Synthesis, characterization, and antioxidant activity of thymol-based paracetamol analogues

Article abstract of DOI:10.1007/s11164-019-03914-0

Thymol (2-isopropyl-5-methylphenol) is an important monoterpene phenol occurring in the essential oils isolated from Thymus vulgaris, Thymus zygis, Thymus hyemalis, etc. Thymol and its derivatives show various activities such as antioxidant, antiinflammatory, antibacterial, and antifungal effects. In the present study, a set of new benzamide derivatives (4a–e), which are structurally similar to paracetamol, were synthesized from thymol using a green synthetic approach and characterized by Fourier-transform infrared (FT-IR) and ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopies, liquid chromatography–mass spectrometry (LC–MS), and X-ray single-crystallographic analysis for derivative 4c. These derivatives were subjected to antioxidant testing by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and antibacterial testing against five microorganisms. Molecular docking studies of all the compounds indicated that they are good inhibitors of heme oxygenase-1. These results extend the development of thymol-based benzamide scaffolds as promising antioxidant agents.

Full text of DOI:10.1007/s11164-019-03914-0

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03914-0
Synthesis, characterization, and antioxidant activity
of thymol‑based paracetamol analogues
Pradnya S. Sathe1 · Jamatsing D. Rajput1 · Shubha S. Gunaga2 ·
Harun M. Patel3 · Ratnamala S. Bendre1
Received: 5 March 2019 / Accepted: 20 June 2019
© Springer Nature B.V. 2019
Abstract
Thymol (2-isopropyl-5-methylphenol) is an important monoterpene phenol occur-
ring in the essential oils isolated from Thymus vulgaris, Thymus zygis, Thymus hye-
malis, etc. Thymol and its derivatives show various activities such as antioxidant,
antiinfammatory, antibacterial, and antifungal efects. In the present study, a set of
new benzamide derivatives (4a–e), which are structurally similar to paracetamol,
were synthesized from thymol using a green synthetic approach and characterized
1
by Fourier-transform infrared (FT-IR) and H and 13C nuclear magnetic resonance
(NMR) spectroscopies, liquid chromatography–mass spectrometry (LC–MS), and
X-ray single-crystallographic analysis for derivative 4c. These derivatives were sub-
jected to antioxidant testing by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and
antibacterial testing against fve microorganisms. Molecular docking studies of all
the compounds indicated that they are good inhibitors of heme oxygenase-1. These
results extend the development of thymol-based benzamide scafolds as promising
antioxidant agents.
Keywords Benzoylation · Thymol · Antioxidant activity · DPPH · Docking ·
Oxygenase-1
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-03914-0) contains supplementary material, which is available to authorized users.
*
Ratnamala S. Bendre
bendrers@redifmail.com
1
Department of Pesticides and Agrochemicals, School of Chemical Sciences, Kavayitri
Bahinabai Chaudhari North Maharashtra University, Jalgaon, Maharashtra 425 001, India
2
3
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry,
R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur (Dhule),
Maharashtra 425405, India
Vol.:(0123456789)
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P. S. Sathe et al.
Introduction
It has been estimated that the genus Thymus includes at least 200 species with
many subspecies, varieties, and forms, both endemic and widespread, distributed
across Europe, Asia, North Africa, and the Canary Islands [1]. Thymus species
are used as medicinal and aromatic plants, as well as in cosmetics and perfumery,
throughout their range [2]. Most aspects of their medicinal use are related to the
essential oils, which contain various levels of thymol and/or carvacrol with strong
and wide-spectrum antimicrobial activity [3, 4]. Essential oils including thymol
have been found to act as functional antioxidants and as antimicrobials in foods
[5]. Essential oils including carvacrol and thymol have been tested for their insec-
ticidal and genotoxic activities against Drosophila [6]. Thymol derivatives have
also been found to exhibit antioxidant, antitumor, and anticancer activities [7].
Thymol, a compound derived from p-cymene, is widely used in medicine for
its antimicrobial, antiseptic, disinfectant, and wound healing properties. Thymol
derivatives such as 1,3,4-oxadiazoles have been synthesized and their antimicrobial
activity screened [8]. Lupo et al. [9] showed that modifed thymol derivatives, viz.
