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Thymol Chemistry: A Medicinal Toolbox

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DOI: 10.2174/1573407214666180503120222

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Current Bioactive Compounds 2019, 15, 454-474

REVIEW ARTICLE
ISSN: 1573-4072
eISSN: 1875-6646

Thymol Chemistry: A Medicinal Toolbox

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Jyoti1, Divya Dheer1,2, Davinder Singh1, Gulshan Kumar1, Manvika Karnatak3, Suresh Chandra4, Ved Prakash Verma3
and Ravi Shankar1,2,*

he
1
Bio-Organic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; 2Academy of
Scientific and Innovative Research (AcSIR), CSIR-IIIM, Jammu campus, Jammu 180001, India; 3Department of Chemis-

is
try, Banasthali University, Banasthali, Rajasthan 304022, India; 4Genetics Resources & Agrotechnology Division,
CSIR-IIIM, Jammu 180001, India

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Abstract: Background: Thymol is a natural phenolic monoterpenoid widely used in pharmaceutical and

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food preservative applications. Thymol isomeric with carvacrol, extracted primarily from Thymus spe-
cies (Trachyspermum ammi) and other plants sources such as Baccharisgrise bachii and Centipeda min-
ima, has ethnopharmacological characteristics.
Methods: This review was prepared by analyzing articles published on thymol moiety in last decade and

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selected from Science Direct, Scopus, PubMed, Web of Science and SciFinder. The selected articles are
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classified and gives brief introduction about thymol and its isolation, illustrates its natural as well as
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ARTICLE HISTORY synthetic sources, and also therapeutic benefits of thymol worldwide

Received: August 10, 2017
Revised: December 22, 2017
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Results: Thymol has been covering different endeavors such as antimicrobial, antioxidant, anti-
inflammatory, antibacterial, antifungal, antidiarrhoeal, anthelmintic, analgesic, digestive, abortifacient,
antihypertensive, spermicidal, depigmenting, antileishmanial, anticholinesterase, insecticidal and many
ie

Accepted: April 04, 2018

others. This phenolic compound is among the essential scaffolds for medicinal chemists to synthesize
se
Current Bioactive Compounds

DOI:
10.2174/1573407214666180503120222 more bio-active molecules by further derivatization of the thymol moiety
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Conclusion: Thymol is an interesting scaffold due to its different activities and derivatization of thymol
is proved to enhance its biological activities. However, more robust, randomised, controlled clinical
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trials would be desirable with well-characterised thymol preparations to corroborate its beneficial effects
in diseased patients. Moreover, in view of the potential use of thymol and thymol-rich essential oils in
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the treatment of human infections, comprehensive studies on chronic and acute toxicity and also terato-
al

genicity are to be recommended.

Keywords: GC-MS analysis, carvacrol, thymol, Thymus species, monoterpene, carvacrol.
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1. INTRODUCTION procured from different Thymus species constituting thymol

[6]. Thymol was first discovered by Neumann in 1719 and
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Natural products play an important role in drug develop-

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further purified by M. Lalleman in 1853. The primary source

ment with a remarkable number of marketed drugs being of thymol is Ajwain (Trachyspermum ammi) that contains
derived from naturally occurring compounds [1]. Approxi-
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Thymol (35-60%) and some amount of carvacrol. Thymol is

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mately 80% of the world’s population uses traditional medi-
cine for primary health care [2]. Most of these therapies in-
volved the use of plant extracts or their active compounds,
such as terpenoids [3]. The terpenoids, also known as iso-
prenoids, are formed by repeated branched units of carbon,
similar to units of isoprene [4]. The nomenclature of terpe-
noids depends on the number of isoprene units further classi-
fied as monoterpene, a sesquiterpene, diterpene, triterpene,
tetraterpene, and polyterpene. Terpenoids exist as cyclic or
acyclic structure, which results from the changes in isopre-
noid chain reactions such as reduction, oxidation, cycliza-
tion, ring breaks or rearrangements [5]. Terpenes as well as
terpenoids are the main constituents of essential oils obtained
from many types of plants and flowers for example thyme,
*Address correspondence to this author at the Bio-organic Chemistry Divi-
sion, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;
Tel: 91-191-2585008; E-mails: rshankar@iiim.ac.in; rshankar@iiim.res.in
readily crystallized from the essential oil on cooling, com-
monly known as Ajwain ka phool or Satajwain [7]. Some
other sources of thymol are Baccharisgrise bachii (Thymol,
18.3%) and Centipeda minima [8, 9]. In many plants, Thy-
mol derivatives are also present which can be isolated from
steam volatile such as thymyl isobutyrate, thymyl respective-
ly from Inula cuspidate and Arnica Montana [10, 11].
1.1. Extraction, Purification, and GC-MS Analysis
Generally, Thymol is procured from natural varieties
especially Thymus species. The essential oils are recovered
through steam-distillation or hydro-distillation. In this pro-
cess, aqueous as well as the organic layers are separated after
extraction. GC-MS technique used to further analyze the
organic layer constituting thymol and its isomer. Distillation,
column chromatography or crystallization methods can be
used for obtaining pure thymol, and purity analysis of thy-
mol can be done by GC-MS (Fig. 1).

