Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol

Article abstract of DOI:10.1016/j.ejmech.2012.08.030

The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of este

Full text of DOI:10.1016/j.ejmech.2012.08.030

European Journal of Medicinal Chemistry 56 (2012) 134e138
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol
and eugenol
*
Vivekkumar K. Redasani , Sanjay B. Bari
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule 425 405 MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present works deals with simple and efficient method of improving therapeutic efficacy of racemic
ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This
is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with
naturally occurring phenolic and alcoholic compounds. Promoieties like menthol; thymol and eugenol
were selected with the aim of getting synergistic effect as these are natural analgesic having traditional
medicinal values. Prodrugs are found to be highly lipophilic as compared to parent drug. All the prodrugs
are found to be highly stable at acidic pH while undergoes hydrolysis at neutral and alkaline pH as
indicated by their t1/2 values. Synthesized prodrugs derivatives show increased anti-inflammatory
activity that might be attributed to synergistic effect as ibuprofen conjugates to natural analgesics.
Ulcer index shows much reduction in gastric ulceration compared to ibuprofen concluding the successful
masking of acidic group.
Received 31 May 2012
Received in revised form
18 August 2012
Accepted 20 August 2012
Available online 28 August 2012
Keywords:
Ibuprofen
Mutual prodrugs
Hydrolysis kinetics
Anti-inflammatory
Gastroprotective
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
Mutual prodrug consists of two pharmacologically active agents
coupled together, in such a way to get synergistic action or some
In clinical practice, the use of therapeutic agent restricts due to
undesirable parameters related to side effects, bioavailability or
physicochemical properties. Ibuprofen, (R,S) [2-(4-isobutylphenyl)
propionic acid] belongs to a class of non-steroidal anti-inflamma-
tory drugs (NSAIDs), acts by inhibiting isoforms of cyclo-oxygenase
(COX) 1 and 2. It is used to treat inflammatory rheumatoid diseases
and relieves acute pain [1]. Progression in the gastrointestinal (GI)
side effects particularly stomach ulceration, bleeding and perfora-
tion are the main constraint in its use which is particularly due to
local action exerted by direct contact of drug with gastric mucosa
[2]. Thus free acidic group plays a key role in maintaining the
effectiveness and producing the gastric ulceration as well [3].
Ibuprofen is available as a racemic mixture with R enantiomer
being metabolically inverted, following oral dosing to humans to
the S (active) enantiomer [4]. In light of this, various approaches
have been used to minimize side effect by masking free acidic
group chemically with retaining the potency.
additional biological action that is lacking in the parent drug
[13,14].
Motivated by above finding; in the present work, a novel series
of mutual prodrugs of racemic ibuprofen is designed by combining
with naturally occurring phenolic antioxidants, thymol and
eugenol as well as alcoholic compound menthol. These phytocon-
stituents are selected so as to get safer promoiety which is always
a challenge in designing of prodrugs. These promoieties have
traditionally in use for their medicinal as well as flavoring prop-
erties with well documented safety profiles [15]. Additionally these
prodrugs were evaluated by partition coefficient, aqueous hydro-
lysis, pharmacological screenings like anti-inflammatory activity
and gastroprotective activity.
2. Results and discussion
2.1. Chemistry
Considerable attention has been focused on development of
prodrugs of ibuprofen by selecting various promoieties with the
aim of reducing GI toxicity. Several prodrugs of ibuprofen are re-
ported [5e10], Few polymeric prodrugs of ibuprofen using acrylates
were reported [11,12].
The designing of prodrug has given the success to overcome the
undesirable properties associated with the existing drug. The
mutual prodrug concept is one step ahead as it minimizes the side
effects along with increase in activity. It was for the first time
synthesis of mutual prodrugs of racemic ibuprofen was achieved
with natural analgesics like menthol, thymol and eugenol as pro-
moieties. The targeted ester derivatives ibuprofenementhol ester
* Corresponding author. Tel.: þ91 9822027806 (mobile); fax: þ91 2563255189.