2-(allyloxy)-1-isopropyl-4-methylbenzene, 4-allyl-2-isopropyl-5-methylphenol, and
2-isopropyl-5-methyl-4-propylphenol, exhibit good antibacterial activity against
Streptococcus aureus 6538 and Escherichia coli 11229. Compounds derived from
4-nitrosothymol showed moderate to good antimicrobial and antituberculostatic
activities [10, 11]. Liang et al. [12] reported the antibacterial activity of seven struc-
turally characterized thymol derivatives isolated from Centipeda minima. The potent
antioxidant activity of isoespintanol may be because of the high stability of radicals
[13]. Schif bases derived from 4-aminothymol were synthesized and screened for
their antioxidant activities [14]. The essential oil composition, total phenolic and
favonoid contents, and antioxidant activity of Thymus species collected from difer-
ent regions of Iran were also reported [15]. Thymol nanoemulsion exhibits poten-
tial antibacterial activity against bacterial pustule disease and a promotory efect on
the growth of soybean [16]. Various derivatives of thymol have been synthesized
and their diferent activities (antimicrobial, antifungal, etc.) studied, confrming the
biological importance of such compounds [17, 18]. Thymol is a well-known natu-
ral phenolic monoterpenoid present as a functional ingredient in numerous prod-
ucts [19]. Paracetamol is a medicine commonly used to treat pain and reduce high
body temperature (fever). It is typically used to relieve mild pain such as headache,
toothache, etc. It is safe to take, and side efects are rare in most people. It is also
observed to exhibit antioxidant activity. Biochemical studies have suggested a direct
relationship between its radical scavenging activity and antipyretic and analgesic
action. Alisi et al. [20] studied the antioxidant activity of various derivatives of par-
acetamol. The DPPH assay revealed that all the paracetamol derivatives exhibited
signifcantly higher efciency than the parent compound and that their radical scav-
enging activity could be increased by introducing a substituent such as an indazole
ring or the ionic N-methyl morpholinium group on acyl moiety.
The aim of the work presented herein is to synthesize paracetamol analogues
from thymol. These derivatives were synthesized in solvent-free condition,
1 3

Synthesis, characterization, and antioxidant activity of…
resulting in good-quality products in short time. All synthesized derivatives were
1
characterized by spectroscopic techniques such as FT-IR and H and 13C NMR
as well as LC–MS and single-crystal X-ray analysis. All the derivatives were
subjected to antioxidant testing using the DPPH assay and antibacterial testing
against fve microorganisms. Docking studies against the active site of human
heme oxygenase-1 indicated that the interaction with many amino acid residues
of human heme oxygenase-1 is vital for their antioxidant activity.
Results and discussion
The synthesized benzamides are structurally similar to paracetamol based on the
hydroxyl group para to –NH – (core moiety of paracetamol) functionality. Paraceta-
mol is a widely used drug exhibiting antipyretic, analgesic, antioxidant, and antiin-
fammatory activities. Antioxidants are molecules that inhibit or quench free radical
reactions and delay or inhibit cellular damage. The title compounds were synthe-
sized in three steps as shown in Scheme 1. In the frst step, thymol (1) was treated
with sodium nitrite and conc. HCl at 0 °C to obtain intermediate 4-nitrosothymol
(2), which was further treated with ammonia and hydrogen sulfde at room tempera-
ture to obtain intermediate 4-aminothymol (3), which was further treated with vari-
ous benzoyl chlorides in neat phase at room temperature to obtain the fnal products
4a–e, which were crystallized from ethanol.
X
H
N
O
HO
4a-e
Scheme 1 Synthesis of thymol-based benzamide derivatives
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P. S. Sathe et al.
