Novel ketoprofen–antioxidants mutual codrugs as safer nonsteroidal anti-inflammatory drugs: Synthesis, kinetic and pharmacological evaluation

Article abstract of DOI:10.1002/ardp.201800339

Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs

Full text of DOI:10.1002/ardp.201800339

Received: 13 December 2018
DOI: 10.1002/ardp.201800339
Revised: 2 April 2019
Accepted: 3 April 2019
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F U L L P A P E R
Novel ketoprofen–antioxidants mutual codrugs as safer
nonsteroidal anti‐inflammatory drugs: Synthesis, kinetic and
pharmacological evaluation
Shikha Sehajpal1*
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Deo Nandan Prasad2
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Rajesh K. Singh2
1Department of Pharmaceutical Chemistry,
Gujranwala Guru Nanak Khalsa College of
Pharmacy, Civil Lines, Ludhiana, Punjab, India
Abstract
Ketoprofen belongs to one of the most common nonsteroidal anti‐inflammatory drugs
(NSAIDs) but its clinical usefulness has been restricted due to the high incidence of
gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs
therapy plays a major role in causing gastric complications. Antioxidants not only prevent
gastric ulceration and lipid peroxidation but also preserve glutathione‐type peroxidase
(GPO) activity. Therefore, the present study investigates the utility of combining anti‐
inflammatory and antioxidant properties of two different compounds in a single molecule
to form a series of 16 ketoprofen–antioxidant mutual codrugs. The free carboxylic group,
which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked
temporarily by simple and double esterification with alcoholic/phenolic–OH of natural
antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants
(IIa–h) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the
in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen‒
antioxidant through the glycolic acid spacer (–CH2COO; IIIa–h), have also been designed
2Department of Pharmaceutical Chemistry,
Shivalik College of Pharmacy, Rupnagar,
Punjab, India
Correspondence
Rajesh K. Singh, Department of
Pharmaceutical Chemistry, Shivalik College of
Pharmacy, Nangal, 140126, Dist, Rupnagar,
Punjab, India.
Email: rksingh244@gmail.com
1
and synthesized. The synthesized codrugs were characterized by IR, H NMR, 13C NMR,
mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the
lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen
at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t1/2
.
The pharmacological evaluation results indicate that these ketoprofen‒antioxidant mutual
codrugs showed the retention of anti‐inflammatory and analgesic activity with a significant
reduction in the ulcer index.
K E Y W O R D S
analgesic, anti‐inflammatory, antiulcer, codrug, enzymatic hydrolysis, ketoprofen
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1
INTRODUCTION
anti‐inflammatory effect in the management of inflammation and
pain in rheumatologic conditions like rheumatoid arthritis, osteoar-
Nonsteroidal anti‐inflammatory drugs (NSAIDS) belong to one of the
most common therapeutically used group of agents in the world for
their analgesic, antipyretic, anti‐thrombogenic effects other than the
thritis, ankylosing spondylitis, gout, and musculoskeletal disorders.[1]
However, the usefulness of NSAIDs is restricted due to the higher
prevalence of gastrointestinal adverse effects including gastric
ulceration, perforation, and their associated complications.[2] Both
therapeutic and side effects of NSAIDs are dependent on cycloox-
ygenase (COX) inhibition[3–5] that results in the inhibition of
*Current address: Research Scholar, Faculty of Pharmacy, I.K. Gujral Punjab Technical
University, Jalandhar, India.
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Arch. Pharm. Chem. Life Sci. 2019;e1800339.
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prostaglandin (PG) synthesis and the reduced PG levels in GIT results
in NSAIDS induced gastropathy as PGs preserve gastric mucosal
blood flow, enhance protective mucus, as well as bicarbonate release,
inside the gastric milieu.[6,7] Various studies revealed that GI
intolerance and poor patient compliance are the major limitations
of NSAIDS therapy and, therefore, to design and develop gastric‐
sparing and gastro‐protecting NSAIDS is a hot area of drug research.
Since the last two decades, NSAIDs have been altered in varied ways
with the aim of designing safe, more effective NSAIDs with reduced
GI toxicity.[8] These approaches include:
ibuprofen,[26] and mefenamic acid[27,28] have been successfully
synthesized with promising results. Because of the benefits of this
approach, various codrugs of NSAIDs have been developed that
are being used clinically and available in the market as shown in
Figure 1.
Ketoprofen is one of the most effective NSAIDs. Besides,
inhibiting PG at the central level, it also activates the serotonergic
mechanism and releases 5‐hydroxytryptamine (serotonin).[29] Thus, it
has superiority over other NSAIDs in treating various neurodegen-
erative diseases like Alzheimer's and Parkinsonism.[30] Its new role
has also been discovered in cancer,[31,32] cardiac,[33] and cerebrovas-
cular[34] diseases. But due to its adverse GI side‐effect on long‐term
use, ketoprofen is not superior to other NSAIDs despite having a dual
effect on PGs and LTs.
1. Design of selective COX‐2 inhibitors with decreased gastric
toxicities[9–11] but there has been an associated risk of
potential liver toxicity and cardiovascular complication[12]
leading to the withdrawal of some potent COX‐2 selective
inhibitors.[13]
It has been well documented that the release of reactive oxygen
species (ROS) plays a vital role in the forming of gastric mucosal
lesions due to NSAIDs therapy.[35] The metabolism of arachidonic
acid, platelets, macrophages, and smooth muscles generate ROS that
may contribute to gastric mucosal damage. NSAIDs affect a variety of
enzyme systems, resulting in an increased ROS concentration within
the cell, with irreversible damage to lipids, proteins, nucleoproteins,
and DNA.[36] Literature study revealed that antioxidants, such as
GSH (glutathione), vitamin E, vitamin C, not only prevent gastric
ulceration and lipid peroxidation but also preserve glutathione‐type
peroxidase (GPO) activity. Hence, it is appropriate to coadminister
the NSAIDs and antioxidants in the form of a single chemical entity
called codrug in which two different compounds having synergistic
therapeutic activity are combined in one molecule. It is suggested
that these codrugs having two pharmacologically synergistic proper-
ties, anti‐inflammatory and antioxidant activity, will result in the
development of more efficacious safer NSAIDs[23,24] by masking
carboxylic group (–COOH). In view of the fact that the GI‐adverse
effects of most NSAIDs having a carboxylic group are largely due to
local phenomenon/direct irritant action.[37]
2. Combining both COX and 5‐lipooxygenase (5‐LOX) dual inhibitors
as it is believed that dual inhibition of both leukotrienes (LTs) and
PGs synthesis may lead to enhanced and wider anti‐inflammatory
activity with less gastric side effects.[14] Results with dual COX/5‐
LOX inhibitors seem to be promising but large numbers of clinical
trials are required to evaluate the safety and efficacy of these
agents.[15–17]
3. Design of nitric oxide‐releasing NSAIDs,[18,19] which were based
on the fact that nitric oxide (NO), is an endogenous gaseous
mediator of GI mucosal defences.[20,21] But recent studies
indicated the possibility of NO‐involvement in the pathogenesis
of arthritis and subsequent tissue destruction.
4. Design of prodrugs of NSAIDS in which two different therapeutic
agents with corresponding pharmacological properties are com-
bined to produce a single chemical entity (a hybrid). This approach
is used to alter the properties of the parent drugs temporarily
with the aim of increasing their usefulness and reducing their
toxic and unwanted side effects.[17,22] Mutual codrugs of various
NSAIDs, such as flurbiprofen,[23] aceclofenac,[24] diclofenac,[25]
FIGURE 1 List of some clinically available prodrugs of NSAIDs. NSAIDs: nonsteroidal anti‐inflammatory drugs