E-mail address: vivek.redasani@gmail.com (V.K. Redasani).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.08.030

V.K. Redasani, S.B. Bari / European Journal of Medicinal Chemistry 56 (2012) 134e138
135
(IME), ibuprofenethymol ester (ITE) and ibuprofeneeugenol ester
(IEE) are obtained to be an enantiomeric mixture, since the parent
drug employed was racemic. The synthesis was carried out
successfully by using N,N0 dicyclohexylcarbodiimide (DCC). DCC
proves to be an effective catalyst for the conversion of carboxylic
acids to esters and amides. It functions by activating the free
carboxylic group. Use of DCC is advantageous over other methods
like conversion of acid to acid chloride and later on to esters [16].
The synthesized compounds were confirmed by FTIR, 1H NMR and
mass spectroscopy. Infra red spectra showed the characteristics
band of C]O stretching in range of 1723e1755 cmꢀ1 and CeO
stretching in range of 1225e1267 cmꢀ1 which confirms the
formation of esters. The 1H NMR spectra of synthesized compounds
shows characteristic chemical shifts, which anticipated the struc-
ture of compounds. The mass spectra of synthesized compounds
showed the parent peak confirming the molecular weight of tar-
geted derivatives.
condition. Values of the rate parameter Kobs for hydrolysis of pro-
drugs at different pH and 37 ꢁC are listed in Table 2 along with the
half-lives (t1/2).
Thus, it confirms that the possibility for gastric irritation
produced by ibuprofen is reduced. The mutual prodrug may have
devoid of gastric irritation in GIT due to unionized form in stomach
and ionized from in intestine and may have synergistic effect that
can also be attributed to anti-inflammatory activity data [20].
Moreover, the increased value of t1/2 for IME than that of ITE and IEE
might be due to presence of aliphatic part in IME that delays the
hydrolysis as compared to that of other two. From the above study,
therefore, the prepared mutual prodrugs of ibuprofen fulfilled the
requirement since they showed good stability at acidic pH and thus,
phytophenols suits to be the best promoieties for ibuprofen.
2.4. Biological evaluation
Anti-inflammatory activity possessed by NSAIDs is credited to
the presence of carboxylic acid moiety which is crucial for binding
to COX 1 and COX 2. But this inhibition is associated with GI and
renal toxicities which limits the use of NSAIDs. Thus the biological
evaluation is done with the aim of retention in activity and
reduction in GI toxicity [21].
2.2. Partition coefficient
To produce a pharmacological response, a drug molecule has to
first cross a biological membrane consisting of lipids and proteins,
which acts as a barrier. The ability of drug molecule to penetrate
this barrier is based in part, on its preference for lipophilicity versus
hydrophilicity. A drug’s partition coefficient is a measure of its
distribution in a lipophilic/hydrophilic phase system, and is indic-
ative of its ability to penetrate biological multiphase system [17].
The partition coefficients of ibuprofen and prodrugs were deter-
mined in octanolewater buffer systems and also calculated by
computational method using Schrodinger software. The result
shows that synthesized esters were found to be more lipophilic
than parent drug, ibuprofen; Table 1. This shows that major fraction
was partitioned toward the organic phase, indicates enhancement
in the lipophilicity, favorable to biological absorption [18].
2.4.1. Anti-inflammatory activity
Anti-inflammatory screening for parent and prodrugs is indi-
cated by percentage inhibition of swelling in carrageenan-induced
edema in rat paw. The prodrugs show better anti-inflammatory
activity with percentage inhibition of 60%e66% as compared to
47% when studied up to 6 h at the interval of every hour, as
tabulated in Table 3. Statistical significance testing using one way
analysis of variance showed that activity of the parent and prodrugs
were effective in comparison with the control group. It is also
evident that improvement in anti-inflammatory potency may be
due to the increased lipophilic character of ester as compared to
parent drug as increased lipophilicity increases cell membrane
2.3. Aqueous hydrolysis
permeability (to
a certain extent) and, ultimately, improves
Hydrolysis kinetics study of prodrugs was determined in acidic,
neutral and alkaline pH to determine the fate of prodrugs. It has
been reported that the essential pre-requisite for success in the use
of prodrugs is that the masked compounds should be acid stable to
prevent the direct contact effects with the gastric mucosa as well as
the local inhibition of the prostaglandins [19]. Therefore, pH values
ranging acidic, neutral and alkaline were selected to mimic the
appropriate clinical range. The chemical degradation of ester pro-
drugs of ibuprofen followed first order kinetics, and quantitatively
converted to ibuprofen as revealed by HPLC analysis. In the acidic
buffer solution of pH 1.2, all prodrugs (IME/ITE/IEE) showed high
chemical stability which implied that the compounds passed
unhydrolyzed through the stomach on oral administration. While
at neutral pH 7.4 their (t1/2) ranging from 170 min to 360 min.