1875-6646/19 $58.00+.00 © 2019 Bentham Science Publishers

 Thymol Chemistry: A Medicinal Toolbox
Moreover, different methods namely, Pressurized Liquid
Extraction (PLE), Supercritical Fluid Extraction (SFE) and
Clevenger-type hydrodistillation also have been reported from
the different Thymus species. The pressurized liquid extrac-
tion, that employs liquid solvents at elevated temperatures and
pressures, was analyzed by either GC-MS or LC-MS. During
this extraction process, the solvent condition inside the PLE
cell approaches the supercritical region which results in more
efficient extractions. The elevated temperature makes a
sample to become more soluble with higher diffusion rate
while the elevated pressure keeps the solvent below its boiling
point. Supercritical fluid extraction is the process of separating
one component (extractant) from another (matrix) using su-
percritical fluids as the extracting solvent. Extraction is usually
from a solid matrix, but it can also be from liquids. Usually,
SFE (Supercritical Fluid Extraction) is used for small-scale
(analytical purposes) as well as commercial interest to either
strip unwanted material from a product (e.g. decaffeination) or
collect the desired product (e.g. essential oils). CO2 is non-
toxic, non-flammable, odorless, tasteless, inert, and inexpen-
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sive as well as entirely adapted to food, aromas, essential oils
and nutraceutical industries. All the properties of CO2 and its
low critical temperature 31°C, help develop most used super-
critical fluids, sometimes modified by co-solvents such as
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ethanol or methanol [12,13]. Ashnagar et al. also reported the
purification of essential oil by using column chromatography
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and sublimation method [14]. Nowadays, analysis for
aroma/volatile natural abundance variations stable isotope
ratio analysis is increasing attention in various scientific fields
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including alteration in isotopic abundance ratio between the
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Fig. (1). Schematic representation of extraction, purification, and analysis of Thymol.
Current Bioactive Compounds 2019, Vol. 15, No. 5 455
isotopic compounds. According to the literature, Gas Chroma-
tography-Mass Spectrometry (GC-MS) is the best choice for
isotope ratio analysis with sufficient accuracy for aroma com-
pounds such as Thymol and its isomers.
Recently, Trivedi et al. described Mass Spectrometric
Analysis of Isotopic Abundance, which gave the GC-MS
spectrum of the control thymol. The results displayed the
presence of molecular ion peak [M+] at m/z 150 along with
seven major fragmented peaks in lower m/z region at the
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retention time (Rt) of 12.43 min. The fragmented peaks at
m/z 135, 115, 107, 91, 77, 65 and 39 might be due to
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C10H15+, C7H15O+, C7H7O+ or C8H11+, C7H7+, C6H5+, C5H5+,
and C3H3+ ions, respectively as shown in Fig. (2) [15].
2. SOURCES OF THYMOL
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Thymol 1 (an isomer of carvacrol 2) has been used tradi-
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tionally in India as well as China for various biological activi-
ties [16]. Different types of thyme species are reported for
thymol sources in the literature (e.g. Thymus vulgaris,
glandulosus, hemyalis, zygis, longicaulis, capitatus, riatarum,
citriodorus, perscius, eriocalyx, daenensis and serpyllum L),
Monarda species (Monarda punctata, didyma, fistulosa),
y
Euphrasia rosstkoviana, Trachyspermum ammi and Origanum
species (Origanum compactum, dicatamnus, vulgare) [17-21].
nl
The importance of thymol for various activities is in-
creasing in every year and for fulfilling the demand of the
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market; various synthetic methods are being used by many
researchers for synthesis of thymol (Fig. 3). Generally, syn-
se
OH
Oil
Water
Propofel
Thymol
Carvacrol
Intensity
6.0 7.0
time / min
 456 Current Bioactive Compounds 2019, Vol. 15, No. 5 Jyoti et al.

135
100 CH3 CH3
Thymol, Control

CH3

OH H3C CH3
C10H15+
+ Exact Mass: 135
H3 C CH3 OH3
C7H15 O+ +
[Mol. Formula- C 10 H14O, M.W.: 150.22
Exact Mass: 115
Relative Intensity (%)

m/z: 150.10 (100%), 151.11 (11.0%)

C3H3+++
150 Exact Mass: 39

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CH3
91
OH
+
50

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115 OH
C5 H5+
CH3 H3C CH3 Exact Mass: 65
+
C7H7 O+
Exact Mass: 107

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107
39 77
117
136

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C6H 5+
65 79 105 +
H 3C CH Exact Mass: 77
41 51 C 8 H11 + CH2
53 Exact Mass: 107 +
66

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151 C 7 H7+
50 55 89 92 121 133
Exact Mass: 91
38 74 80 93 131
44 145 152
0 Proposed fragmentation
40 60 80 100 120 140 160
Mass-to-chargeratio (m/z)

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Fig. (2). GC-MS analysis and proposed fragmentation of control Thymol [15].
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thesis of thymol at industrial scale, m-cresol 3 used as a tivity is one of the most studied areas [32]. It has been well
starting material. In this method, m-cresol was converted to defined in the literature that thymol shows antimicrobial ac-

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thymol by using Friedel craft reaction and other various pro- tivity due to its phenolic structure [33, 34]. Botelho group
cesses [22-25]. p-Cymene and piperitone have also been tested antimicrobial activity of thymol against cariogenic
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discovered for the synthesis of thymol [26]. A similar alkyla- bacterial species of genus Streptococcus and Candida
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tion with n- or iso- propanol in the presence of a catalyst albicans with MIC values ranging from 0.625 to 10.0
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under microwave conditions synthesized the desired thymol mg/mL [35]. Simatenously, Desai et al. synthesized
in good yields [27]. Although, many industries are also using cyanopyridine 6, 7, pyrazoline 8 thymol derivatives and
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p-cymene 4 [28] and piperitone 515e as suitable starting screened them for the same activities [36]. 1, 2, 4-oxadiazole
material for the synthesis of thymol (Fig. 3). derivatives of thymol 9, 10 have been synthesised by Roda et
m

al. for the antimicrobial activity [37]. Recently, different

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3. BIOLOGICAL ACTIVITIES thymol derivatives were also isolated from Inula hupehensis
by Zhao et al. and all the derivatives were tested for their
Natural products are always demanding due to having
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antimicrobial activity against the Staphylococcus aureus,

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extensive importance in the involvement of bioactive mole-

cules [29]. It has been confirmed that up to 25% conventional Methicillin-resistant S. aureus, and Escherichia coli. In all
tested compounds, 8-Hydroxy-9,10-diisobutyloxy thymol 12
drugs are related directly or indirectly to natural substances
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was the most active at MIC values 62.3, 62.8 and 250 µg/mL
mostly of plant origin [30]. Recently, thymol and its deriva-
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respectively. This compound has also shown inhibitory ac-

tives have gained much more attention, owing diverse biologi-
tivities against three plant pathogenic fungi (Rhizoctonia
cal functions, phyto-pharmaceutical preparations, food pre-
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solani, Phytophthora melonis and Peronophythora litchi

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servatives and also as an aromatic ingredient in most of the

applications. The most effective compound in essential oils with EC50 of 157, 180 and 141 µg/mL, respectively [38].
has been found to be thymol having a lowest minimum inhibi- Recently, Mannich bases of thymol were synthesized and
tory concentration (MIC, 35-128 µg/ml) followed by eugenol tested for carbonic anhydrase inhibition; cytotoxicity studies
and carvacrol [31]. Thymus vulgaris L. is broadly used as and results suggested that compound 2-isopropyl-5-methyl-
traditional medicine in the treatments of a variety of diseases 4-(morpholinomethyl)phenol 13 can be considered as cyto-
such as gastroenteric and bronchopulmonary disorders. Addi- toxicity enhancing drug candidate for further investigations
tionally, thymol based motifs are known to exhibit a broad [39]. Nagle group also synthesized thymol containing pyri-
spectrum of biological activities such as anticancer, antitumor, done moieties 14-16 and evaluated for antioxidant and anti-
anti-HIV, antibacterial, anti-inflammatory, antiviral, antifun- microbial properties, showed better antibacterial and anti-
gal, antipyretic, anticonvulsant and antidepressant (Fig. 4). fungal activity than thymol [40, 41].

3.1. Antimicrobial Activity 3.2. Antibacterial Activity

From earlier centuries, thymol containing essential oil Thymol and its derivatives also showed antibacterial ac-
has been evaluated for their possible benefits in medical ap- tivity against the different strain. Aerial parts of Origanum
plications (Fig. 5). Among wide range, its antimicrobial ac- vulgare L. was assayed against 26 MSS and 21 MRS, using
 Thymol Chemistry: A Medicinal Toolbox Current Bioactive Compounds 2019, Vol. 15, No. 5 457

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Fig. (3). Natural and synthetic sources of Thymol.

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Fig. (4). Some examples of thymol based bioactive molecules.