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In the present study, we envisage designing various codrugs of
COX‐1 site.[43] This explains their better analgesic and anti‐
inflammatory activities with reduced GI‐toxicities. Based on these
facts, various ketoprofen–phytophenols/alcohol ester codrugs were
synthesized without spacer (IIa–h) and with the glycolic (–OCH2-
COO–) linkage double ester derivatives (IIIa–h) as per Scheme 1.
Sometimes simple aliphatic/aromatic esters may not be sufficiently
labile in vivo.[32] So as to ensure sufficiently high rate and extent of
release of parent drug from the codrug, double ester codrug
approach is used in which the terminal ester group is sterically less
hindered due to the presence of glycolic acid spacer –OCH2-
COO.[25,44,45] All the prepared sixteen codrugs were evaluated for
their solubility, lipophilicity, and stability study in different gastric
simulated fluids. They were also investigated for their anti‐
inflammatory, analgesic, antiulcer, and antioxidant properties. These
ketoprofen–antioxidant codrugs are likely to be absorbed through
the GIT in an inactive form and release the parent ketoprofen and
the antioxidant (phytophenols/alcohols) after enzymatic cleavage.
ketoprofen by chemical combination with various antioxidants for
increasing efficacy and reducing side‐effects of ketoprofen. To fulfill
the above objectives, we have used various natural antioxidants, such
as thymol, guaiacol, eugenol, vanillin, sesamol, curcumin, gallic acid,
and the phytoalcohol, including menthol to combine with ketoprofen.
Literature studies reveal the analgesics, anticarcinogenic, anti‐
inflammatory, and antioxidant properties of these natural antiox-
idants.[38–40] These herbal antioxidants are being used as food
additives for ages so they have proven safety.[41] In our previous
work, we have found that ketoprofen linked to antioxidants through
glycolic spacer showed encouraging results.[42] Hence, in this study,
we have designed and synthesized different ester codrugs of
ketoprofen with various other antioxidants. It has already been
studied that conversion of conventional NSAID to the ester
derivatives increases the size of the molecule that causes the
molecule to be selective fits into COX‐2 active site compared with
FIGURE 2 Proposed mechanism of codrug activation inside the body

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SCHEME 1 Sequence of steps for the synthesis of ketoprofen–antioxidants (IIa–h) and ketoprofen–OCH2COO–antioxidants (IIIa–h) mutual
codrugs
That may evade gastric side‐effects through masking of the
carboxylic group of ketoprofen and through the antioxidant proper-
ties by quenching ROS (Figure 2).
absorption of drugs molecules in vivo.[46] The partition coefficient is
the measure of the lipophilicity of the drug. Absorption is increased
by high lipophilicity of drugs so the partition coefficient. The
solubility of 10 μg/ml drug and a partition coefficient of 100 or more
(i.e., log P > 2) are found to be optimum for the drugs to be
bioavailable effectively after oral administration. Limited solubility
(≤1%) in GI fluids resulted in poor GI‐absorption. For the lipophilicity
measurements, the octanol/water partition coefficient P and log P are
used which is calculated as:
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2
RESULTS AND DISCUSSION
Solubility and partition coefficient
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2.1
The physicochemical properties like solubility and partition coeffi-
cient influence the therapeutic efficacy and pharmacokinetic profile
of drugs. For codrugs to be bioavailable, they should have optimum
solubility and lipophilicity. Therefore, these physicochemical proper-
ties have been taken into account while predicting the passive
Partition coefficient (P)
Concentration of drug in octanol × Dilution factor
=
Concentration of drug in buffer

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TABLE 1 Rf values, % yield, solubility, and log P of the ketoprofen–antioxidants codrugs (IIa–h)
S. No
Compound
Standard (I)
K‐T (IIa)
Ar/R
Rf‐value
0.5
Yield (%)
Solubility (μg/ml) (pH = 7.4)
Log P
3.21
6.38
1
2
H
–
51
0.45
49.2
5.67
3
4
K‐G (IIb)
K‐M (IIc)
0.95
0.82
43.4
38.5
12.46
9.86
4.83
5.99
5
6
K‐V (IId)
K‐E (IIe)
0.81
0.41
46.5
51.7
13.39
9.68
4.71
5.74
7
8
K‐Se (IIf)
K‐Cu (IIg)
0.39
0.64
45.3
46.2
12.05
12.16
4.12
5.37
9
K‐Ga (IIh)
0.90
39.8
11.73
3.28
Ketoprofen has limited solubility so its ester codrugs were
prepared and they were found to have a fair solubility in phosphate
buffer (pH = 7.4) and greater lipophilicity than ketoprofen. The
results for solubility and partition coefficient studies for ketopro-
fen–OCH2COO–phytophenols/alcohol are given in Table 1 and Table
2. From the results, it is clear that the prepared ketoprofen codrugs
are suitable for oral administration.
the kinetic studies were carried out in triplicate. The k values from
the plot were calculated separately and the average and
k
standard deviation value was determined. Pseudo‐first‐order rate
constants for the appearance of ketoprofen in different media
were determined by linear regression analysis of the plot of log
concentration of ketoprofen versus time. The observed rate
constant of hydrolysis (Kobs) was calculated from the slope of
the curve, and the half‐life was calculated according to the
following equation that derivative from the first order kinetic law:
Kobs = slope × 2.303 and t1/2 = 0.693/Kobs
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2.2
Kinetics of hydrolysis studies in SIF and 80%
human plasma
The results are collected in Table 3 and Table 4 showing the
calculated half‐lives for codrugs in different media. It is revealed that
these codrugs (IIa–h) were chemically stable in pH 7.4 and pH 1.2
with half‐lives ranging from 28–44 hr to 74–128 hr, respectively. In
the case of ketoprofen–OCH2COO–phytophenols/alcohol mutual
codrugs (IIIa–h), the t1/2 in phosphate buffer (pH7.4) and pH 1.2 were
found to be 35–48 hr and 81–124 hr, respectively. It can be
concluded that the synthesized codrugs are relatively stable in pH
1.2 and 7.4 and, hence, suitable for oral administration.
It is the crucial requirement of any codrugs/codrugs to remain
chemically stable at the undesired site and rapidly undergo
enzymatic cleavage at the desired site to release the parent drug.
Accordingly, our synthesized codrugs, during their passage
through the gastric tract should be chemically stable and should
be hydrolyzed to parent drug after absorption in the blood.
Therefore, these codrugs were subjected to various in vitro
hydrolysis studies to evaluate their stability in simulated gastric
fluid and blood plasma. In this study, UV spectrophotometer was
used to detect and monitor the hydrolysis of tested codrugs. All
The rate constants and t1/2 for ketoprofen–phytophenols/
alcohol mutual codrugs in plasma (80%, pH 7.4) were found in the

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TABLE 2 Rf values, % yield, solubility, and log P of the ketoprofen–OCH2COO–antioxidants (IIIa–h) mutual codrugs
S. No
Compound
Ar/R
Rf‐value
Yield (%)
Solubility (μg/ml) (pH = 7.4)
Log P
1.
KTS (IIIa)
0.63
56.4
5.06
6.09
2.
3.
KGS (IIIb)
KMS (IIIc)
0.54
0.79
48.3
42.6
10.37
7.81
4.23
5.76
4.
5.
KVS (IIId)
KES (IIIe)
0.72
0.63
52.5
48.9
12.52
7.89
4.21
5.16
6.
7.
8.
KSeS (IIIf)
KCuS (IIIg)
KGaS (IIIh)
0.41
0.39
0.51
54.1
42.8
43.7
10.17
8.94
9.25
4.39
5.67
3.35
Note. KCuS: ketoprofen–curcumin with spacer; KES: ketoprofen–eugenol with spacer; KGaS: ketoprofen–gallic acid with spacer; KGS: ketoprofen–guaiacol
with spacer; KMS: ketoprofen–menthol with spacer; KSeS: ketoprofen–sesamol with spacer; KTS: ketoprofen–thymol with spacer; KVS: ketoprofen–vanillin
with spacer.
range of 0.367–0.537 hr−1 and 21.99–32.23 hr, respectively. The
result suggests that the mutual codrugs are readily hydrolyzed in
plasma to release the parent NSAID. In comparison to the rate of
hydrolysis in SGF (pH 1.2) and hydrolysis in SIF (pH 7.4), the rate
of hydrolysis in plasma is faster showing that the enzymatic
reactivities of codrugs are greater than their respective pH
reactivity.
2.3
Biological evaluation/ pharmacological
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studies
The ketoprofen was combined with the natural antioxidants to design
codrugs in the hope to develop novel molecules having improved
anti‐inflammatory and analgesic activity and devoid of gastric side‐
effects. Hence, these codrugs were evaluated for anti‐inflammatory,
TABLE 3 In vitro hydrolysis/chemical stability rates of ketoprofen–phytophenols/alcohol mutual codrugs (IIa–h)
Compound
KT (IIa)
KpH7.4 (hr−1) × 10−3
T1/2(pH7.4) (hr)
400.58
KpH1.2 (hr−1) × 10−4
T1/2(pH1.2) (hr)
1174.58
1386.00
1136.06
1082.82
1117.74
1019.12
949.32
KPlasma (hr−1
1.17
)
T1/2Plasma (min)
35.54
1.73
1.82
3.43
1.86
1.97
1.79
1.58
1.97
5.9
5.0
6.1
6.4
6.2
6.8
7.3
7.9
KG (IIb)
KM (IIc)
KV (IId)
KE (IIe)
380.77
1.13
36.80
202.04
1.29
32.23
372.58
1.25
33.26
351.78
1.36
30.57
KSe (IIf)
KCu (IIg)
KGa (IIh)
387.15
1.33
31.26
441.40
1.27
32.74
351.77
877.21
1.47
37.13
Note. KCu: ketoprofen–curcumin; KE: ketoprofen–eugenol; KGa: ketoprofen–gallic acid; KG: ketoprofen–guaiacol; KM: ketoprofen–menthol; KSe:
ketoprofen–sesamol; KT: ketoprofen–thymol; KV: ketoprofen–vanillin.