Furthermore, the degradation of all three prodrugs at alkaline pH
10.0 showed comparative less half lives than at neutral pH with t1/2
ranging from 80 to 163 min indicating hydrolysis pattern at alkaline
bioavailability [22]. This increased anti-inflammatory might be due
to the resultant synergistic effect by conjugation with natural
analgesics. The probable reason might be the ability for inhibition
to COX 1 and 2 possessed by menthol [23], eugenol [24], and
thymol [25].
2.4.2. Gastroprotective
The synthesized prodrugs show very less gastric ulcers than
parent drug. The data presented in Table 3 indicates that the risk of
ulcer induction is reduced almost 2.5 folds in prodrugs. This is
indicative of minimized GI side effects obtained by modification to
esters. This might be due to inhibition of direct contact of carboxylic
group of the parent drug to the gastric mucosa; mainly responsible
for gastric damage. Moreover complementary evidence supported
to the fact that esterification may be good enough to minimize the
ulcerogenic toxicity of NSAIDs [22]. It may also be due to no
hydrolysis in acidic buffer. These findings suggested the successful
Table 1
Table 2
Partition coefficient of ibuprofen and prodrugs.
Kinetic data for the hydrolysis of prodrugs at different pH and 37 ꢁC.
System
Partition coefficient
pH IME
ITE
IEE
Ibuprofen
IME
ITE
IEE
Kobs
t1/2 (min) Kobs
t1/2 (min) Kobs
t1/2 (min)
Octanolewater
Computational method
3.71
3.48
6.69
6.99
6.27
6.84
5.63
6.24
7.4 1.92 ꢂ 10ꢀ3 360.44
2.22 ꢂ 10ꢀ3 311.16
4.06 ꢂ 10ꢀ3 170.52
10.0 4.25 ꢂ 10ꢀ3 163.00
4.77 ꢂ 10ꢀ3 145.05
8.63 ꢂ 10ꢀ3 80.30
IME e ibuprofenementhol ester.
ITE e ibuprofenethymol ester.
IEE e ibuprofeneeugenol ester.
IME e ibuprofenementhol ester.
ITE e ibuprofenethymol ester.
IEE e ibuprofeneeugenol ester.

136
V.K. Redasani, S.B. Bari / European Journal of Medicinal Chemistry 56 (2012) 134e138
Table 3
Pharmacological screening of mutual prodrugs of ibuprofen.
Compound
Anti-inflammatory activity (% inhibition)a
Ulcer index
1 h
2 h
3 h
4 h
5 h
6 h
Ibuprofen
IME
ITE
18.33 ꢃ 0.36
31.58 ꢃ 0.57
29.36 ꢃ 0.75
27.93 ꢃ 0.77
22.12 ꢃ 0.38
34.08 ꢃ 0.35
32.52 ꢃ 0.51
31.43 ꢃ 0.58
40.94 ꢃ 0.31
48.49 ꢃ 0.35
47.63 ꢃ 0.31
48.06 ꢃ 0.37
43.97 ꢃ 0.28
55.00 ꢃ 0.50
55.17 ꢃ 0.37
55.26 ꢃ 0.89
46.81 ꢃ 0.22
64.01 ꢃ 0.41
61.50 ꢃ 0.32
56.17 ꢃ 0.44
47.62 ꢃ 0.17
66.84 ꢃ 0.36
64.01 ꢃ 0.23
60.33 ꢃ 0.37
2.41 ꢃ 0.27a
0.91 ꢃ 0.15
0.83 ꢃ 0.17
1.08 ꢃ 0.15b
IEE
Data represented as mean ꢃ SEM, n ¼ 6.
a
Statistical analysis was performed with ANOVA followed by Dunnett test P < 0.01 with respect to control.