 458 Current Bioactive Compounds 2019, Vol. 15, No. 5
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Fig. (5). Representative thymol derivative containing antimicrobial compounds.
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an agar dilution method. The results demonstrated that the
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best MIC values for thymol (0.03-0.06%, v/v) and deriva-
tives of thymol 2-(allyloxy)-1-isopropyl-4-methylbenzene
17, 4-allyl-2-isopropyl-5-methylphenol 18, 2-isopropyl-5-
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methyl-4-propylphenol 19 showed good antibacterial activity
against S. aureus 6538 and E. coli 11229 strains [42].
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Thymol derivatives 4-thiazolinone 20, 2-azetidinones 21 and
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4-imidazolinone 22 have also been tested for antimicrobial
and antituberculostatic activity [36]. (-)-Isochaminic acid 23
and 1α, 6α)-10-hydroxycar-3-ene-2-one 24 thymol deriva-
tives, isolated from the roots of Ageratina adenophora also
showed moderate in vitro antibacterial activity against all
five tested Gram-positive bacterial strains, with MIC values
ranging from 15.6 to 62.5 µg/ml [43].
During the period of 2007, Liang et al. isolated some
new derivatives of thymol 25-31 from Centipeda minima and
tested for antibacterial activities [44]. Thymol-β-D-
glucopyranoside 32 was found to be active for in vitro anti-
campylobacter activity when evolution in a mixed culture of
gut microbes and provided the first evidence that oral
administration of this conjugated compound, in comparison
with free thymol [45] (Fig. 6).
Jyoti et al.
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3.3. Antioxidant Activity
Molecules acting as antioxidants are capable of scaveng-
ing Reactive Oxygen Species (ROS). An anti-oxidant activi-
ty of thymol is attributed to its phenolic structure because of
their redox properties, which plays an essential role in the
adsorbing and neutralizing the free radicals or decomposing
peroxides [46-47]. A wide range of thymol derivatives were
explored for Structure-radical scavenging activity. By com-
paring the structural properties of the thymol derivatives,
their antioxidant activity was explained by the formation of
an intramolecular hydrogen bond. The radicalization of the
hydroxyl groups gave rise to species in which the odd elec-
tron appeared to be delocalized over the whole molecule and
stabilized by hydrogen bond interactions [48]. Generally, two
possible reaction pathways were reported through which
phenolic compounds can scavenge free radicals. Firstly by
rapid donation of the hydrogen atom to a radical form,
forming a new radical which is more stable than the initial
one (mechanism leading to the direct O–H bond breaking).
Secondly, by the chain-breaking mechanism by which the
primary antioxidant donates an electron to the free radical
present in the system (e.g., lipid or some other radical)
 Thymol Chemistry: A Medicinal Toolbox
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Fig. (6). Representative thymol derivative containing antibacterial activity.
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leading to indirect H-abstraction. Recently, the substituted
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benzoic acid as well as cinnamic acid thymol moieties have
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been characterized and studied by Ashraf group in 2015 and
observed that 2-[5-methyl-2-propan-2-yl)phenoxy]-2-
oxoethyl-3,4-dihydroxybenzoate 34 exhibited higher antiox-
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idant potential with IC50 value 11.30 µM than standard
ascorbic acid with IC50 value 24.20 µM [49]. Carvacrol and
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thymol have been widely studied for their ability to control
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food spoilage and to extend shelf-life of food products due to
their antioxidant activities. A poor aqueous solubility limits
their application in food systems. Infact, cyclodextrins have
considerably been studied to enhance the water solubility
issue of enormous medicinal compounds. Similarly, Four-
mentin group studied encapsulation of thymol in cyclodex-
trins (CDs) 33 and observed that the position of the hydroxy
group in carvacrol and thymol did not affect the
stoichiometry of the inclusion complexes but led to different
binding stability with CDs [50]. Additionally, concentration
dependent results enabled the calculation of 50% inhibition
(IC50) values as; 773 μg/mL, 834 μg/mL and 476 μg/ mL for
Thymol/HPβCD-IC NF, Thymol/HPγCD-IC NF and
Thymol/ MβCD-IC NF, respectively [50]. Results proved
that the encapsulation in CDs could be valuable for applica-
tions of carvacrol and thymol in food [51-53]. Zhang group
Current Bioactive Compounds 2019, Vol. 15, No. 5 459
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nl
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made thymol to solubilize in Tween 80 micelle to study the
solubilization mechanism of thymol and the effect of solubil-
ization on its antioxidant activity. Ferric Reducing Antioxi-
dant Potential (FRAP) and Cupric ion Reducing Antioxidant
Capacity (CUPRAC) assays showed that the reducing anti-
oxidant activity of free thymol did not change after solubil-
ized in Tween 80 micelles (Fig. 7). Compared to free thy-
mol, the solubilized thymol in between 80 40 showed higher
activities to scavenge DPPH (2,2-diphenyl-1-picrylhydrazyl)
and hydroxyl radicals [54]. Different derivatives of 1,2-
dihydro-6-(4-hydroxy-5-isopropyl-2-methylpnenyl)-2-oxo-4-
arylpyridine-3-carbonitrile were synthesized and evaluated
for their in vitro antioxidant antimicrobial activity. Com-
pounds 35-39 showed remarkably better antioxidant activity
than other derivatives [40].
3.4. Antifungal Activity
As compared to marketed antifungal agents, medicinal
plant extracts are also responsible for its antifungal action
which selectively eliminates fungal pathogens with minimal
toxic effects to the host [55, 56]. In this direction, Castro
et al. investigated the antifungal activity of thymol against
Candida tropicalis and Candida krusei and determined its
mode of action and synergistic effect when combined with
 460 Current Bioactive Compounds 2019, Vol. 15, No. 5 Jyoti et al.

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Fig. (7). Different derivatives or complex of thymol for antioxidant activity.

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the synthetic antifungal drug, nystatin. Thymol showed ac- the number of methylene group in dimer ester, it had no sig-
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tivity with MIC value 39 µg/mL for C. albicans and C. nificant effect on antifungal potency except bis(2-isopropyl-
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krusei, and 78 µg/mL for C. tropicalis. Moreover, the anti-
fungal test results remain unchanged in the presence of sor-
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bitol whereas MIC value of thymol against C. albicans en-
hanced eight times (39.0-312.5 µg/mL) increase in the pres-
ence of exogenous ergosterol [57]. Later, in vitro antifungal
m
5-methylphenyl) malonate 49, as found in the study [61].
Shah et al. suggested that the compound 4,4'-((sulfonylbis
(4,1-phenylene))bis(diazene-2,1-diyl))bis(2-isopropyl-5-me
thylphenol) 50 showed moderate antifungal activity against
Aspergillus niger, Trichophyton rubrum and Candida

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activity of thymol was found against 24 fluconazole (FLC)- glabrata (Fig. 8) [62].
resistant and 12 FLC-susceptible clinical isolates of clinical
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albicans [58]. Kelly and co-workers investigated that the 3.5. Anthelmintic Activity
on

essential oil of Thymus vulgaris and its phenolic component

Thymol is the most important compound known for its
thymol possessed good antifungal activity. Essential oil and
anthelmintic activity especially against Haemonchus
thymol interacted with ergosterol and consequently, they
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contortus. The in vitro and in vivo anthelmintic activity of