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TABLE 4 In vitro hydrolysis/chemical stability rates of ketoprofen–OCH2COO‐phytophenols/alcohol mutual codrugs (IIIa–h)
Compound
KTS (IIIa)
KGS (IIIb)
KMS (IIIc)
KVS (IIId)
KES (IIIe)
KSeS (IIIf)
KCuS (IIIg)
KGaS (IIIh)
KpH7.4 (hr−1) × 10−3
T1/2(pH7.4)
360.94
422.56
244.01
357.22
285.18
366.67
378.69
320.83
KpH1.2 (hr−1) × 10−4
T1/2(pH1.2)
1136.07
1215.79
597.41
KPlasma (hr−1
)
T1/2Plasma (min)
28.28
1.92
1.64
2.84
1.94
2.43
1.89
1.83
2.16
6.1
5.7
1.47
1.39
29.91
11.6
6.9
1.71
24.32
1004.35
815.29
1.38
30.13
8.5
1.69
24.6
7.1
976.06
1.44
28.88
7.6
911.84
1.63
25.51
8.1
855.56
1.41
29.49
Note. KCuS: ketoprofen–curcumin with spacer; KES: ketoprofen–eugenol with spacer; KGaS: ketoprofen–gallic acid with spacer; KGS: ketoprofen–
guaiacol with spacer; KMS: ketoprofen–menthol with spacer; KSeS: ketoprofen–sesamol with spacer; KTS: ketoprofen–thymol with spacer; KVS:
ketoprofen–vanillin with spacer.
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Analgesic activity
analgesic and GI‐ulceration properties. Institutional Animal Ethics
Committee approves the experimental protocol and written permis-
sion has been taken from the in‐house ethics committee (CPCSEA/
SCOP/2017/IAEC/10/02) to complete this study.
2.3.2
Ketoprofen shows major inhibition in writhing at 20 mg/kg dose. The
results are shown in Table 5. Lower analgesic activities are shown by
codrugs K‐T and K‐M in equimolar doses. The codrug K‐G showed a
similar analgesic effect to that of parent NSAID ketoprofen. The
other codrugs (K‐E, K‐V, K‐Se, KCu, and KGa) showed significant
analgesic activity than that of the standard (ketoprofen). In the
results of with glycolic (–CH2COO) spacer codrug derivatives the
codrugs KTS, KMS, KGS, KVS, and KES showed lesser analgesic
activity than that of the parent NSAID, ketoprofen. But the codrugs
KSeS, KCuS, and KGaS showed analgesic activity comparable to that
of ketoprofen.
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2.3.1
Anti‐inflammatory activity
Tissue damage by infection, inflammation, trauma, etc. results in
increased production of various inflammatory mediators like PGs, LTs,
cytokines, ROS, etc. When the pro‐oxidant conditions dominate either
due to increased generation of the free radicals or due to poor
scavenging of the free radicals due to deficiency of endogenous or
dietary antioxidants, then it leads to tissue injury and subsequent
diseases. Although oxidative stress is a secondary event to many
inflammatory reactions it plays an important role in furthering the
tissue injury. Hence, the concomitant administration of an antioxidant
with an NSAID increases their anti‐inflammatory action.[47–49] The
results of left hind paw edema test for the codrugs with the spacer and
without spacer are as given in Table 5. The codrugs K‐V, K‐E, K‐Se,
K‐Cu, and K‐Ga showed increased anti‐inflammatory activity to the
standard (ketoprofen). This may be due to the antioxidant activity of
the phytophenolic promoiety. The codrugs K‐V and K‐G showed
comparable activity to that of the standard (ketoprofen) and the
codrugs K‐M and K‐T showed significantly lesser activity as compared
to standard (ketoprofen) that may be due to the lower antioxidant
profile of menthol/thymol promoieties, respectively. The mutual
codrugs of ketoprofen–phytophenols/alcohol with the –CH2COO–
spacer (KTS, KGS, KMS, KVS, KES, KSeS, KCuS, and KGaS) have been
evaluated for their anti‐inflammatory activity at equimolar doses to
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2.3.3
Antiulcer/gastrointestinal erosion assay
The results showed that there is a significant reduction in the ulcer
index as compared with the parent NSAID, ketoprofen (Table 6,
Table 7). There is a marked decrease in ulcer index of the codrugs
(for both with the spacer and without spacer derivatives). The
codrugs K‐Se, K‐Cu, and K‐Ga showed the maximum decrease in
ulcer index whereas the codrugs derivatives with thymol and
menthol showed lesser antiulcer activity as compared with the
derivatives with sesamol, eugenol, vanillin, curcumin, and with gallic
acid. The antiulcer activity of these test compounds are directly
related to their respective antioxidant potential. KTS and KMS
showed lesser antiulcer activity (higher ulcer index 2.64 and 2.93) as
compared with KGS, KCuS, KGaS, KGS, and KSeS (antioxidant
potential). This significantly reduced ulcer index may be due to the
combined effect of antioxidant properties of the promoieties and
masking of the free carboxylic group of the parent NSAID (combined
synergistic effects).
ketoprofen (20 mg/kg). KES, KSeS, KCuS, and KGaS showed
a
significant increase in anti‐inflammatory activity. KVS and KGS
showed a lesser increase in activity, whereas KMS and KTS showed
comparable activity than ketoprofen. This increased activity may be
due to the antioxidant profile of their promoiety. The introduction of
–OCH2COO– spacer showed an increase in activity compared with
the activity of simple ester codrugs without the spacer. This may be
due to better release profile of spacer codrugs in human plasma, as
shown by stability studies data.
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2.3.4
Antioxidant studies (in vitro)
In addition to NSAIDs induced GI‐pathogenesis due to PG inhibition
(PG induce the synthesis of protective mucus), generation of ROS
(reactive oxygen species) also plays an important role in the

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TABLE 8 % DPPH radical scavenging
TABLE 6 Grades for the observed lesions
Compounds
% Scavenging (DPPH*)
47.10 2.16
79.55 2.45
6.59 1.52
Grades
[0]
Lesions
Guaiacol
Normal colored stomach
Red coloration
Eugenol
[0.5]
[1.0]
[1.5]
[2.0]
[3.0]
Vanillin
Spot ulcers
Menthol
5.23 0.06
Hemorrhagic streaks
Ulcer >3 but <5
Ulcers >5
Sesamol
46 2.36
Thymol
14.77 1.01
70.45 0.09
46.48 1.12
94.27 1.67
GA
Curcumin
pathogenesis of GI ulceration, which is proven by various studies. The
ester codrugs of NSAIDs with phytophenols/alcohol are prepared
with the aim to have an antioxidant action of phytophenols/alcohol
to counteract this side effect of NSAIDs. Antioxidant studies (in vitro)
were done (Table 8) to find out whether the prepared codrugs
possess antioxidant properties. Among the antioxidants tested,
eugenol and gallic acid have antioxidant activity compared with
vitamin C, whereas guaiacol and curcumin have lesser antioxidant
activity but better activity than menthol, vanillin, and thymol.
Vit. C (standard)
*p < 0.05 as compared to control.
optimum physicochemical properties like solubility and partition
coefficient, suggesting their improved bioavailability. The absence of
gastric damage in all the cases of codrug derivatives (with and
without spacer) may be due to the combined effect of the antioxidant
activity of the phytophenols/alcohol promoieties as well as the
masking of the –COOH group of the NSAID. It has been concluded
that there is a definite advantage of administering these codrugs for
the treatment of chronic inflammatory disorders like rheumatoid
arthritis, osteoarthritis, Alzheimer’s disease, cancer, etc. Further, the
introduction of –OCH2COO– spacer did not show a significant
increase in the activity but retained the activity of the parent
ketoprofen with reduced gastric side‐effects. They showed better
activity than that of respective simple ester (without spacer) codrugs.
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3
CONCLUSION
The synthesis of various mutual codrugs of ketoprofen–antioxidant
has been done by using those naturally occurring phytophenols/
alcohols that have proven therapeutic utility in various inflammatory
conditions. It has been observed that codrugs synthesized were of
TABLE 7 Acute antiulcer/gastrointestinal erosion assay (GIER) studies of ketoprofen–antioxidants (IIa–h) and ketoprofen–OCH2COO–
antioxidants (IIIa–h) mutual codrugs of ketoprofen
S.NO.
Treatment
Molar equivalent dose mg/kg, p.o.
Ulcer index mean EM
0.18 0.06
1
2
3
4
5
6
7
8
Control
0.5%
80
Standard (ketoprofen) Without spacer prodrugs
K‐G (ketoprofen‐guaiacol prodrug)
K‐V (ketoprofen–vanillin prodrug)
4.27 0.63*
121.52
122.16
125.92
117.72
190.12
133.96
1.88 0.54**
1.57 0.63**
1.98 0.84**
1.76 0.39**
1.17 0.28**
1.58 0.12**
K‐E (ketoprofen–eugenol prodrug)
K‐Se (ketoprofen–sesamol prodrug)
K‐Cu (ketoprofen–curcumin prodrug)
K‐Ga (ketoprofen–gallic acid prodrug)
With spacer prodrugs
9
KTS (ketoprofen‐OCH2COO‐thymol prodrug)
KVS (ketoprofen‐OCH2COO‐vanillin prodrug)
KES (ketoprofen‐OCH2COO‐eugenol prodrug)
KMS (ketoprofen‐OCH2COO‐menthol prodrug)
KCuS (ketoprofen‐OCH2COO‐curcumin prodrug)
KSeS (ketoprofen‐OCH2COO‐sesamol prodrug)
KGaS (ketoprofen‐OCH2COO‐gallic acid prodrug)
KGS (ketoprofen‐OCH2COO‐guaiacol prodrug)
139.76
140.40
144.16
141.16
208.36
133.96
146.08
131.6**
2.64 0.21**
1.24 0.39**
1.63 0.15**
2.93 0.41**
0.95 0.33**
0.96 0.51**
1.03 0.25**
1.73 0.46**
10
11
12
13
14
15
16
*p < 0.05 as compared to control.
**p < 0.05 as compared to standard.