Biological evaluation
The antioxidant activity of compounds is related to their electron or hydrogen
radical releasing abilities with DPPH [21]. The mechanism of generation and the
stabilization of free radicals of the newly synthesized benzamides during the anti-
oxidant reaction are shown in Fig. 1. The DPPH radical scavenging activity of all
the compounds was found to be good to moderate. The presence of free phenolic
–OH and –NH–C=O groups in the benzamide might be the cause of such anti-
oxidant activity [22]. Compared with 4a, c, e, the percentage inhibition of com-
pounds 4b and 4d was closer to that of butylated hydroxytoluene (BHT) standard
at all concentrations. This may be due to the presence of ortho and para sub-
stituent on the phenyl ring, which infuences the antioxidant potency of the mol-
ecule, while compounds 4a, c, e exhibited inferior antioxidant activities (Fig. 2;
Table 1).
The results for the antibacterial activity revealed that all the synthesized com-
pounds showed less antibacterial activity compared with chloramphenicol against
only Staphylococcus aureus (Gram +ve bacteria), while the remaining com-
pounds did not show any antibacterial activity (Fig. 3).
Fig. 1 Proposed mechanism of formation and stabilization of free radical in benzamides
1 3

Synthesis, characterization, and antioxidant activity of…
Radical scavenging activity of benzamides
90
80
70
60
50
40
30
20
10
0
4a
4b
4c
4d
4e
BHT
Concentration μg/mL
0.5
2.5
5
10
20
Fig. 2 Percentage radical scavenging at diferent concentrations
Table 1 Antioxidant activity of benzamide series
Compound
Concentration (μg/mL)
0.5 2.5
5
10
20
4a
0.02 0.001
0.0187 0.0003
27.79 0.015
0.0162 0.0002
37.33 0.02
0.02 0.001
22.77 0.01
0.0181 0.004
30.11 0.015
0.0191 0.003
26.25 0.015
0.0056 0.0019
50.87 0.015
0.0173 0.0004
33.20 0.03
0.0151 0.003
41.69 0.01
0.019 0.001
26.64 0.02
0.017 0.001
34.36 0.020
0.0177 0.0001
31.66 .02
0.016 0.0003
38.22 0.015
0.0147 0.0003
43.24 0.01
0.0178 0.0004
31.27 0.015
0.0158 0.0003
38.99 0.020
0.0158 0.001
38.99 0.015
0.0036 0.0002
68.42 0.02
0.0141 0.0003
45.55 0.01
0.014 0.0002
45.94 0.015
0.0153 0.0002
40.92 0.02
0.0139 0.0001
46.33 0.03
0.0139 0.0001
47.10 0.02
Inhibition (%)
4b
Inhibition (%)
4c
Inhibition (%)
22.77 0.01
0.0177 0.0003
31.66 0.015
0.0212 0.00073
16.98 0.01
0.0196 0.00015
24.32 0.01
0.0205 0.010
20.84 0.01
4d
Inhibition (%)
4e
Inhibition (%)
BHT
Inhibition (%)
0.0074 0.00025
35.08 0.020
0.0042 0.0002
63.15 0.03
0.0027 0.00023
76.3 0.015
X‑ray Single‑crystal difraction studies
Crystal of suitable size was mounted on Bruker APEX-II CCD difractometer
equipped with graphite-monochromated Mo Kα radiation with wavelength of
0.71073 Å. The crystallographic parameters, data collection, and refnement are
summarized in the Electronic Supplementary Material. The single crystal of ben-
zamide demonstrated the monoclinic system in space group P21. The ORTEP
diagram with numbering is shown in Fig. 4, supporting the formation of the
expected benzamide [23, 24].
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P. S. Sathe et al.
Fig. 3 Antimicrobial susceptibility testing of synthesized compounds 4a–e against diferent bacterial and
fungal species
Fig. 4 Crystal structure (ORTEP plot) of 3-fuoro-N-(4-hydroxy-5-isopropyl-2-methylphenyl)benzamide
(4c), showing that benzene ring of the thymol moiety and that of benzamide portion are almost perpen-
dicular to each other
Molecular docking results
The docking of ligand molecules with human heme oxygenase-1 (3CZY) indicated
that all the derivatives exhibited bonding with one amino acid in the active pocket
(Fig. 5), thus being considered as good inhibitors of heme oxygenase-1 (3CZY). The
benzamide scafolds attached to the key residues GLY139, ASP140, and ARG136.