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could be represented as different therapeutic agents in the

T. vulgaris essential oil was carried out against this gastroin-
treatment of mucormycosis [59]. In another study, among the testinal parasite on sheep farms. The oil and thymol were
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tested phytochemicals (geraniol, carvacrol, thymol, linalool,

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able to inhibit egg hatching by 96.4 to 100%, larval devel-

p-cymene, terpinolene and citral), thymol showed best anti-
opment by 90.8 to 100%, and larval motility by 97 to 100%,
fungal activity with MIC value 128 mg/mL against Penicilli-
compared to the standard drug, levamisole [63]. Similarly, in
um. Interestingly, thymol derivative 2-isopropyl-5-
comparison with albendazole, anthelmintic efficacy of T.
methylphenyl 5-phenylfuran-2-carboxylate 41 containing 5-
capitatus was evaluated against Haemonchus contortus [64].
phenyl-2-furan and other analogues were synthesized by Another study aimed at investigating the potency of com-
Zining et al. in 2014 and concluded that most compounds
bined albendazole with thymol on mice infected with Echi-
possessing a considerable effect on the selected fungi [60]. In
nococcus multilocularis metacestodes. The combination of
fact, ether 42, 43 and ester 44-46 derivatives of thymol have
the two compounds had a considerably stronger in vivo ef-
also been synthesized for antifungal potency against Asper-
fect showing a reduction in the protoscoleces viability by
gillus niger, Aspergillus oryzae, Fusarium oxysporum and
62% [65]. In a different study, thymol (76.6%) obtained
Alternaria alternate. Consequently, thymol ethers showed from Lippia sidoides plant extract showed in vitro antipara-
better antifungal potency than esters [60]. On the other hand,
sitic effect on Haemonchus contortus in sheep [66]. Again
dithymyl ethylene ether thymol derivative 47 showed the
thymol (50.07%) was extracted from Trachyspermum ammi
highest antifungal activity against A. niger and dithymyl
in order to be used as a natural scolicidal agent. One hundred
methylene ether thymol derivative 48 was found to be more
percent scolicidal activity was observed with thymol rich
potent against the F. oxysporum. If there was an increase in
ajwain essential oil at concentration of 10 mg/mL after 10
 Thymol Chemistry: A Medicinal Toolbox
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Fig. (8). Representative thymol derivative containing antifungal activity.
min of exposure [67]. Another group analyzed the effects of
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alcoholic extracts of thyme (T. vulgaris) and salvia (Salvia
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officinalis) as well as thymol and menthol on the viability of
Echinococcus granulosus protoscolices in vitro [68]. Inter-
estingly, thirty-four phytoterpenoids were studied for their
nematicidal effect using the model nematode Caenorhabditis
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elegans. Among these, oxygenated terpenoids and phenolic
terpenoids exhibited higher nematicidal activity than hydro-
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carbon terpenoids and thymol was the most effective among
them [69]. In vitro cultures of two nematodes namely,
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C. elegans and Ascaris suum were observed for the nemati-
cidal activity of monoterpenoids. Thymol at 0.67 mM caused
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a mortality rate of 99±1% in C. elegans and with A. suum
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thymol at 0.33 mM caused a mortality rate of 80%, com-
pared to standard mebendazole [70]. Another work described
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an in vitro efficacy of T. vulgaris and Origanum vugare
on
essential oils against protoscoleces and cysts of E. granu-
losus. Essential oils were added to the medium resulting in
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thymol final concentrations of 10 µg/mL. Thymol as well as
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the essential oils induced cell apoptosis of protoscoleces
after short incubation times. They also had anthelmintic
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effect on E. granulosus murine cysts in vitro [71].
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3.6. Anti-Inflammatory and Analgesic Activity
Botelho et al. in 2016 evaluated the effect of a nanostruc-
tured thymol gel 1.2 mg/g on acute phase of ligature-induced
periodontitis model in rats. The thymol gel was able to pro-
vide a significant myeloperoxidase decrease in gingiva tissue
confirming to be effective in reduction of gingival inflamma-
tion [72]. The same group also acknowledged the anti-
inflammatory effect of thymol using the mouse models of
acute induced ear inflammation. The topical application of
the essential oil at a single dose of 2mg significantly reduced
ear edema [73]. Later, the hepatoprotective activity of the
main constituents of Thymus spp., carvacrol and thymol,
were evaluated in light of acetaminophen-induced hepatotox-
icity. Thymol was better than carvacrol as it also possessed
Current Bioactive Compounds 2019, Vol. 15, No. 5 461
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higher antioxidant activity with reduced pro-inflammatory
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cytokines, such as tumor necrosis factor alpha and interleu-
kin 1-beta [74]. Elastase was considered as a marker of in-
flammatory diseases and thymol has been explored to check
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its interference with the release of elastase by human neutro-
phils stimulated with synthetic chemotactic peptide N-
formyl-Methionyl-Leucyl-Phenyl-alanine (fMLP). Thymol
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may inactivate calcium channels machinery, thus triggering a
corresponding reduction in elastase. These characteristics
can help thymol in controlling the inflammatory processes
present in many infections [75]. According to another study,
the potent anti-inflammatory activity may have resulted from
the fact that T. vulgaris essential oil inhibits the production
of interferon-γ and lipopolysaccharide mediated nitric oxide
production via suppression of inducible nitric oxide synthase
mRNA expression in murine macrophage cells [76]. Com-
bined prodrugs of flurbiprofen and various antioxidants were
developed in order to reduce the gastrointestinal (GI) side
effects of drug. The free carboxylic group (-COOH) was
temporarily masked by esterification with phenolic –OH of
essential oils for reducing the GI toxicity. Flurbiprofen-
thymol prodrug 51 significantly (P<0.001) reduced the in-
flammation against carrageenan and egg albumin-induced
paw edema at 4h of study (Fig. 9). This prodrug possessed
greater affinity to bind at cyclooxygenase-2 (COX-2) when
compared with cyclooxygenase-1 (COX-1) [77]. Similar
hybrids have been formed for ibuprofen using thymol in (S)-2-
isopropyl-5-methylphenyl 2-(4-isobutylphenyl)propanoate 52
and other natural antioxidants which were chemically stable,
biolabile and exhibited retention of anti-inflammatory and
analgesic activity with a significant reduction in ulcerogenicity
as compared to the free drug [60]. Similar kind of work has
been carried out by Redasani et al. in 2012 [78].
As tremendous research has been going on this monoter-
pene, thymol extracted from Lippia gracilis Schauer (Verbe-
naceae) was observed to be a promising compound to be
used in the treatment of inflammatory processes as well as