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SEHAJPAL ET AL.
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In conclusion, the results are promising and indicate that these
codrugs showed the retention of anti‐inflammatory and analgesic
activity with a significant reduction in ulcer index. Still, we hope that
the outcome of this study endows with an indispensable knowledge
base for the prospective design of novel safer NSAIDs.
carbonate solution (3 × 25 ml), distilled water (3 × 25 ml), HCl (5%,
3 × 50 ml), NaOH (5%, 3 × 50 ml), and finally with brine solution
(2 × 50 ml) and dried over sodium sulfate to get gummy residue. Then
the product was purified by column chromatography with gradient
elution with methanol in chloroform (up to 10%) using silica gel
(80–120 mesh), to obtain the final product (IIa–h) (Table 1).
|
4
EXPERIMENTAL
Chemistry
|
4.1.3
Chemical characterization of the synthesized
codrugs‐antioxidant codrugs without a spacer (IIa–h)
|
4.1
Ketoprofen, 2‐(3‐benzoylphenyl)propanoic acid (I)
|
4.1.1
General
IR (KBr, νmax, cm−1): 3054 (OH, ‐COOH), 2995–3000 (CH, Ar), 2880
(CH), 1655, 1697 (C=O), 1420, 1445 (C‐C), 1285 (C‐O), 966 (O‐H),
716 (CH “oop” Ar). 1H‐NMR (CDCl3): δ 11 (1H, s, ‐COOH), 7.5–7.8
(9 H, m, ArH), 3.9–4.3 (1H, q, ArH), 1.6 (3H,d, CH3). 13C‐NMR (in
ppm): 14 (CH3CH), 426 (CHCH3), 130–135 (ArCs), 142 (ArC=OAr).
Ketoprofen was obtained from Infinity Laboratories Pvt. Ltd., Derabassi.
All the phytoalcohols/phenols were purchased from S.D. Fine Chemicals
Ltd. and from Loba Chemie. The melting points were determined on
Veego melting point apparatus and are uncorrected. 1H‐NMR and
13C‐NMR spectra were obtained using Bruker AC‐400 F, 400 MHz
spectrometer and are reported in parts per million (ppm), downfield from
tetramethylsilane as an internal standard. Infrared (IR) spectra were
obtained with Perkin Elmer 882 spectrometer and RXI, FT‐IR model using
KBr‐pellets.The TOF‐MS‐ES+ spectra of the compounds were recorded
on Waters micromass Q‐TOF mass spectrometer. Elemental analyses
were carried out on a Perkin–Elmer 2400 CHNS/O elemental analyzer.
TLC plates were prepared with silica gel G (60–120 mesh, BDH) and
activated at 110°C for 30 min and analyzed with iodine vapors for
monitoring of reactions and to check the homogeneity of products. All
the solvents were dried and freshly distilled before use, according to
standard procedure.
Ketoprofen–thymol (K‐T), 2‐isopropyl‐5‐methylphenyl‐2‐(3‐
benzoylphenyl)propanoate (IIa)
IR (KBr, νmax, cm−1): 2990, 2985 (C‐H), 1736 (C=O ester), 1650 (C=O
ketone), 1457 (Ar C=C), 1371 (CH(CH3)2) 1231 (C‐O‐C asym.), 1043
(C‐O‐C sym.), 935, 847 (C‐H Ar). 1H‐NMR (CDCl3): δ 7.7‒7.8 (3H, m,
ArH), 7.6 (1H, dt, ArH), 6.0−7.6 (2H, m, ArH), 7.4–7.5 (3H, m, ArH),
6.6‒6.7 (3H, m, ArH ‐ thymol), 1.27–1.29 (6H, d, CH(CH3)2 ‐ thymol),
1.53‒1.55 (3H, s, CH‐CH3), 2.30 (3H, s, Ar‐CH3), 2.90‒2.95 (1H, m,
CH(CH3)2 ‐ thymol), 3.79‒3.86 (1H, q, CHCH3), 4.73‒4.90 (2H, q, O‐
CH2‐COO). 13C‐NMR (in ppm): 21.2 (Ar‐CH3), 23.4 (CH‐CH3), 27.6
(CH(CH3)2 ‐ thymol), 122‒133 (Ar‐Cs), 176.4 (CH3CHC=O), 197.5
(ArC=OAr). MS (ESI): m/z 387 (M+H)+. Anal. calcd. for C28H28O5: C,
75.65; H, 6.35 Found: C, 75.45; H, 6.48.
The InChI codes of the investigated compounds together with
some biological activity data are provided as Supporting Information.
Ketoprofen–guaiacol (K‐G), 2‐methoxyphenyl‐2‐(3‐benzoyl-
phenyl)propanoate (IIb)
|
4.1.2
General procedure for preparation of
ketoprofen–antioxidants ester codrugs without
spacer (IIa–h)
IR (KBr, νmax, cm−1): 2952 (aromatic C‐H), 1735 (C=O esters), 1658
(C=O ketone), 1281 (C‐O ester), 1207, 1165 (Ar‐OCH3), 950, 850,
704 (C‐H Ar). 1H‐NMR (in CDCl3): δ: 7.26‒7.81 (13H, m, Ar‐H), 3.82
(1H, q, CH‐CH3), 3.80 (3H, d, CHCH3), 3.68 (3H, s, O‐CH3). 13C‐NMR
(in ppm): 19.4 (CH‐CH3), 45.1 (ArCHCH3), 52.0 (Ar‐OCH3), 128‒141
(Ar‐C), 150.9 (Ar‐C‐OCH3), 175.2 (–C=O(OAr), 197.3 (Ar‐CO‐Ar).
MS (ESI): m/z 360 (M+). Anal. calcd. for C28H22O6: C, 71.76; H, 5.30
Found: C, 71.88; H, 5.18.
Step I: Synthesis of ketoprofen chloride
Ketoprofen (0.504 g, 2 mmol) and few drops of DMF were dissolved
in dry benzene in the round bottom flask and stirred for 15 min inside
an ice bath at 0°C. Then, a slight excess of freshly distilled in thionyl
chloride (0.7 ml, 10 mmol) was added dropwise over 15–20 min.
Stirring was continued at room temperature for 8 hr. After
completion of the reaction, the excess of thionyl chloride was
removed by distillation under reduced pressure to obtain a yellow
semi‐solid which was used in next step without further purification.
Ketoprofen–menthol (K‐M), 2‐isopropyl‐5‐methylcyclohexyl‐
2‐(3‐benzoylphenyl)propanoate (IIf)
IR (KBr, νmax, cm−1): 2986 (ar‐C‐H), 2954 (aliph. C‐H), 1726 (C=O ester),
1650 (C=O), 1457 (C=C), 1371 (CH (CH3)2), 1232 and 1033 (C‐O‐C)
937–730 (Ar‐C‐H). 1H‐NMR (CDCl3): δ 7.7–7.8 (3H, m, Ar‐H), 7.6 (1H, dt,
Ar‐H), 7.5–7.6 (2H, m, Ar‐H), 7.4–7.5 (3H, m, Ar‐H), 4.6–4.7 (1H, m, CH‐
O), 3.9–4.0 (1H, q, CHCH3), 1.6–1.9 (3H, d, CHCH3), 0.9–1.0 (3H, d, CH3‐
menthol), 1.6–1.7 (6H, d, CH(CH3)2), 0.9–1.1 (4H, m, CH2‐menthol),
1.4–1.5 (2H, m, CH2‐menthol), 1.8–1.7 (1H, m, CH(CH3)2), 3.9 (1H, m, O‐
CH‐menthol). 3C‐NMR (in ppm): 15.9 (CH‐CH3‐menthol), 18.5 (CHCH3‐
ketoprofen), 21.2‒22.1 CH(CH3)2, 23.1 (CH2 menthol), 26.3 CH(CH3)2,
Step II: Synthesis of ketoprofen–phytoalcohol/phenols ester
A mixture of respective phytoalcohol/phenols (2 mmol), triethylamine
(TEA) (0.7 ml, 10 mmol) and dry chloroform (25 ml) was stirred in ice‐
salt mixture at −10°C. To this reaction mixture, a solution of
ketoprofen chloride (2 mmol) in dry chloroform (25 ml) was added
dropwise with constant stirring at −10°C for 1 hr and then kept at
room temperature overnight. After completion of the reaction,
indicated by TLC, chloroform layer was washed with 1 M sodium