The docking score, model, and binding energy are recorded for analysis of the results
(Table 2). The theoretical outcomes highlight that the minimum binding energy
of all the molecules with the targeted enzyme is lower than biliverdin, suggesting
that the synthesized benzamides are good inhibitors of heme oxygenase-1 (3CZY).
1 3

Synthesis, characterization, and antioxidant activity of…
Fig. 5 A Biliverdin in complex with heme oxygenase-1 (hydrogen bond interaction with Arg 136 and
Gln 138); B compound 4a interacting with Gly 139; C compound 4b interacting with Asp 140; D com-
pound 4c interacting with Arg 136; E compound 4d interacting with Arg 136; F compound 4e interact-
ing with Arg 136 and Gly 139
Table 2 Docking results for
Sr. no.
Compound
Docking score
Binding energy
benzamides
01
02
03
04
05
06
4a
− 6.2345
− 8.9573
− 7.8224
− 9.2345
− 9.5643
− 11.23
− 45.1234
− 63.6753
− 61.3456
− 66.4573
− 68.3456
− 82.4532
4b
4c
4d
4e
Biliverdin
Therefore, it is noteworthy that these docking simulation results extend the scope of
development of thymol-based benzamide scafolds as promising antioxidant agents.
Materials and methods
Reagents and chemicals
All chemicals and reagents were procured from Sigma-Aldrich and Fisher Sci-
entifc with purity of 98% and used without further purifcation. The synthesized
compounds were characterized by using 1H, 13C NMR, IR spectra, and LC–MS. IR
spectra were recorded on an FTIR-8400 Shimadzu spectrophotometer. NMR spectra
(CDCl3) were recorded on a Bruker AC spectrophotometer (400 MHz for 1H NMR,
1 3

P. S. Sathe et al.
100 MHz for 13C NMR) with tetramethylsilane (TMS) as internal standard. The
crystal structure was examined using a Bruker APEX-II CCD difractometer.
General procedure for synthesis of 2‑isopropyl‑5‑methyl‑4‑nitrosophenol (2)
Synthesis of 2-isopropyl-5-methyl-4-nitrosophenol (2) was carried out using a previ-
ously reported method [25].
General procedure for synthesis of 4‑amino‑2‑isopropyl‑5‑methylphenol (3)
Synthesis of 4-amino 2-isopropyl-5-methylphenol (3) was carried out using a previ-
ously reported method [26].
General procedure for synthesis of benzamides 4a–e [27]
Benzamides were prepared by reacting equimolar quantities of 4-amino-2-isopro-
pyl-5-methylphenol (3) and substituted benzoyl chlorides in neat phase. The reac-
tion mixture was stirred for some time. Instantaneously it became hot with evolution
of HCl gas and became a solid mass or paste. Crushed ice was then added to the
contents of the beaker and stirred well with a glass rod. The thick reaction mixture
gradually became soft, and product began to deposit on the walls of the beaker by
dissolution of any hydrochloride adhered with the product or by gradual dispersion
of traces of benzoyl chloride in aqueous phase during stirring, and fnally the super-
natant aqueous layer became clear when precipitation of the product was complete
as a crystalline product. The reaction time usually ranged on average from 3–5 min.
The product was fltered and washed with water to free it from any adhering amine
hydrochloride, and further crystallized from ethanol to obtain the pure product.
N‑(4‑Hydroxy‑5‑isopropyl‑2‑methylphenyl)benzamide (4a) Molecular
formula:
C17H19O2N, molecular weight: 269, physical nature: white solid, melting point:
174–176 °C, yield: 86 (%); LC–MS m/z, found: 270 [M+1]. IR (cm−1): 3493
1
(O–H), 3290 (N–H), 2962 (C–H), 1643 (C=O), 1521, 1282. H NMR (CDCl3): δ
1.18 (6H, d, J=6.8 Hz), 2.15(3H, s), 3.23 (1H, m) 6.68 (1H, s), 7.05 (1H, s), 7.48
(3H, m), 7.98 (2H, d, J=7.2 Hz), 8.80(1H, s), 9.40 (1H, s). 13C NMR (CDCl3):
δ 17.33, 22.28, 26.10, 116.33, 124.17, 127.16, 127.87, 130.79, 131.61, 132.11,
134.56, 152.37, 165.76.