 462 Current Bioactive Compounds 2019, Vol. 15, No. 5
Pu
e
nc
ie
Fig. (9). Representative thymol derivative containing Anti-Inflammatory activity [77].
Sc
wound healing [79, 80]. Marsik and co-workers determined
U
its analogues, thymohydroquinone 53, thymoquinone 54 and
dithymoquinone 55 from N. sativa seeds, and consider their
m
in vitro anti-inflammatory activity using COX-1 and COX-2
al
assays [81]. Chen and coworkers have isolated different
compounds from aerial part of Eupatorium cannabinum, sub
ha
on
species asiaticum, out of which compounds 56-61 exhibited
moderate inhibition activity [82]. Nesterkina et al. synthe-
sized esters based mono-terpenoid with glycine. According
nt
to this study, 2-isopropyl-5-methylphenyl 2-aminoacetate 62
rs
showed both anti-inflammatory and analgesic activity [83].
Be
Pe
Fig. (10). Representative thymol derivative containing antihyper-
tensive activity.
3.7. Antihypertensive Activity
Various plant sources of thymol namely, Trachyspermum
ammi (35-60% thymol), Thymus serpyllums L. (40% thy-
mol), Carum copticum (97.9% thymol) have known to pos-
sess antihypertensive activity. The calcium channel blockade
has been found to mediate the spasmolytic effects of plant
Jyoti et al.
rs
he
is
bl
y
nl
O
se
materials and it is being considered that this mechanism con-
tributed to their observed result and supported the traditional
use of the plants in hyperactive disease states of the gut such
as colic and hypertension [84].
A novel study investigated the vasorelaxant activity of
Trachyspermum ammi seeds containing thymol (38.1%), 1-
(2-isopropyl-5-methylphenoxy)-3-(isopropylamino)propan-
2-ol 63 and 1-(tert-butylamino)-3-(2-isopropyl-5-methylphe-
noxy)propan-2-ol 64 (Fig. 10). The inhibitory effect of T.
ammi on the aortic rings precontracted with KCl and phe-
nylephrine was considerably reduced by standard calcium
channel blocker, nifedipine. These findings hypothesized
that the vasorelaxation caused by T. ammi is completely
endothelium independent and the extracellular Ca2+ influx
was also inhibited by thymol [85]. Stanojevic et al. in 2013
proved the potential antihypertensive effect of T. serpyllum
in spontaneously hypertensive and normotensive rates [86].
An interesting study reported the bronchodilator effect of C.
copticum seed extract in presence of high K+ (50mM) and
carbachol on guinea pig tracheal preparation. Results
demonstrated that C. copticum produced dose-dependent
relaxation (dose 0.1-1mg/mL) with a possible mechanism of
calcium channel blocking effect [87].
3.8. Depigmenting Activity
Various chemical agents or physical therapies are availa-
ble for the treatment of acquired skin hyperpigmentation, but
none are completely satisfactory [88]. Hyperpigmentation is
 Thymol Chemistry: A Medicinal Toolbox
Fig. (11). Representative thymol derivative as depigmenting agents.
an abnormal darkening of the skin mostly derived from ex-
Pu
cessive melanin production. Tyrosinase is the rate-limiting
enzyme of melanin synthesis and the main target of
antihyperpigmentation remedies. Novel interest is focused
on compounds which were able to inhibit tyrosinase activity
e
nowadays, especially natural products [89]. Kang and group
synthesized hydroxybenzoates, alkoxybenzoates and 3, 4, 5-
nc
trimethozycinnamate containing thymol moiety and screened
them for high-level inhibitory activity against melanin syn-
thesis in cultured melanocytes to obtain effective and safe
ie
topical depigmenting agents. Compounds 2-isopropyl-5-
methylphenyl 3,4-dimethoxy-5-methylbenzoate 65 and (E)-
2-isopropyl-5-methylphenyl 3-(3,4-dimethoxy-5-methylphe-
Sc
nyl)acrylate 66 showed more potent depigmenting effect
(IC50= 10 µM) with low cytotoxicity (IC50 = 200 µM) (Fig.
11) [90]. Pigmentation of human skin, eye and hair is due to
the melanin pigment that is synthesized by melanogenesis
m
process. Numerous enzymatic catalyzed chemical reactions
al
are involved in melanogenesis process, the enzymes such as
tyrosinase and Tyrosinase-Related Protein-1 (TRP-1) and
ha
on
TRP-2 playes a major role in melanin synthesis. According
to the study, different thymol analogs associated with hy-
droxylated benzoic acid and cinnamic acids were reported as
nt
mushroom tyrosinase inhibitors. The cinnamic acid-derived
rs
thymol derivatives 67-71 out of which, 2-(2-isopropyl-5-
methylphenoxy)-2-oxoethyl cinnamate compound with
Be
Pe
methanol (1:1) 67 (Fig. 12) showed better tyrosinase inhibi-
tion with IC50 value 91.5 µM than benzoic acid derivative 2-
(2-isopropyl-5-methylphenoxy)-2-oxoethyl 4-hydroxyben-
zoate 72 with IC50 value 15.20 µM [91]. Another study
showed that the presence of phenolic –OH at para-position on
cinnamic acid ring was found to play an important role in ty-
rosinase inhibition. Further, the tyrosinase inhibitory activity
with IC50 value 15.20 mM was comparable with kojic acid
IC50 value 16.69 mM. Out of different analogs, 73-76 pos-
sessed moderate mushroom tyrosinase inhibition activity [49].
3.9. Antileishmanial Activity
Many published studies have demonstrated that essential
oils are also responsible for in vitro and in vivo antileishma-
nial activities. Morais et al. in 2014 surveyed thymol as well
Current Bioactive Compounds 2019, Vol. 15, No. 5 463
rs
he
is
bl
as eugenol derived 2-isopropyl-5-methylphenyl acetate 77
and benzoyl derivative 2-isopropyl-5-methylphenyl benzoate
78 for antileishmanial activity against Leishmania infantum
chagasi. Thymol derivatives demonstrated greater activity
y
than the eugenol derivatives, benzoyl-thymol (8.67±0.28
µg/mL) and acetyl thymol (9.07±0.06 µg/mL) being the
nl
strong inhibitors [92]. Recently, Morita-Baylis-Hillman ad-
ducts (MBHAs) were synthesized using eugenol, thymol and
O
carvacrol and their bioevaluation against promastigotes of
Leishmania amazonensis were carried out. Hybrids derived
from thymol exhibited higher antileishmanial activity than
the corresponding essential oil ingredients. The study re-
se
vealed that the nitrated MBHAs presenting an ortho nitro
group in 2-isopropyl-5-methylphenyl 2-(hydroxy(2-nitro-
phenyl)methyl)acrylate 79 on the aromatic ring (5.91±0.30
U
µg/mL) was more bioactive against promastigotes of L.
amazonensis than the corresponding meta in 2-isopropyl-5-
methylphenyl 2-(hydroxy(3-nitrophenyl)methyl)acrylate 80
(10.56±0.53 µg/mL) and para in 2-isopropyl-5-methylphenyl
2-(hydroxy(4-nitrophenyl)methyl)acrylate 81 (11.40±0.57
µg/mL) nitroaryl isomers (Fig. 13) [93]. In another study, the
effects of essential oils from Lippia sidoides (LSEO) and its
major compound thymol (78.37% relative amount) were
analyzed on the growth, viability and ultrastructure of
L. amazonensis. thymol and LSEO indicated significant ac-
tivity against promastigote forms of L. amazonensis with
IC50 19.47 and 44.38 µg/mL respectively [94]. Later, the
essential oils were obtained from leaves of plant Lippia
gracilis and tested for leishmanicidal activity from LGRA-
106 & LGRA-110 assayed by using tetrazolium dye (MTT)
colorimetric method. The oxygenated monoterpene thymol
was the main component of the essential oil from genotype
LGRA-106. Among the genotype tested, LGRA-106 essen-
tial oil exhibited leishmanial activity with IC50 at 86.32
µg/mL and the best fungicidal activity at 46.87 µg/mL [95].
In another study, three thymol derivatives were charac-
terized from the ethanolic extract and fractions of Mikania
decora. These compounds were significantly cytotoxic
against a panel of human tumor cell lines. Compound (2-(5-
methoxy-4-methyl-2-((3-methylbut-1-en-2-yl)oxy)phenyl)
oxiran-2-yl)methyl acetate 82 was moderately active against
 464 Current Bioactive Compounds 2019, Vol. 15, No. 5 Jyoti et al.