SEHAJPAL ET AL.
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35.0 (CH2‐menthol), 47.2 (CH‐menthol), 75.4 (COO‐C), 130‒141 (Ar‐Cs),
174.0 (COO), 194.2 (ArC=OAr). MS (ESI): m/z 393 (M+). Anal. calcd. for
C28H34O5: C, 74.64; H, 7.61 Found: C, 74. 55; H, 7.50.
(=O)‐). MS (ESI): m/z 604 (M+). Anal. calcd. for C37H32O8: C, 73.50; H,
5.33 Found: C, 73.72; H, 5.65.
Ketoprofen–gallic acid (K‐Ga), 4‐(2‐(3‐benzoylphenyl]propa-
noyl)oxy)‐3,5‐dihyroxybenzoic acid (IIg)
Ketoprofen–vanillin (K‐V), 4‐formyl‐2‐methoxyphenyl‐2‐
(3‐benzoylphenyl)propanoate (IId)
IR (KBr, νmax, cm−1): 2450–3245 (COOH), 3475 (OH‐phenolic), 3327
(‐COOH), 2936 (C‐H Ar), 1718 (C=O ester), 1232 and 1042
(C‐O ester), 1647 (C=O ketone), 1660 (C=C), 813–730 (Ar‐C‐H).
1H‐NMR (CDCl3): δ 9.97 (1H, ‐COOH gallic acid), 7.26‒7.81 (11H,
m, Ar‐H), 6.99 (2H, s, phenolic‐OH), 3.81 (1H, q, CHCH3), 3.68 (3H, d,
CHCH3). 13C‐NMR (CDCl3, ppm): 18.6 (CHCH3), 44.3 (CH‐CH3),
128.4‒138 (Ar‐Cs), 141 (COO‐C), 175 (HC‐C=O (OAr) and (‐COOH),
197 (ArC=OAr). MS (ESI): m/z 406 (M+). Anal. calcd. for C23H18O7: C,
67.98; H, 4.46 Found: C, 67.75; H, 4.36.
IR (KBr, νmax, cm−1): 3003 (Ar C‐H), 1762 (C=O ester), 1697 (C=O
aldehyde), 1650 (C=O ketone), 1497 (C=C), 1235 and 1044 (–OCH3),
1232 and 1042 (C‐O), 937, 748 (Ar C‐H). 1H‐NMR (CDCl3): δ 9.9
(1H, s, CHO) 7.1–7.9 (12H, m, Ar‐H), 4.1–4.2 (1H, q, CHCH3),
1.67–1.69 (3H, d, CHCH3), 3.9–4.0 (3H, s, Ar‐OCH3). 13C‐NMR (in
ppm): 18.6 (CH‐CH3), 45.3 (CHCH3), 56 (Ar‐OCH3), 123–138
(Ar‐Cs), 140 (ArC‐C=O), 145 (ArC‐OC=O), 152 (Ar‐C‐OCH3), 172
(CH3CHC=O), 191 (CHO), 197 (ArC=OAr). MS (ESI): m/z 388 (M+).
Anal. calcd. for C26H22O7: C, 69.95; H, 4.97 Found: C, 69.76; H, 4.85.
|
4.1.4
Preparation of the ketoprofen–antioxidants
Ketoprofen–eugenol (K‐E), 4‐allyl‐2‐methoxyphenyl‐2‐
(3‐benzoylphenyl) propanoate (IIc)
ester codrugs with glycolic spacer (IIIa–h)
IR (KBr, νmax, cm−1): 3469 (C=C‐H), 2984 (ArC‐H), 2936 (aliph. C‐H), 1737
(C=O esters), 1662 (C=O ketone), 1453 (Ar‐C=C), 1233 (C‐O ester), 1044
and 1235 (C‐H Ar –OCH3). 1H‐NMR (CDCl3) δ: 6.7–7.8 (12H, m, Ar‐H),
6.7 (1H, m, CH2CH=CH2), 5.0–5.1 (2H, m, CH2CH=CH2), 4.06‒4.08 (1H,
q, CH‐CH3), 3.6–3.7 (2H, d, Ar‐CH2CH=CH2), 3.3–3.4 (3H, s, Ar‐OCH3),
1.6–1.7 (3H, d, CH‐CH3). 13C‐NMR (in ppm): 18.7 (CH‐CH3), 40.0
(Ar‐CH2), 45.3 (CH‐CH3), 55.7 (Ar‐OC H3), 116.1 (CH=CH2), 138.0
(CH2CH=CH2), 112.7–140.6 (Ar‐Cs), 150.8 (Ar‐C‐OCH3), 172 (‐C=O
(OAr)), 197 (Ar‐C=O Ar). MS (ESI): m/z 400 (M+). Anal. calcd. for
C26H24O4: C, 77.98; H, 6.04 Found: C, 77.75; H, 5.88.
The general methods for the synthesis of ketoprofen and phytoalco-
hol/phenols with the glycolic acid spacer mutual codrugs are as
follows:
Step I: Synthesis of chloroacetyl ester of phytoalcohol/phenols
A reaction mixture containing phytoalcohol/phenols (10 mmol), TEA
(0.7 ml, 10 mmol) in dried chloroform (20 ml) was stirred in ice bath
at −10°C. To this reaction mixture chloroacetyl chloride (0.8 ml,
10 mmol) in dry chloroform, 25 ml was added dropwise at −10°C,
then stirred at room temperature for 8 hr. Then afterward workup
was done with HCl (5%, 3 × 50 ml), NaOH (5%, 3 × 50 ml), and finally
with brine solution (2 × 50 ml). The organic layer was dried over
sodium sulfate. The product was purified by column chromatography
by gradient elution with methanol in chloroform, using silica gel (80–
120 mesh) to obtain the respective chloroacetyl derivatives of
respective phytophenol/alcohol.
Ketoprofen–sesamol (K‐Se), benzo[d][1, 3]dioxol‐5‐yl‐2‐
(3‐benzoylphenyl)propanoate (IIe)
IR (KBr, νmax, cm−1): 3026 (ArC‐H), 2847 (Ar‐O‐CH3), 1758 (C=O
ester), 1668 (C=O ketone), 1497.56 (C=C Ar), 1249 and 1042 (C‐O‐
C), 936–730 (Ar‐C‐H). 1H‐NMR (CDCl3): δ 6.97−7.83 (12H, m, ArH),
3.78–3.96 (1H, q, CHCH3), 1.69‒1.71 (3H, d, CHCH3), 5.92–6.09
(2H, s, CH2 sesamol). 13C‐NMR (in ppm): 13.9 (CHCH3), 40.8
(CH‐CH3), 101.2 (OCH2O sesamol), 128.6–1498.2 (Ar‐Cs), 171.46
(HC‐C=O(OAr)), 190.52 (ArC=OAr). MS (ESI): m/z 374 (M+). Anal.
calcd. for C23H18O5: C, 73.79; H, 4.85 Found: C, 73.65; H, 4.65.
Step II: Synthesis of ketoprofen–phytoalcohol/phenols mutual
codrugs with glycolic acid spacers (IIIa–h)
The respective chloroacetyl derivative of phytophenol/alcohol
derivatives from above reaction was mixed with sodium iodide
(0.749 g, 10 mmol), DMF (25 ml) as the solvent at 0°C followed by
few drops of TEA. Then, ketoprofen (2.54 g, 10 mmol) in DMF (25 ml)
was added dropwise at 0°C and then stirred at room temperature
overnight. To this mixture ice‐cold water was added and then
extracted with ethyl acetyl (4 × 25 ml). The combined organic layers
were worked up with HCl (5%, 3 × 50 ml), NaOH (5%, 3 × 50 ml), and
finally with brine solution (2 × 50 ml) and dried over sodium sulfate.
The product was purified by column chromatography by gradient
elution of ethyl acetate in n‐hexane up to 6% using silica gel (80–120
mesh) to obtain the respective ketoprofen–antioxidants ester
codrugs with the glycolic spacer (IIIa–h) (Table 2).
Ketoprofen–curcumin (K‐Cu), [2‐(4‐((1E,6E)‐7‐(4‐hydroxy‐3‐
methoxyphenyl)]‐3,5‐dioxohepta‐1,6‐dien‐1yl)‐2‐methoxyphe-
nyl‐2‐(3‐benzoylphenyl)propanoate (IIh)
IR (KBr, νmax, cm–1): 3081 (Ar ‐C‐H), 2985 (aliph. ‐C‐H), 2848 (Ar‐O‐
CH3), 1647 (C=O ketone), 1739 (C=O ester), 1486 (C=C), 1235, 1044
(‐OCH3), 1232 and 1042 (C‐O), 936–730 (Ar‐C‐H bend). 1H‐NMR
(CDCl3): δ 7.8–6.8 (15H, m, Ar‐H), 7.60 (2H, s, CH=CH‐Ar), 6.9 (2H, s,
O=C‐CH=CH‐Ar), 6.2–5.4 (1H, s, phenolic‐OH), 4.6–4.5 (2H, s, O=C‐
CH2C=O), 3.9‒3.5 (6H, s, Ar‐OCH3 curcumin), 3.5 (1H, q, CHCH3),
1.6–1.4 (3H, d, CHCH3). 13C‐NMR (ppm): 13.9 (CHCH3), 40.1 (CH‐
CH3), 115.2–157.9 (Ar‐C), 174.2 (HC‐C=O(O‐Ar)), 57.1 (Ar‐O‐CH3),
61.0 (C=OCH2C=O), 130.0 (Ar‐CH=CHCH2), 143.0 (Ar‐CH=CH‐CH3),
144.2 (Ar‐C‐OH), 150 (ArC‐OCH3), 173.0 (‐COO‐), 200.4 (‐C(=O)‐C
The general chemical structures of the synthesized mutual
codrugs of ketoprofen (I) with various phytophenols/alcohol through