2‑Fluoro‑N‑(4‑hydroxy‑5‑isopropyl‑2‑methylphenyl)benzamide (4b) Molecular for-
mula: C17H18O2NF, molecular weight: 287, physical nature: white solid, melting
point: 114–116 °C, yield: 90 (%); LC–MS m/z found: 288 [M+1]. IR (cm−1): 3400
1
(O–H), 3307 (N–H), 2945, 1614 (C=O), 1546-1413, 1209. H NMR (CDCl3): δ
1.21 (6H, d, J=8 Hz); 2.17 (3H, s), 3.16 (1H, m), 6.39 (1H, s), 6.51 (1H, s), 7.19
(1H, m), 7.25 (1H, m), 7.33 (1H, s), 7.55 (1H, m), 8.21 (2H, m). 13C NMR (CDCl3):
1 3

Synthesis, characterization, and antioxidant activity of…
δ17.49, 22.56, 26.78, 116.02, 117.48, 121.12, 123.12, 125.11, 127.45, 130.30,
132.42, 133.69, 151.81, 159.47, 161.92 (JCF=245 Hz), 162.41.
3‑Fluoro‑N‑(4‑hydroxy‑5‑isopropyl‑2‑methylphenyl)benzamide (4c) Molecular for-
mula: C17H18O2NF, molecular weight: 287, physical nature: white solid, melting
point: 170–172 °C, yield: 60 (%); LC–MS m/z found: 288 [M+1]. IR (cm−1): 3294
(O–H), 3196 (N–H), 3076, 1643 (C=O), 1585, 1282-1228, 1188. 1H NMR(CDCl3):
δ 1.18 (6H, d, J=8 Hz),2.14 (3H, s), 3.22 (1H, m), 6.68 (1H, s),7.01 (1H, s), 7.24
(1H, m), 7.45 (1H, m), 7.75 (1H, dd, J=11 and 4 Hz), 7.83 (1H, t, J=8 Hz), 8.81
(1H, s), 9.56 (1H, s). 13C NMR (CDCl3): δ 17.37, 22.31, 26.08, 114.24, 117.75,
123.15 124.39, 126.89, 129.69, 131.94, 136.82, 152.60, 160.76 (JCF=245 Hz),
163.20, 164.29.
4‑Fluoro‑N‑(4‑hydroxy‑5‑isopropyl‑2‑methylphenyl)benzamide (4d) Molecular for-
mula: C17H18O2NF, molecular weight: 287, physical nature: white solid, melting
point: 176–178 °C, yield: 99 (%); LC–MS: m/z found 288[M+1]. IR (cm−1): 3400
1
(O–H), 3236 (N–H), 2964 (C–H), 1643 (C=O), 1600-1477, 1290, 1240, 1097. H
NMR (CDCl3): δ 1.19 (6H, d, J=8 Hz), 2.15 (3H, s), 3.23 (1H, m), 6.69 (1H, s),
7.10 (3H, m), 8.03 (2H, dt, J=11 and 4 Hz), 8.63 (1H, s), 9.21 (1H, s). 13C NMR
(CDCl3): δ 17.28, 22.24, 26.08, 114.80, 116.36, 124.23, 126.94, 129.56, 130.70,
131.74, 132.18, 152.43, 162.74 (JCF=245 Hz), 163.68, 164.71, 165.23.
2,6‑Difuoro‑N‑(4‑hydroxy‑5‑isopropyl‑2‑methylphenyl)benzamide
(4e) Molecular
formula: C17H17O2NF2, molecular weight: 305, physical nature: white solid, melt-
ing point: 168–170 °C, yield: 92 (%); LC–MS m/z found: 306 [M+1]. IR (cm−1):
1
3263 (O–H), 3194 (N–H), 3034, 2962, 1639(C=O), 1529-1346, 1220, 1197. H
NMR (CDCl3): δ 1.18 (6H, d, J=8 Hz), 2.17 (3H, s), 3.20 (1H, m), 7.04 (2H, t,
J=7.6 Hz), 7.44 (1H, m), 8.92 (1H, s), 9.74 (1H, s). 13C NMR (CDCl3): δ 17.34,
22.00, 25.30, 111.43, 115.66, 116.36, 123.87, 126.31, 130.81, 131.33, 132.00,
152.69, 157.89, 158.63, 160.38 (JCF=245 Hz), 162.68.