a) b) PRO253
TRP254

GLU O
A:33 O

O 4.90
H
O 5.14
Residue Interaction PHE
A:34
PHE66
Electrostatic TRP

rs
ASP A:254 4.69
van der Waals A:69
4.62
Covalent bond ARG

he
A:30 4.60
1.99
Water 3.81
4.81
Metal
PHE34
GLU29

is
4.05

bl
ARG30

Pu
Fig. (12). The interaction of compound 67 with the active site of mushroom tyrosinase (PDBID), a) shows two-dimensional interaction pat-
terns. The ligand inset represents the interaction between ligand atoms and amino acid residues of the protein. b) shows three-dimensional
docking of the compound in the binding pocket and, dashed lines indicate bond distances between interacting functionalities of the ligand and
receptor [91].

y
e

nl
nc

O
ie

se
Sc

U
m

al
ha

on
nt

rs
Be

Pe

Fig. (13). Representative thymol derivative as antileishmanial agents.

 Thymol Chemistry: A Medicinal Toolbox
L. amazonensis axenic amastigotes, while compound 3-
acetoxy-2-hydroxy-2-(2-hydroxy-5-methoxy-4-methylphen-
yl)propyl isobutyrate 83 exhibited a higher antileishmanial
effect [96]. The findings by another group showed that while
Glucantime essentially eradicated the parasite from the le-
sion, thymol and its hemisynthetic derivative 6-isopropyl-3-
methyl-2,4-dinitrophenol 84 decreased the parasite burden,
by 46 and 23% respectively [97]. Edison et al. suggested that
thymol and its synthetic derivatives nitro and methoxy de-
rived compounds 85-91 showed antileishmanial activity and
they also showed less toxicity against U-937 with LC50>100
µg/ml [98].
3.10. Anticholinesterase and Insecticidal Activity
Acetylcholinesterase (AChE) inhibitors are agents used
to inhibit the acetylcholinesterase enzyme from breaking
down of acetylcholine, resulting in the increased amount of
acetylcholine neurotransmitter. To this date, the therapeutic
management of cholinergic dysfunction is limited to provide
Pu
symptomatic relief through the use of AChE inhibitors only
[99]. Larvicidal and AChE inhibitory activities of Apiaceae
plant essential oils and their constituents have been studied
by Seo et al. in 2012 against Aedes albopictus. Results
showed that all the compounds including thymol exhibited
e
>80% larval mortality when used at 0.1 mg/mL whereas
thymol moderately inhibited AChE inhibition assay (Fig. 14)
nc
[100]. In a similar study, Yeom et al. evaluated insecticidal
and AChE inhibition activity of same Apiaceae plant essen-
tial oils and constituents on Blatella germanica. The obser-
ie
vations confirmed that thymol showed strong insecticidal
activity against German cockroaches by direct contact, and
Sc
not via fumigation [101]. Recently, Sammi group elaborated
the potential of thyme oil at individual components for cur-
tailing cholinergic deficits. According to the study, the
thyme oil augments neurotransmission by modulating synap-
tic Acetylcholine (ACh) levels and nicotinic ACh receptor
m
activity through up regulation of genes cho-1, unc-17 and
al
unc-50. It was found that on individual components revealed
ha
para-cymene (1-methyl-4-propan-2-ylbenzene) as the active
on
component of thyme oil, contributing its effects through up-
regulation of cho-1, cha-1, unc-17 and unc-50, while down-
regulating ace-1 and ace-2 [102]. Interestingly, thymol has
nt
rs
also been screened against acetyl- as well as butyrylcholines-
terase enzymes and has shown good inhibitory activity
Be
[103]. In another research work, thymol and carvacrol deriv-
Pe
atives with carbamate moiety were synthesised and their
inhibitory effects on the Acetylcholinesterase (AChE) and
Butylcholinesterase (BuChE) were determined (Fig. 15). The
analog, 5-isopropyl-2-methylphenyl(3-fluorophenyl)carba-
mate 92 was found to be the most potent AChE inhibitor
with IC50 values at 2.22 µM, and 5-isopropyl-2-methylphenyl
(4-flurophenyl) carbamate 93 was the strongest against
BuChE with IC50 value of 0.02 µM [104]. Infact, in case of
Alzheimer disease, restoration of cholinergic function occurs
through inhibition of acetylcholinesterase, thereby facilitat-
ing cholinergic neurotransmission, acetylcholinesterase ac-
tivity of thymol seems to play a substantial role in improving
cognitive function. The current study thus evaluated the effi-
cacy of thymol and carvacrol against cognitive deficits in-
duced by Amyloid β (Aβ) or scopolamine. Thymol appeared
to be more potent than carvacrol in reducing the Aβ or the
Current Bioactive Compounds 2019, Vol. 15, No. 5 465
scopolamine-induced learning deficits [105]. In a different
study, Zanthoxylum piperitum and Zanthoxylum armatum oil
constituents and related constituents were studied for their
toxicity against Stomoxys calcitrans. Thymol produced
strong acetlycholinesterase inhibition as potential insecticide
for the control of stable fly populations [106]. Thymus vul-
garis essential oil insecticidal activity was reported with
LC50 value 57.48 mg/L against Pochazia shantungensis
nymphs using the leaf dipping bioassay and 75.80 mg/L
rs
against P. shantungensis adults by spray bioassay method.
Based on the structure-toxicity relationship between thymol
analogs and insecticidal toxicities against P. shantungensis
he
and P. shantungensis adults, the LC50 values of thymol, car-
vacrol, citral, 2-isopropylphenol, 3-isopropylphenol, and 4-
isopropylphenol were 28.52, 56.74 and 89.12, 71.41, 82.49,
is
and 111.28 mg/L, respectively [107]. Grodnitzky et al. dis-
covered Quantitative Structure-Activity Relationship (QSARs)
bl
in order to estimate insect toxicity of monoterpenoids (Thy-
mol) and their derivatives 94-100 (2-isopropyl-5-methyl-
phenyl acetate 94, 2-isopropyl-5-methylphenyl propionate
95, 2-isopropyl-5-methylphenyl pivalate 96, 2-isopropyl-
5-methylphenyl 2,2,2-trichloroacetate 97, 2-isopropyl-5-
methylphenyl 2,2-dichloro-2-fluoroacetate 98, 2-isopropyl-
y
5-methylphenyl isobutyrate 99 and 2-isopropyl-5-methyl-
phenyl 3-chloro-2,2-dimethylpropanoate 100) that have not
nl
yet been synthesized or experimentally tested, and correla-
tions were found between toxicity and assured quantum and
O
traditional chemical parameters [108].
3.11. Antidiarrhoeal Activity
se
Thymol has also been discovered for antidiarrhoeal activ-
ity. In this direction, novel thymol derivative isolated from
the leaves of Ageratina glabrata, namely, (8S)-10benzoy-
U
loxy-8,9-epoxy-6-hydroxylthymol isobutyrate 101 showed
the most potent antiamoebic and antigiardial activity (Fig.
16). It showed good selectivity for antiamoebic activity
comparable to the standard antiprotozoal drugs, emetine and
metronidazole. Compound, [2-(5-acetoxy-2-(isobutyryioxy)-
4-methylphenyl)oxiran-2-yl]methyl benzoate 102 also showed
good antidiarrhoeal activity [109]. The same group also in-
vestigated thymol derivative (R)-(2-(4-acetyl-5-hydroxy-2-
(isobutyryloxy)phenyl)oxiran-2-yl)methyl benzoate 103 for
antidiarrhoeal activity against Entamoeba histolytica and
Giardia lamblia protozoa, isolated from the leaves of Ager-
atina cylindrica earlier [110].
3.12. Anticancer Activity
1,688,780 new cancer cases and 600,920 cancer deaths
have been projected in United States in 2017. Therefore, in
order to curb this issue, natural sources can be of vital im-
portance. Kang and group evaluated anticancer effects of thy-
mol by suppressing cell growth, inducing apoptosis, producing
intracellular reactive oxygen species, depolarizing mitochon-
drial membrane potential and activating the proapoptotic mi-
tochondrial proteins Bax, cysteine aspartases (caspases), and
poly ADP ribose polymerase in human gastric AGS cells
[111, 112]. Surprisingly, the combination of thymoquinone
and resveratrol has potential to work synergistically to inhib-
it cell growth in breast cancer cell lines, as well as to stop
development of breast cancer in mice. Antitumor activity of
 466 Current Bioactive Compounds 2019, Vol. 15, No. 5 Jyoti et al.