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SEHAJPAL ET AL.
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the glycolic acid spacer (‐OCH2COO) are IIIa–h and their respective
Ketoprofen–vanillin with spacer (KVS), 2‐(4‐formyl‐2‐meth-
oxyphenoxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate (IIId)
IR (KBr, νmax, cm−1): 3460 (Ar‐C‐H st), 2985 (aliph. C‐H st), 1735
(C=O ester), 1696 (C=O aldehyde), 1649 (C=O ketone), 1497 (Ar
C=C st), 1440 (C‐C bend), 1234 and 1042 (C‐O ester), 936 (ArC‐H
bend). 1H‐NMR (CDCl3): 9.9 (1H, s, CHO), 7.8–7.7 (3H, m, Ar‐H), 7.6
(1H, dt, Ar‐H), 7.6–7.5 (2H, m, Ar‐H), 7.5–7.4 (2H, m, Ar‐H vanillin),
7.40 (3H, m, Ar‐H), 7.3–7.2 (1H, m, Ar‐H vanillin), 4.9–4.7 (2H, q, O‐
CH2COO), 3.9 (3H, s, Ar‐OCH3 vanillin), 3.9–3.7 (1H, q, CHCH3), 1.6
(3H, d, CHCH3). 13C‐NMR (CDCl3): 19.6 (CH‐CH3), 40.4 (CHCH3),
55.2 (Ar‐OCH3), 61.0 (O‐CH2‐COO), 122–136 (Ar‐Cs), 141.2 (Ar‐C‐
OCH3), 150.5 (Ar‐C‐OC=O), 167.3 (CH2C=O), 176.6 (CH3CHC=O),
197.2 (ArC=OAr). MS (ESI): m/z 446 (M+H+). Anal. calcd. for
C26H22O7: C, 69.95; H, 4.97 Found: C, 69.78; H, 4.85.
Ar/R are shown in Table 2.
|
4.1.5
Chemical characterization of the synthesized
codrugs–OCH2COO–antioxidant codrugs
Ketoprofen–thymol with spacer (KTS), 2‐(2‐isopropyl‐5‐
methylphenoxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate
(IIIa)
IR (KBr, νmax, cm−1): 3460 (Ar‐ C‐H st), 2985 (aliph.‐ C‐H st), 1735
(C=O ester), 1649 (C=O ketone), 1457 (aromatic C=C), 1440 (C‐C
bend), 1231 and 1043 (C‐O). 1H‐NMR (CDCl3): 7.8–7.7 (3H, m, Ar‐H),
7.6 (dt, 1H, Ar‐H), 7.6–6.1 (2H, m, Ar‐H), 7.5–7.4 (3H, m, Ar‐H), 6.7‒6.6
(3H, m, Ar‐H), 2.3 (3H, s, Ar‐CH3), 2.95–2.90 (1H, m, CH(CH3)2
thymol), 3.86–3.79 (1H, q, CHCH3), 4.90–4.73 (2H, s, O–CH2‐COO),
1.3 (6H, d, CH(CH3)2 thymol), 1.6 (3H, s, CH‐CH3). 13C‐NMR (CDCl3):
20.6 (Ar‐CH3), 22.8 (CH‐CH3), 26.8 (CH(CH3)2 thymol), 60.7 (O‐CH2‐
COO), 121.79–136.49 (Ar‐Cs), 167.0 (CH2C=O), 176.14 (CH3CHC=O),
196.97 (Ar‐C=OAr). MS (ESI): m/z 444 (M+). Anal. calcd. for C28H28O5:
C, 75.65; H, 6.35 Found: C, 75.78; H, 6.48.
Ketoprofen–eugenol with spacer (KES), 2‐(4‐allyl‐2‐methoxy-
phenoxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate (IIIe)
IR (KBr, νmax, cm−1): 3018 (Ar‐C‐H), 2957 (aliph. C‐H), 1737 (C=O
esters), 1235 and 1044 (C‐O), 1650 (C=O ketone), 1452 (Ar C=C).
1H‐NMR (CDCl3) δ: 7.7–6.7 (12H, m, Ar‐H ketoprofen and eugenol),
5.1 (2H, m, CH2CH=CH2), 6.7 (1H, m, CH2CH=CH2), 5 (2H, q, COO‐
CH2‐C=O), 3.9–3.8 (1H, q, CH‐CH3), 3.8 (3H, s, Ar‐OCH3), 3.3 (2H, d,
Ar‐CH2CH=CH2), 1.5 (3H, d, CH‐CH3). 13C‐NMR (ppm): 18.7 (CH‐
CH3), 30 (CH‐CH3), 55.0 (Ar‐OCH3 and Ar‐CH2), 60.5 (O‐CH2‐CO),
116.1 (CH=CH2), 138.0 (CH2CH=CH2), 112.7–140.6 (Ar‐Cs), 150.0
(Ar‐C‐OCH3), 196.5 (Ar‐C=O Ar). MS (ESI): m/z 458 (M+). Anal. calcd.
for C28H26O6: C, 73.35; H, 5.72 Found: C, 73.18; H, 5.80.
Ketoprofen–guaiacol with spacer (KGS), 2‐(2‐methoxyphe-
noxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate (IIIb)
IR (KBr, νmax, cm−1): 3631.7 (Ar‐C‐H st), 2985 (aliph.‐C‐H st), 1736 (C=O
esters), 1647 (C=O, ketone), 1486 (aromatic C=C), 1231 (C‐O st, ester),
750–789 (substituted Ar rings). 1H‐NMR (CDCl3): 7.7–7.2 (9H, m, Ar‐H
ketoprofen), 7.1 (2H, d, Ar‐H guaiacol), 7.0–6.9 (2H, t, Ar‐H guaiacol), 5.24
(2H, s, O‐CH2‐COO‐), 3.9–3.8 (1H, q, CH‐CH3), 3.8 (3H, s, O‐CH3). 13C‐
NMR (CDCl3): 10.5 (CH‐CH3), 45.3 (Ar‐CH2 and CHCH3), 52.2 (Ar‐
OCH3), 61.5 (O‐CH2‐COO), 128.3–141.0 (aromatic‐Cs), 150.9 (Ar‐C‐
OCH3 and CH2C=O), 174.7 (HC‐C=O (OCH2)), 177.6 (–C=O(OAr)), 196.7
(Ar‐CO‐Ar). MS (ESI): m/z 418 (M+). Anal. calcd. for C25H22O6: C, 71.76;
H, 5.30 Found: C, 71.58; H, 5.42.
Ketoprofen–sesamol with spacer (KSeS), 2‐(benzo[d][1,3]‐
dioxol‐5‐yloxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate
(IIIf)
IR (KBr, νmax, cm−1): 3081 (Ar‐C‐H), 2985 (aliph. C‐H), 1739 (C=O
ester), 1235 and 1044 (‐OCH3), 1232 and 1042 (C‐O), 1647 (C=O
ketone), 1486 (C=C), 937–730 (Ar‐C‐H). 1H‐NMR (CDCl3): δ 7.5–7.8
(9H, m, Ar‐H ketoprofen), 3.8 (1H, q, CHCH3), 1.7–1.5 (3H, d,
CHCH3), 5.2 (2H, s, O‐CH2‐COO), 6.6 (1H, d, Ar‐H sesamol), 6.7 (1H,
d, Ar‐H sesamol), 6.8 (1H, ddAr‐H), 5.9 (2H, s, CH2 sesamol). 13C‐
NMR (ppm): 16.3 (CHCH3 ketoprofen), 40.2 (CH‐CH3 ketoprofen),
191.4 (ArC= OAr), 172.2 (HC‐C= O(OAr)), 167.3 (O‐CH2C=O),
127–138 (Ar‐Cs), 104–148 (Ar‐C sesamol), 101.4 (OCH2O sesamol.
MS (ESI): m/z 432 (M+). Anal. calcd. for C25H20O7: C, 69.44; H, 4.66
Found: C, 69.30; H, 4.52.
Ketoprofen–menthol with spacer (KMS), 2‐((2‐isopropyl‐5‐
methylcyclohexyl)oxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)pro-
panoate (IIIc)
IR (KBr, νmax, cm−1): 3429 (Ar‐C‐H st), 2985 (aliph.‐ C‐H), 1735 (C=O
ester), 1649 (C=O ketone), 1457 (Ar C=C st), 1371 (C‐H bend CH (CH)3),
1235 and 1043 (C‐O ester), 936–730 (Ar‐C‐H bend). 1H‐NMR (CDCl3):
7.8–7.7 (3H, m, Ar‐H), 7.6 (1H, dt, Ar‐H), 7.6–7.5 (2H, m, Ar‐H), 7.5–7.4
(3H, m, Ar‐H), 5.1 (2H, s O‐CH2‐COO), 3.90 (1H, m, O‐CH menthol),
3.8‒3.7 (1H, q, CHCH3), 1.9–1.6 (3H, d, CHCH3), 1.82–1.77 (1H, m, CH
(CH3)2), 1.52–1.39 (2H, m, CH2 menthol), 1.11–0.97 (2H, m, CH2
menthol), 0.92–0.88 (6H, d, CH(CH3)2), 0.8–0.7 (3H, d, CH3 menthol).
13C‐NMR (CDCl3): 16.42 (CH‐CH3 menthol), 18.45 (CHCH3 ketoprofen),
21.09–22.10 (CH(CH3)2 menthol), 23.12 (CH2 menthol), 26.63 (CH(CH3)2
menthol), 34.7 (CH2 menthol), 45.22 (CH‐CH3 ketoprofen), 47.04 (CH
menthol), 71.78 (O‐CH menthol), 128.56–141.74 (Ar‐Cs), 167.2 (O‐
CH2C=O), 173.8 (ArC=OAr). MS (ESI): m/z 451 (M+H+). Anal. calcd. for
C28H34O5: C, 74.64; H, 7.61 Found: C, 74.52; H, 7.78.
Ketoprofen–curcumin with spacer (KCuS), 2‐(4‐((1E,6E)‐7‐(4‐
hydroxy‐3‐methoxyphenyl)]‐3,5‐dioxohepta‐1,6‐dien‐1yl)‐2‐
methoxyphenoxy)‐2‐oxoethyl‐2‐(3‐benzoylphenyl)propanoate
(IIIg)
IR (KBr, νmax, cm−1): 3081 (Ar‐C‐H), 2985 (aliph. C‐H), 1739 (C=O
ester), 1647 (C=O ketone), 1486 (C=C), 1235 and 1044 (C‐O), 937–
730 (Ar‐C‐H bend). 1H‐NMR (CDCl3) (J in Hz): δ 7.8–7.4 (9H, m, Ar‐H
ketoprofen), 7.60 (2H, s, CH=CH‐Ar), 7.30 (1H, s, Ar‐H curcumin),
7.2–7.1 (2H, d, Ar–H), 6.9 (2s O=C‐CH=CH‐Ar), 6.8–6.9 (2H, d, Ar‐H