P < 0.05 with respect to control.
b
masking of carboxylic group of ibuprofen when coupled with that
of promoieties that protect the gastric mucosa from injury evoked
by ibuprofen.
CH2, cyclohexane),
(m,1H, eCH), 1.94 (m,1H, eCH),
2H, eCH2), 3.84 (m,1H, cyclic ring),
(4H, aromatic). Mass: (70 eV) m/z 344.
d
1.61 (d, 3H, CH3),
2.01 (m,1H, cyclic ring),
3.92 (m,1H, eCH), 7.09e7.16
d
1.63 (m,1H, cyclic ring),
d 1.86
d
d
d
2.46 (d,
d
d
d
3. Conclusion
4.2.2. (R,S) 2-Isopropyl-5-methylphenyl 2-(4-isobutyl phenyl)
propanoate (ITE)
The present work utilizes natural phytophenols for achieving
the synergistic effect and reducing the gastrointestinal toxicity
associated with ibuprofen. It is found to be the appropriate method
for increasing therapeutic effectiveness of ibuprofen with safer
promoieties. The studies showed that prodrug approach can be
successfully applied in attaining the goal of minimized gastroin-
testinal toxicity with retention of desired anti-inflammatory
activity. Mutual prodrug approach therefore gives an opportunity
in medicinal chemistry to improve the clinical and therapeutic
effectiveness of a drug that is suffering from some undesirable
properties hindering its clinical usefulness.
Yield: 74%; mp 67e68 ꢁC, UV (CHCl3): lmax 267 nm, IR (KBr)
cmꢀ1: 1723 (C]O str. ester), 1231 (CeO str. ester), 1H NMR
(300 MHz, CDCl3):
(d, 3H, CH3), 1.81 (m, 1H, eCH),
eCH2), 3.05 (m, 1H, eCH), 3.65 (s, 1H, eCH), d
d
0.87 (d, 6H, 2CH3),
2.32 (s, 3H, eCH3),
7.07e7.22 (7H,
d
1.21 (d, 6H, eCH3),
d 1.47
d
d
d
2.42 (d, 2H,
d
d
aromatic ibuprofen & thymol). Mass: (70 eV) m/z 338.
4.2.3. (R,S) 4-Allyl-2-methoxy phenyl 2-(4-isobutyl phenyl)
propanoate (IEE)
Yield: 62%; mp 38e39 ꢁC, UV (CHCl3): lmax 266 nm IR (KBr)
cmꢀ1: 1755 (C]O str. ester),1267 (CeO str. ester), 1H NMR
(300 MHz, CDCl3):
1H, eCH), 2.43 (d, 2H, eCH2),
CH), 3.83 (s, 3H, eOCH3), 5.0 (m, 2H, ]CH2),
6.76e6.98 (3H, aromatic eugenol), 7.05e7.24 (4H, aromatic
ibuprofen). Mass: (70 eV) m/z 352.