Bioassay
Antioxidant activity
The in vitro antioxidant properties of the newly synthesized compounds 4a–e at
diferent concentrations were examined by a well-documented reported assay, viz.
DPPH free radical scavenging assay. The synthesized compounds and standard
(butylated hydroxytoluene) were assessed based on their radical scavenging efect
of the stable DPPH free radical. The absorbance of each solution was determined
at 519 nm using spectrophotometer. DPPH solution (100 ppm) in methanol was
prepared, and 1.0 mL was added to solutions of compound at diferent concen-
trations. Thirty minutes later, the absorbance was determined. The antioxidant
1 3

P. S. Sathe et al.
activities of the compounds are related to their electron or hydrogen radical
releasing abilities for DPPH [28]. All determinations were carried out in tripli-
cate. The radical scavenging activity was expressed as % inhibition of DPPH.
DPPH radical scavenging activity (%)=[Abs(control) −Abs(sample)]×100/Abs(control)
,
where Abs(control) is the absorbance of DPPH radical+methanol and Abs(sample) is the
absorbance of DPPH radical+extract/standard.
Antimicrobial activity
The agar well difusion method [29] was used for determination of antimicrobial
activity of compounds 4a–e against four bacterial and one fungal strain, viz. Staphy-
lococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and
Aspergillus niger. Stock solution of 1000 micrograms per milliliter of each com-
pound in dimethylsulfoxide (DMSO) was taken, and the assay carried out by tak-
ing 100 micrograms per disk. HiMedia antibiotic disk containing chloramphenicol
(10 µg/disk) and amphotericin B (100 units/disk) was moistened with water and
used as standard. All bacterial and fungal strains were incubated at 28 °C. The aver-
age diameter of inhibition zone surrounding the wells was measured in mm [30].
Molecular docking
Docking study was performed under the Windows XP operating system, using
Glide and QuickPro module (Schrodinger, LLC, New York, USA, 2008). An ear-
lier reported protein structure of keap1 (PDB ID: 1s8c) was used for grid genera-
tion. Benzamides were optimized using LigPrep 2.2, and conformers were generated
using a “rapid torsion angle” search approach, followed by minimization of each
generated structure using the Merck Molecular Force Field (MMFF). The crystal
structure of the heme oxygenase-1 complex [PDB: 1s8c] was obtained from the Pro-
tein Data Bank (PDB). The protein structure of heme oxygenase-1 complex consists
of four chains. Protein preparation was carried out using the protein preparation wiz-
ard in Maestro 8.0 in two steps: preparation and refnement. After ensuring chemical
correctness, water molecules in the crystal structures were deleted, and hydrogens
were added, wherever necessary. Using the OPLS 2005 force feld, the energy of
the crystal structure was minimized. To study the interaction of the compounds with
heme oxygenase-1, the molecules were selectively docked on a chain representing
where biliverdin is bound, using the extra precision (XP) docking mode. The fnal
evaluation was done based on the glide score (docking score), and the single best
pose was generated as the output for a particular ligand [31–34].
Conclusions
Novel benzamides were synthesized from thymol using a three-step pathway with
good practical yield and screened for their in vitro antioxidant and antibacterial
activities. The results revealed that all the synthesized compounds exhibited nota-
ble antioxidant activity and antibacterial activity against Staphylococcus aureus
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Synthesis, characterization, and antioxidant activity of…
(Gram +ve bacteria). Thus, hybrids prepared using these structural motifs could
also lead to potent biologically active agents; such compounds would represent a
proftable matrix for development of a new class of antioxidant agents from phe-
nolic monoterpenes.
Acknowledgements The authors are grateful to UGC SAP (New Delhi) for providing fnancial
assistance.
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