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curcumin), 5.4 (1H, s, phenolic‐OH), 5.0 (2H, s, O‐CH2‐COO), 4.6–4.5
(2H, s, O=C‐CH2C=O), 3.8 (1H, q, CHCH3), 1.6 (3H, d, CHCH3). 13C‐
NMR (CDCl3 in ppm): 14.1 (CHCH3 ketoprofen), 40.2 (CH‐CH3
ketoprofen), 56.5 (Ar‐O‐CH3), 62.3 (O‐CH2‐C=O), 111–151 (Ar‐C
curcumin), 128–135 (Ar‐C ketoprofen), 130.4 (ArCH=CHCH2), 143.1
(Ar‐CH=CH‐CH3), 167.3 (O‐CH2C=O), 174.4 (HC‐C=O(OAr)), 180.9
(CH2C=O), 199.2 (‐C(=O)‐C(=O)‐). MS (ESI): m/z 462 (M+). Anal. calcd.
for C39H34O10: C, 70.69; H, 5.17 Found: C, 70.50; H, 5.28.
Partition coefficient (P)
Concentration of drug in octanol × Dilution factor
=
Concentration of drug in buffer
|
4.3
Kinetics of hydrolysis study
Chemical stability
|
4.3.1
The chemical stability (in vitro hydrolysis) study was carried out in non‐
enzymatic simulated gastric fluid (SGF) of pH 1.2 and in nonenzymatic
simulated intestinal fluid (SIF) of pH 7.4 in isotonic buffers.[23] SGF is pH
1.2 HCl solution prepared by combining 0.2 M KCl solution with 0.2 M
HCl solution, while SIF is pH 7.4 monobasic potassium phosphate buffer
solution. The total buffer concentration was 20 mM and constant ionic
strength of 0.5 M for each sample was maintained by adding KCl.
The hydrolysis of the codrug was initiated by dissolving 10 mg
of the codrug in 90 ml of preheated SGF (pH 1.2), or in SIF (pH 7.4).
The solutions were sealed in screw‐capped glass vials and then
placed into a thermostatically controlled water bath at 37 0.5°C.
Then 10 ml of the solution was withdrawn from each test tube at
15, 30, 60, 120, 240 and 480 min and transferred to microcen-
trifuge tubes, then centrifuged at 3000 rpm for 15 min. From this
5 ml of clear supernatant was taken and measured by UV‐
spectroscopy for the amount of parent NSAID (ketoprofen),
released after the hydrolysis in buffer solutions at 260 nm.
Pseudo‐first order rate constants (Kobs) and half‐lives (t1/2) were
determined by using the equations:
Ketoprofen–gallic acid with spacer (KGaS), 4‐(2‐((2‐(3‐ben-
zoylphenyl]propanoyl)oxy)acetoxy‐3,5‐dihyroxybenzoic acid
(IIIh)
IR (KBr, νmax, cm−1): 2450–3245 (COOH), 3026 (Ar‐C‐H), 2931 and
2883 (aliph. C‐H), 1235 and 1044 (‐OCH3), 1718 (C=O Ester), 1232
and 1042 (C‐O ester), 1647 (C=O ketone), 1587 (C=C), 2848 (Ar‐O‐
CH3), 937–930 (Ar‐C‐H). 1H‐NMR (CDCl3): δ 9.5 (1H –COOH gallic
acid), 7.8–7.4 (9H, m, Ar‐H ketoprofen), 7.3 (2H, s, Ar‐H, gallicacid),
5.35 (2H, s, phenolic‐OH), 5.0 (2H, s, O‐CH2‐COO), 3.8 (6H, s,
Ar‐O‐CH3 Curcumin), 3.78 (1H, q, CHCH3), 1.61 (3H, d, CHCH3). 13C‐
NMR (in ppm): 14.3 (CHCH3 ketoprofen), 44.1 (CH‐CH3 ketoprofen),
127–132 (Ar‐C ketoprofen), 62.4 (O‐CH2C=O), 178.2 (HC‐C=O
(OAr)), 136–138 (Ar‐C gallic acid), 169.4 (‐COOH). MS (ESI): m/z
464 (M+H+). Anal. calcd. for C25H20O9: C, 64.65; H, 4.34 Found: C,
64.52; H, 0.23.
|
4.2
Physicochemical studies
Solubility studies
|
4.2.1
Kobs = slope × 2.303,
An excess amount of each compound was added to 10 ml of
phosphate buffer (pH 7.4) in a screw cap test tube and shaken for
24 hr at 37 0.5°C in water bath shaker. Solutions were then filtered
through Whatman filter paper after appropriate dilution in the same
buffer and it was analyzed spectrophotometrically for the amount of
codrug. The solubility studies data is reported in Table 1.
t
1/2 = 0.693/Kobs.
|
4.3.2
Enzymatic hydrolysis study (80% human
plasma)
The hydrolysis studies were carried out in 80% human plasma
fractions with isotonic phosphate buffer (pH 7.4) at 37 + 0.5°C as per
the reported procedure with some modification.[46,47] Human plasma
fraction was obtained by centrifugation of the blood samples
containing 0.3% citric acid at 3000 rpm for 20 min. Human plasma
fractions (4 ml) were diluted with 1 ml of phosphate buffer (pH 7.4,
isotonic) to give the final volume of 5 ml of diluted human plasma
80%.
|
4.2.2
Partition coefficient determination
The partition coefficients of the synthesized compounds were
determined in octanol/phosphate buffer (pH 7.4) at 37 0.5°C
using the shake flask method. Octanol and phosphate buffer (pH
7.4) were mutually saturated by shaking overnight. The system
was left undisturbed for half an hour and the layers were
separated. A saturated solution of each codrug was prepared in n‐
octanol (5 ml). Then an equal volume of phosphate buffer (5 ml)
was added to the solution in conical flasks. The sealed flasks were
kept for shaking in a water bath shaker maintained at 37 0.5°C
or 24 hr. After shaking the two phases were separated by
centrifugation at 3000 rpm for 10 min. Then both the phases
were analyzed spectrophotometrically. Partition coefficient is
calculated as:
The reactions were started by adding 0.5 ml of stock solution
(1000 µg/ml) of the codrugs in ethanol to 5 ml of preheated, diluted
human plasma (80%). Then the samples were withdrawn at appropriate
time intervals (15, 30, 60, 120, 240 min), further diluted with phosphate
buffer and then analyzed spectrophotometrically at 260 nm for the
appearance of the free drug (ketoprofen) with time. The rate of hydrolysis
(Kobs) and t1/2 were calculated using the equations:
Kobs = slope × 2.303,
t1/2 = 0.693/Kobs.

