32. Saygin et al (2016) have reported
the effects of methotrexate (MTX) on the lung via
inflammatory and apoptotic pathway biomarkers and the
role of gallic acid (GA). GA significantly reduced the
comet score and IMA levels in the blood, TOS and OSI
values in the lung tissue in MTX+GA group compared
with MTX group (p < 0.05)33.
Couto et al (2013) have reported the anti-inflammatory and
antiallodynic effects of spray dried powders starting from
leaves, stems, roots, the mixture of leaves and stems, as
well as the whole plant aqueous solutions of Phyllanthus
niruri L., Phyllanthaceae. Gallic acid, used as chemical
marker, was quantified by HPLC in the spray dried
powders. Investigators revealed the direct relationship of
anti-inflammatory and antiallodynic effects with the gallic
acid content especially in the spray dried powders of
leaves, they have been used of spray dried powders of
leaves plus stems showed to be more effective, further they
suggesting a synergic effect between their constituents34.
Kroes et al (1992) have investigated the anti-inflammatory
activity of gallic acid. Gallic acid was found to possess
anti-inflammatory activity towards zymosan-induced
acute food pad swelling in mice. Structure-activity
relationship analysis showed that the o-dihydroxy group of
gallic acid is important for the inhibitory activity in vitro35.
Anti-inflammatory activity has been evaluated by various
inflammatory induced animal models likely- zymosan
induced acute food pad swelling in mice, carrageeenan-
induced paw edema, acetic acid induced writhing response
and formalin induced pain by investigators. Also they have
reported possible anti-inflammatory mechanism of gallic
acid due to its scavenging of superoxide anions, inhibition
of myeloperoxidase release and activity as well as
interference with activity of NADPH-oxidase36.
Wound Healing Activity
Yang et al (2016) have reported the effects of gallic acid
(GA, 3, 4, 5-trihydroxybenzoic acid, a plant-derived
polyphenolic compound) on wound healing in normal and
hyperglucidic conditions, to mimic diabetes, in human
keratinocytes and fibroblasts. The study reveals that GA is
a potential antioxidant that directly up regulates the
expression of antioxidant genes. Further, GA treatment
activated factors known to be hallmarks of wound healing,
such as focal adhesion kinases (FAK), c-Jun N-terminal
kinases (JNK), and extracellular signal-regulated kinases
(Erk), underpinning the beneficial role of GA in wound
repair37. Nhat et al (2012) have reported that the gallic acid
is a main phytoconstitutents of plant in
ethnopharmacological survey on the traditional use of
Ximenia Americana among healers in Mali. Gallic acid,
gallotannins and flavonoids were identified in the genus
Ximenia. Healers interviewed reported the use against
throat infections, amenorrhea, as tonic, for wound healing
and against pain38. Kokane et al (2009) have evaluated the
wound healing activity of Mimosa pudica root extract and
they have concluded the phenol constituents such as gallic
acid responsible for it. The methanolic extract of plant has
effective in wound healing effect in animals39.
Hepatoprotective Activity
Tung et al (2009) have reported the hepatoprotective
effects of A. confuse bark extract (ACBE) and its active
constituent gallic acid was evaluated against carbon
tetrachloride (CCl4)-induced hepatotoxicity in rats. Liver

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histopathology also showed that ACBE, gallic acid or
silymarin could significantly reduce the incidence of liver
lesions induced by CCl440. The hepatoprotective activities
of T.bellerica extract and gallic acid in alleviating CCl4
induced liver damaged in rats have been reported41. Gallic
acid also showed protective effect in liver damage by
sodium fluoride-induced oxidative stress42.
Anticancer Activity
Hsun et al (2010) have investigate the effect of phenolic
acids found abundantly in vegetables, i.e. gallic acid (GA),
caffeic acid (CA) and protocatechuic acid (PCA), on the
inhibition of gastric adenocarcinoma (AGS) cell
metastasis. GA had potent inhibitory effects on AGS cell
migration. Investigators have concluded that, GA may
have the potential to be an effective agent for prevention
and treatment of gastric cancer metastasis43. Chen et al
(2009) have investigated the role of gallic acid present in
active constituents in leaf extract of Toona sinensis, gallic
acid is identified as the major anti-cancer compound in T.
sinensis leaf extracts. In addition, gallic acid has a
synergistic effect with doxorubicin in suppressing the
growth of DU145 cells. Through this study, investigators
suggest that gallic acid has the potential to be developed
into an anti-prostate cancer drug and is worthy of further
studies44.
It has been reported antimutagenicity induced by N
nitroso-compounds in mouse as well as obviating mouse
lung adenomas by amines or ureas plus nitrate and by
nitroso compounds45. Gallic acid has been reported to
suppress cell viability, proliferation, invasion and
angiogenesis in human glioma cells, inhibits the growth of
HeLa cervical cancer cells via apoptosis and necrosis,
induces apoptosis in tumoral cells lines and inhibits
lymphocyte proliferation46. It has also inhibits
ribonucleotide reductase and cyclooxygenases in human
HL-60 promyelocytic leukemias cells, causes inactivating
phosphorylation via ATM-ChK2 activation, leading to cell
cycle arrest47-49.