d
0.91 (d, 6H, 2CH3),
3.21 (d, 2H, eCH2),
5.92 (m, 1H, eCH),
d
1.56 (d, 3H, CH3),
d 1.82 (m,
4. Experimental
d
d
d
3.78 (s, 1H, e
d
d
d
4.1. General experimental protocols
d
d
Menthol, eugenol and thymol are obtained from Loba Chemie
Pvt. Ltd., Mumbai (India). All solvents were of analytical grade
distilled and dried before use as required. Thin layer chromatog-
raphy (TLC) was done on pre-coated aluminum plates using suit-
able mobile phase. Infra red (FTIR) spectra were recorded using KBr
on FTIR-8400S Shimadzu. 1H NMR spectra recorded on Joel-FT-
NMR-300 MHZ using CDCl3 as solvent and tetramethylsilane (TMS)
as internal standard. Mass spectra were recorded on HELWETT
PACKARD G180017 GCD system. Partition coefficient was computed
using Schrodinger molecular modeling Interface Inc., LLC, New
York. The chromatographic system consisted of a pump (Agilent
4.3. Determination of partition coefficient
The partition coefficient of ibuprofen and prodrugs were
determined in octanolewater system at 25 ꢁC by reported method
[17]. 100 mg of ibuprofen/IME/ITE/IEE drug was added to 10 mL of
aqueous phase and 10 mL of organic phase was added to it. This
mixture was shaken for 1 h and left for 2 h at 25 ꢁC. Concentration
was determined by HPLC method and partition coefficient was
calculated as the ratio of concentration of drug in organic phase to
the concentration of drug in aqueous phase.
1200),
a
PDA detector with
a Qualisil BDS C18 column
m) using methanol: water (30:70 v/v) as
(200 mm ꢂ 4.6 mm 5
m
mobile phase for determination and flow rate of 1.0 mL/min with
UV detection at 254 nm.
4.4. Aqueous hydrolysis
4.2. Synthesis of title compounds
The hydrolysis kinetics of prodrugs was studied at pH 1.2
(acidic), pH 7.4 (neutral) and pH 10.0 (alkaline) at 37 ꢁC using HCl,
phosphate and NaOH buffer. The total buffer concentration was
20 mM and constant ionic strength of 0.5 M for each sample was
maintained by adding KCl. Hydrolysis of prodrugs were initiated by
adding the samples to buffer solution. The solutions were sealed in
screw-capped glass vials and then placed into a thermostatically
controlled water bath at 37 ꢁC. The samples were withdrawn at
appropriate time interval (15, 30, 60, 120, 240 min) and assayed for
the presence of ester and hydrolysis product by HPLC according to
the previously described method [6,8]. Pseudo first-order rate
constants (Kobs) for the individual reactions were calculated with
the help of equation, Kobs ¼ 2.303/t ꢂ log (a/a ꢀ x), Where, ‘a’ is
initial concentration, ‘x’ is the amount of drug hydrolyzed and ‘t’ is
An enantiomeric mixture of targeted ester derivatives as mutual
prodrugs IME/ITE/IEE were synthesized by using DCC according to
the method reported with slight modification [26] (Scheme 1). The
synthesized compounds were purified by column chromatography.
The products were characterized for purity and confirmations of
their structures.
4.2.1. (R,S) 2-Isopropyl-5-methylcyclohexyl 2-(4-isobutyl phenyl)
propanoate (IME)
Yield: 67%; mp 48e49 ꢁC, UV (CHCl3): lmax 264 nm, IR (KBr)
cmꢀ1: 1753 (C]Ostr. ester),1225 (CeOstr. ester),1HNMR (300 MHz,
CDCl3): d 0.89 (d,12H, 4CH3), d 0.96 (s, 3H, eCH3), d 1.53e1.77 (6H, e

V.K. Redasani, S.B. Bari / European Journal of Medicinal Chemistry 56 (2012) 134e138
137
Scheme 1. Synthesis of racemic targeted ibuprofen ester prodrugs. DCC e N,N0 dicyclohexylcarbodiimide, DCM e dichloromethane, IME e ibuprofenementhol ester, ITE e
ibuprofenethymol ester, IEE e ibuprofeneeugenol ester.
time in minutes. The corresponding half-life (t1/2) was then ob-
Acknowledgments
tained from the equation: t1/2 ¼ 0.693/Kobs
.
Authors are thankful to Cadila Health Care Limited; Ahmedabad
(India) for providing gift sample of ibuprofen.
4.5. Biological evaluation
4.5.1. Materials/animals
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volume was measured with the help of Ugo Basile Plethysmometer
(7140). Results are expressed as mean ꢃ SEM. Statistical evaluation
was performed using analysis of variance followed by Dunnett test
for sub group comparison.
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