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4.4
Pharmacological studies
anti‐inflammatory dose) of ketoprofen (80 mg/kg) and the
equimolar doses of the test compounds as shown in Table 7
was introduced by oral route once daily for four days as a
suspension in 0.5% CMC in aqueous vehicle used in a volume of
0.5 ml/100 g of animal weight. After the administration of the
fourth dose, the food was removed and using chloroform/ether
fumes the animals were killed. At necropsy, the stomachs were
removed and opened along the greater curvature and were
examined under the magnifying lens for lesions.[53] The results
are as shown in Table 7 and the grades for observed lesions are
given in Table 6.
|
4.4.1
Anti‐inflammatory activity
The parent drug ketoprofen in the dose of 20 mg/kg of body weight was
used as a reference standard. The doses of the codrugs were chosen on
equimolar bases as shown in Table 5. Carrageenan‐induced hind paw
edema method was used to test for anti‐inflammatory activity.[50] The
edema is expressed as percentage increase in left hind paw in comparison
to the un‐injected right hind paw. Albino rats, weighing 200–250 g of
either sex, were selected and divided into groups of six each. Paw edema
was induced in rats by means of subplantar injection into the left hind
paw of rats by injecting 0.1 ml of 1% carrageenan suspension under the
plantar region of the left hind paw. In the right paw, saline (1 ml, 0.9%)
was injected (as the control). Ketoprofen and other test drugs were
administered orally 1 hr before the irritant. The paw volume up to a fixed
mark at the level of lateral malleolus was measured using plethysm-
ometer after 2 hr, 4 hr of the carrageenan injection. Increase in paw
volume was calculated as:
|
4.4.4
Antioxidant studies (in vitro)
To assess the free radical scavenging activity of ketoprofen–
OCH2COO–phytophenols/codrugs, 1,1‐diphenyl‐2‐picrylhydrazyl
radical (DPPH) assay was carried out.[54] DPPH is a stable free
radical having a purple color that after reduction, for example
with some antioxidants, gets reduced and changes its color to
yellow. IC50‐values are used to quantify the antioxidant activity.
IC50 value, calculated from the inhibition curve, is the concentra-
tion of the sample (in μg/ml) required to scavenge 50% DPPH free
radical. A 100 µM solution of DPPH in methanol was added to the
separate solutions of thymol, guaiacol (10–100 µg/ml), eugenol
(10–100 µg/ml), vanillin (10–100 µ/ml), sesamol (10–100 µg/ml),
gallic acid (10–100 µg/ml), curcumin (10‐100 µg/ml), and the
phytoalcohol menthol (10–100 µg/ml). The absorbance was read
at 515 mm after 20 min. The radical scavenging activity was
expressed as:
% increase in paw volume = V − V /VR × 100,
L
R
where V = Volume of left paw
L
V = Volume of right paw (control)
R
The mean + SEM values were calculated for each group for the
% edema.
|
4.4.2
Analgesic activity
Writhing tests in mice are the most common method for measuring
peripheral analgesic activity which is determined using acetic acid‐
induced writhing assay procedure.[51,52] To induce writhing freshly
prepared acetic acid solution (1% w/v in saline pH = 2.7, 10 ml/kg) was
given by intraperitoneal (ip) injection. Different treatment groups of rats
were made as shown in Table 5 containing six animals in each group.
Ketoprofen (20 mg/kg) and the test codrugs were administered in the
equimolar doses. All these were administered by the oral route,
emulsified in 0.5% sodium carboxymethyl cellulose vehicle, 30 min
before the introduction of acetic acid. The writhing responses
(constriction of the abdomen, turning of trunk, and extension of hind
limbs) were recorded starting from 3 min after injection of acetic acid till
20 min. The degree of analgesia was expressed as % inhibition as
compared to the average of the vehicle‐treated control group.
Ac–As × 100
% DPPH radical scavenging =
,
Ac
where Ac = absorbance of control (i.e.
of DPPH without sample),
As = absorbance of sample solution.
ACKNOWLEDGMENTS
The authors wish to thanks and acknowledge the support provided
by the management of Shivalik College of Pharmacy, Nangal (Punjab),
Gujranwala Guru Nanak Khalsa College of Pharmacy, Ludhiana
(Punjab) and I.K. Gujral Punjab Technical University, Jalandhar.
Authors are also thankful to Director, SAIF, Panjab University,
Chandigarh, India for cooperation in getting the spectral data.
% inhibition = 1 − (Nt /Nc) × 100,
where, Nc = Average number of writhes incontrol,
Nt = Average number of writhes in drug treated rats.
The control group (vehicle treated group) showed an
average writhing of 78 + 1.52.
CONFLICT OF INTERESTS
The authors declare that they have no conflict of interests.
|
4.4.3
Antiulcer/gastrointestinal erosion assay
(GIER)
ORCID
Different treatment groups of albino rats of 6 animals each (150–
250 g) were made. The ulcer‐inducing dose (four times of their
Rajesh K. Singh
http://orcid.org/0000-0002-5943-3498

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How to cite this article: Sehajpal S, Prasad DN, Singh RK.
Novel ketoprofen–antioxidants mutual codrugs as safer
nonsteroidal anti‐inflammatory drugs: Synthesis, kinetic and
pharmacological evaluation. Arch. Pharm. Chem. Life Sci.
2019;e1800339. https://doi.org/10.1002/ardp.201800339
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