rs
he
is
Fig. (14). Anticholinesterase and antiinsecticidal compounds having thymol moiety.

bl
PHE PHE ARG HIS GLY
297 295 296 TYR 438 439 LEU TYR
H 2O 125
440 128
TYR SER GLY TYR

Pu
ASP 72 293 122 124 TRP H GLY
74 430 N O 115 THR
TYR 122
341 HIP
ALA O TYR
O 447 F
328 114

y
TYR
337 GLY
F N O
e TYR MET TRP 121

nl
H
332 437 82
PHE
nc
TRP VAL 338 GLY THR
286 294 116 120

O
Charged (negative) p- p stacking p-cation
ie

Charged (positive) H2O Water H-bond (backbone)

H-bond (side chain)
Polar
se
Solvent exposure
Sc

Hydrophobic Glycine
U
Fig. (15). 2D ligand interaction diagrams of top-docking poses of 1 (left) and 2 (right) at the active sites of AChE (acetylcholinesterase) and
BuChE(butylcholinesterase), respectively [102].
m

al
ha

on
nt

rs
Be

Pe

Fig. (16). Representative thymol derivative for antidirrahoeal activity.

thymoquinone was tested through different methods, includ-
ing induction of apoptosis, inhibition of VEGF expression
and stimulation of immune system [113]. Compounds 8,10-
didehydro-9-(3-methylbutanoyl)thymol 3-O-tiglate 104, 9-O-
angeloyl-8-methoxythymol3-O-isobutyrate 105, 9-acetoxy-
8,10-epoxythymol 3-O-tiglate 106 and 10-acetoxy-9-O-
angeloxyl-8-hydroxylthymol 107 were isolated from the
roots of Eupatorium cannabinum, sub species asiaticum by
Chen et al. in 2014. Compounds 104-106 were most
cytotoxicites against DLD-1, CCRF-CEM and HL-60 cell
lines with IC50 values of 0.02±0.01, 1.02±0.07 and 1.36±
0.12 µg/mL, respectively, whereas, compound 107 showed
cytotoxicites, with IC50 value of 1.14±0.16 against DLD-1,
CCRF-CEM cell lines [114]. Interestingly, Mannich bases of
thymol were synthesized by Halise and group, through ami-
nomethylation reaction at ortho and para position of phenol.
 Thymol Chemistry: A Medicinal Toolbox
Pu
Fig. (17). Different anticancer compounds having thymol moiety.
e
Compound 2-((dipropylamino)methyl)-6-isopropyl-3-methyl-
phenol 108 showed cytostatic activity against the oral squa-
nc
mous cell carcinoma cell lines at 16-32-fold lower concen-
trations as compared to normal cells. Infact, triazole based
heterocycles have been well exploited for the generation of
ie
many medicinal scaffolds exhibiting par excellent activities
[115]. In continuation, thymol based triazoles have been in-
vestigated which further enhanced its biological activity.
Sc
After reviewing literature, we found that compound 2-((4-
benzyl-5-((2-isopropyl-5-methylphenoxy)methyl)-4H-1,2,4-
triazol-3-yl)thio)-N-(4-sulfamoylphenyl)acetamide 109 and
2-((4-benzyl-5-((2-isopropyl-5-methylphenoxy)methyl)-4H-
m
1,2,4-triazol-3-yl)thio)-N-(4-chlorophenyl)acetamide 110
al
showed antitumor activity with IC50 value of 5.96 mM
against PC-3 cells and 7.90 mM against A549/ATCC, re-
ha
on
spectively (Fig. 17) [116, 117].
3.13. Digestive Stimulant Activity
nt
rs
As a result of in vivo experiments in rats, this natural
monoterpene also reduces the food transient time [118, 119].
Be
In another enzyme modulatory study, thymol reinforced the
Pe
pancreatic lipase and amylase effectiveness, which may sup-
port the digestive stimulant action [120]. Another study eval-
uated the potential of thymol and carvacrol as dietary sup-
plements with Carboxy Methyl Cellulose (CMC) on hepatic
functions of broilers by analyzing their plasma biochemical
profile and on broiler performance, intestinal digesta viscosi-
ty and pH and plasma lipids and also investigated whether a
mixture of thymol and carvacrol would be able to counteract
the CMC-induced growth depression in broiler chickens.
Thymol and carvacrol decreased digesta viscosity and con-
sequently improved the performance of broilers fed the
CMC-based diet [121]. The same group observed that feed
supplementation with thymol and carvacrol enhanced per-
formance, increased antioxidant enzyme activities, retarded
lipid oxidation, enhanced digestive enzyme activities, and
improved immune response of broilers [122]. According to
Current Bioactive Compounds 2019, Vol. 15, No. 5 467
rs
he
is
bl
y
the literature, luminal regulation of normal and neoplastic
nl
human enterochromaffin (EC) cell serotonin release is medi-
ated by bile salts, amines, tastants, and olfactants. Therefore,
O
Kidd et al. evaluated whether neuroendocrine EC cells act as
luminal sensors for a wide variety of nutrients and defined
the secretory mechanisms of this process. Thymol was used
as an olfactant which stimulated normal and neoplastic EC
se
cell 5-HT secretion (EC50=1.2 nM to 2.1 µM release) [123].
Recently, spasmolytic and anti-spasmodic action of thymol
rich Trachyspermum ammi essence on rat’s ileum contrac-
U
tion was analyzed and positive results were gained [124].
3.14. Abortifacient Activity and Spermicidal Activity
Large doses of thymol have been associated with aborti-
facient activity as well as teratogenicity. In an extraordinary
case study, pregnancy was continued in spite of the herbal
drug administration. As a result, foetuses showed various
skeletal defects and several other visceral defects. Conse-
quently, they expressed concern at the remarkable potential
of the putative abortifacient herbal drugs to affect foetuses
adversely [125]. Infact, the plentiful thymol bearing plant
Trachyspermum ammi aqueous extract has been reported as
abortifacient at a dose of 175 mg/kg in rats [126]. Therefore,
thymol use during pregnancy is not recommended except