Miscellaneous Pharmacological Activity
The other reported pharmacological activities of gallic acid
are anti depressant50, antiparkinson51, antimalarial52,
diuretic53, Cardioprotective54, anti-viral55, antifungal56,
wound healing57, anthelmintic58 and anxiolytic59.
It also reported gallic acid, when combine with other
natural product such as, calycosin, reported to
synergistically attenuate neutrophil infiltration and
subsequent injury in isoproterenol-induced myocardial
infarction60. It has been reported that gallic acid has anti-
microbial activity against methicillin-resistant
Staphylococcus aureus and Helicobacter pylori61-62. Gallic
acid was found to significantly reduce allergen and platelet
activating factor induced bronchial hyper-reactivity in
guinea pigs63. Gallic acid inhibits pancreatic cholesterol
esterase by binding to bile acids and reducing the solubility
of cholesterol in micelles64. Authors have investigated the
role of gallic acid and linoleic acid as antihyperlipidemic
action in C57BL/6 mice fed a high-fat diet65. Gallic acid
having cardioprotecting role in isoproterenol-induced
myocardial infarction in rats66.
Toxicological Study of Gallic Acid
Many investigations have been attempted to explore the
toxicity profile of gallic acid. Some are discussing here,
Oral administration of gallic acid in mice at a dose as high
as 500 mg/kg did not produce any signs of toxicity or
mortality. Gallic acid at a dose of 1000 mg/kg body weight
did not significantly alter the hematological parameters.
Further, no appreciable change was noted in the various
biochemical parameters such as AST or ALT, as well as
many serum constituents such as protein, cholesterol, urea,
and bilirubin. Therefore, from this study, it may be
concluded that gallic acid is non-toxic up to a level of 5000
mg/kg body weight, when given orally. In addition, the
subacute study indicated the absence of cumulative
toxicity, as reflected by the non significant alterations in
the parameters investigated. The no-observed-adverse-
effect-level (NOAEL) was 5000 mg/kg body weight, the
highest dose tested. As gallic acid is non-toxic at an acute
dose of 5000 mg/kg body weight, this is considered the
NOAEL for gallic acid in mice. A subacute administration
of 1000 mg/kg body weight also confirmed its safety at this
level67.
Subchronic toxicity of gallic acid was investigated in F344
rats by feeding diets containing 0, 0.2, 0.6, 1.7 and 5%
gallic acid for 13 weeks. Each group consisted of 10 rats
of each sex; and 0.2% was determined to be the NOAEL
in rats. This level was translated into 119 and 128
mg/kg/day, respectively, for male and female rats68. Joint
FAO/WHAO committee 1962, 1965, 1974 and 1976, have
been found the acute oral toxicity of propyl gallate in mice,
rats, hamsters and rabbits varies from 2000 to 3800 mg/kg
body weight69-72.
In guinea-pigs, propyl gallate showed sensitizing
properties which were more powerful after intradermal
application than after epicutaneous treatment.
Sensitization did not occur when there were oral pre-
exposure73. Recently a 4-week feeding study in rats was
performed by investigators, in this study; a dose level of
25,000 mg/kg feed of gallic acid produced growth
retardation, anaemia, hyperplasia in the tubuli of the outer
kidney medulla and increased activity of several
microsomal and cytoplasmic hepatic drug-metabolizing
enzymes. The increased liver enzyme activities were also
found at 5000 mg/kg. And also no toxicities effects were
found at 1000 mg/kg dose of gallic acid74. Investigators
have been observed an inhibitory effect by propyl gallate
on the intragastric formation of an N-nitrosamine. The
inhibition was complete at an oral dose level of 225 mg/kg
body weight but was absent at 25 mg/kg75. The
teratogenecity study of propyl gallate has been shown in
rats. The dose levels of 4000, 10,000 and 25,000 mg/kg
diet, maternal toxicity and slight retardation of foetal
development occurred at the highest dose level, but
teratogenic effects were not observed76.
Conclusion and future perspectives
To conclude, it is evident that gallic acid play a pivotal role
in imparting medicinal properties of the plant and therefore
it is considered as promising lead molecule for new drug
development. Gallic acid is a very important common
antioxidant. It is found naturally in various plants and used
in several polyherbal formulations. Thus, it is imperative

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IJPPR, Volume 10, Issue 4: April 2018 Page 136
to promote more credible research on exploring medicinal
properties of gallic acid and its congeners. The present
review is an attempt to summarize the medicinal and
toxicological properties of the gallic acid and its
derivatives in various forms for different purpose. The
information gathered herein is particularly drawn from
scientific investigations worldwide which would be
beneficial to scientific community in various sectors.
Further research involving natural or synthetic may
provide the exploration and development of newer
properties or biological potential of these compounds.
Gallic acid is well known for its role in drug development.
However, information on clinical research is scanty, which
is essential for its ultimate application in treating and
preventing various deadly diseases.
Even though, in the last few years there has been an
increase in the numbers of publications on gallic acid, it
might be more appropriate to carry out such research on
human subjects following established system of
standardization.
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