under the supervision of a qualified healthcare practitioner.
In case of spermicidal activity, two thymol derivatives goss-
ypol 111 and hemigossypol 112 are being widely used all
over the world as potential male antifertility agents (Fig. 18)
[127].
3.15. Miscellaneous
Extraordinary work regarding thymol has been reported
by tremendous research groups. The synthesis and pharma-
cological evolution have been carried out for a series of
pyrrolidine analogues of thymoxiamine. Compounds 5-
isopropyl-2-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenol 113
 468 Current Bioactive Compounds 2019, Vol. 15, No. 5
Fig. (18). Spermicidal compounds having thymol moiety.
and 6-isopropyl-7-(2-(pyrrolidin-1-yl)ethoxy)-1H-indole 114
showed selectivity for the α-adrenoreceptor both in radiore-
ceptor and functional assays. The introduction of different
basic residues, such as N-(2-methoxyphenyl) piperazine con-
taining compounds 115 and 116 possibly drive to different
kinds of interaction with the receptors α1, α2, 5HT2, 5HT1A
and D2. Compound 114 showed same uroselectivity as that
of standard phentolamine and tamsulosin [128] (Fig. 19).
Various amide derivatives of 4-(4-butoxy-5-isopropyl-2-
methylphenyl)-6-(4-methoxyphenyl)pyrimidin-2-amino, 117-
Pu
122 have been reported for the molecular modelling investi-
gation with known ligand Catabolite gene activator protein
(CAP)/DNA complex+Adenosine-3,5,-cyclic-monophosphate
(PDB code -1CGP) and, most of the derivatives showed
e
good binding affinity with Adenosine A1 Receptor Antago-
nists [129]. Infact, thymarnicol 123, a dimeric thymol de-
nc
rivative isolated from Arnica sachalinensis showed antifeed-
ant, phytotoxic and anti-inflammatory activity [130]. Also,
chlorothymol 124 showed larvicidal activity against Culex
ie
pipiens and its N-methyl carbamate derivative 125 showed
higher larvicidal activity than chlorothymol [131].
Sc
4. THYMOL AND ITS CLINICAL STUDIES
Thymol at clinical level can be found in numerous find-
ings based on animal as well as human models. In case of
m
al
ha
on
nt
rs
Be
Pe
Fig. (19). Miscellaneous compounds bearing thymol moiety.
Jyoti et al.
T. vulgaris L., the effect of thymol and carvacrol were ana-
lyzed for the inflammatory response in the following exper-
imental animal models, namely, ear edema, carrageenan-
induced pleurisy, and chemotaxis in vitro. According to the
results, all ingredients including thymol significantly inhibit-
ed inflammatory edema in the pleurisy model. In the in vitro
chemotaxis experiment, carvarol inhibited leukocyte migra-
tion, whereas thymol exerted a potent chemoattractant effect
[132]. In another case study of an ex vivo human skin model,
rs
polyphenols such as thymol from T. vulgaris leaf extract
have been proposed for the prevention of ultraviolet
radiations-induced skin damage. The effect of T. vulgaris L.
he
extract (1.82 μg/ml) or thymol (1 μg/ml) was evaluated on
all samples treated for 1h before UVB irradiation. Resultant-
ly, Thymus has a protective action for all of the endpoints
is
evaluated but the action of the extract was less pronounced
on epidermal proliferation and morphological features [133].
bl
One more animal study on asthma revealed that pretreatment
with thymol reduced the level of ovalbumin-specific IgE,
inhibited recruitment of inflammatory cells into airway, and
decreased the levels of interleukins IL-4, IL-5 and IL-13 in
bronchoalveolar lavage fluid (BALF) [134]. Study on obesi-
ty observed that thymol treatment has significantly (p<0.001)
y
decreased body weight gain, visceral fat-pad weights, lipids,
alanine aminotransferase, aspartate aminotransferase, lactate
nl
dehydrogenase, blood urea nitrogen, glucose, insulin and
leptin levels in high-fat diet induced obese rats [135] .
O
CONCLUSION
Thymol is a monoterpenoid found in the oil of thyme and
se
extracted from Thymus vulgaris as well as other kinds of
plants. It is an interesting molecule due to its different prop-
erties and possible functions in various fields. The results
U
obtained by a number of investigations observed in the last
decade motivated researchers for the use of thymol and its
 Thymol Chemistry: A Medicinal Toolbox Current Bioactive Compounds 2019, Vol. 15, No. 5 469

derivatives in the food and cosmetic industries and it has
great potential as a bioactive component in the pharmaceuti-
cal field. Thymol has been reported for various biological
activities like antibacterial, antifungal, antioxidant, anti-
inflammatory, antimicrobial, antihypertensive, antidiarrhoe-
al, anthelmintic, analgesic, digestive stimulant, abortifacient,
antihypertensive, spermicidal, depigmenting, antileishmani-
al, anticholinesterase, insecticidal and many others. Infact,
thymol has been supposed to enhance its biological action
acknowledge the financial support by DST-SERB, Dehli,
India.
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FUNDING
This work was funded by the Department of Science and
Technology, DST-SERB with Grant number: EMR/2016/
002304 and EEQ/2016/000102, New Delhi, India, and
CSIR-IIIM communication no. IIIM/2183/2018.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
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Dr. Dheer thank CSIR-New Delhi, India for her research
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