Pharmacological evaluation of isochromen-1-ones and their thioanalogues derived from anti-inflammatory drug ketoprofen

Article abstract of DOI:10.1007/s11164-012-0690-y

The 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-one, 2 and their thio-analogues 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-thione, 3 and 3-{1-[3-(benzothioyl) phenyl]ethyl}-1H-isochromen-1-one, 5 were successfully obtained in good yield and purity from

Full text of DOI:10.1007/s11164-012-0690-y

Res Chem Intermed (2013) 39:1343–1351
DOI 10.1007/s11164-012-0690-y
Pharmacological evaluation of isochromen-1-ones
and their thioanalogues derived from anti-
inflammatory drug ketoprofen
•
A. Arumugham Napoleon Swati Bhagwat
Fazlur-Rahman Nawaz Khan
•
Received: 14 January 2012 / Accepted: 12 June 2012 / Published online: 12 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract The 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-one, 2 and their
thio-analogues 3-[1-(3-benzoylphenyl)ethyl]-1H-isochromen-1-thione, 3 and 3-{1-
[3-(benzothioyl) phenyl]ethyl}-1H-isochromen-1-one, 5 were successfully obtained
in good yield and purity from anti-inflammatory drug ketoprofen, 1 and its thio
analogue, 4. The compounds were successfully characterized by FT-IR, MASS,
1HNMR and 13CNMR spectral techniques. The in vitro anti-inflammatory and anti-
oxidant screening revealed that 3-[1-(3-benzoylphenyl) ethyl]-1H-isochromen-1-
one, 2 possesses better anti-oxidant and anti-inflammatory activity whereas 3-(1-(3-
benzoylphenyl)ethyl)-1H-isochromene-1-thione, 3 and 3-(1-(3-benzothioyl) phenyl]
ethyl}-1H-isochromen-1-one, 5 showed moderate anti-oxidant activity in compar-
ison to ketoprofen.
Keywords Isochromen-1-one ꢀ Thionation ꢀ Ketoprofen ꢀ Homophthalic acid ꢀ
Antioxidant ꢀ Anti-inflammatory
Introduction
Presently, numerous non-steroidal anti-inflammatory drugs (NSAIDs) are used for
reducing elevated body temperature, inflammations, muscular pain, tooth ache,
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-012-0690-y) contains supplementary material, which is available to authorized users.
A. A. Napoleon ꢀ S. Bhagwat
Pharmaceutical Chemistry Division, VIT University, Vellore 632 014, Tamil Nadu, India
F.-R. N. Khan (&)
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of
Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
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A. A. Napoleon et al.
Scheme 1 Synthesis of isochrome-1-one and their thioanalogues derived from the anti-inflammatory
drug ketoprofen
rheumatoid arthritis, pain due to any accident, migraine pain, tissue injuries, and any
musculoskeletal pain. However, most of them are producing significant unwanted
serious side effects, especially ulcers or gastric bleeding, resulting in hospitalization
[1]. Rofecoxib (Vioxx) was voluntarily withdrawn by the manufacturer from the
U.S. market in 2004 due to concerns of an increased risk of cardiovascular events
(including heart attack and stroke) for continued use of more than 18 months.
However, NSAIDs remain among the most commonly used medications worldwide
as an analgesic and antipyretic.
Ketoprofen, a non-steroidal anti-inflammatory drug (NSAIDs) with analgesic and
antipyretic effects [2], acts by inhibiting prostaglandin formation and is used
generally for arthritis-related inflammatory pains, severe toothaches, and treatment
of musculoskeletal pain [3, 4]. Isochromen-1-ones exhibits a broad range of
pharmacological activities including anti-inflammatory [5], anti-allergic, anti-
microbial [6, 7], anti-fungal [8], cytotoxic [9], immunomodulatory [10] enzyme
inhibitory [11], anti-cancer, and anti-oxidant [12]. Because of the widespread
importance of ketoprofen, and in order to explore the pharmacological activities of
isocchromen-1-ones and their thioanalogues derived from it, and because of our
continued interest in pharmacologically important compounds [13–36], the present
work is envisioned on the synthesis of isochromen-1-ones and their thioanalogues
from ketoprofen. A pharmacological evaluation has been carried out and compared
with that of ketoprofen.
The synthetic methodology adopted in the present study is depicted in Scheme 1.
Results and discussion
The isochromen-1-ones, and their thioanalogues 2, 3 and 5 derived from ketoprofen,
were synthesized successfully. The compound 3-[1-(3-benzoylphenyl) ethyl]-1H-
isochromen-1-one, 2, as synthesized is confirmed with the 1HNMR spectra showing
18 protons in which 13 protons are aromatic and 13CNMR spectra shows 24 carbons
in which the carbonyl group of isocoumarine gives a peak at 163.00, and the other
123

Pharmacological evaluation of isochromen-1-one and their thioanalogues
1345
carbonyl group is confirmed with the spectra at 196.20 (Supplementary Fig. 4), and
the mass spectra further confirm the molecular ion peak at 355.1 (Supplementary
Fig. 2). In the 1H NMR spectrum, compound 2 shows the singlet of three protons at
d 2.43 for the methyl group and the CH proton appeared at d 4.17 ppm. The value d
6.07 is the characteristic peak of C4-proton present in the isocoumarins ring. All the
remaining 13 aromatic protons appeared in the region of d at 7.34–8.29 ppm. In 13
C
NMR, the carbonyl peak of isochromen shows at d 163.11 and the free carbonyl
peak shows at d 196.20.
The compound 3-(1-(3-benzoylphenyl) ethyl)-1H-isochromen-1-thione, 3 was
obtained from 3-[1-(3-Benzoylphenyl) ethyl]-1H-isochromen-1-one, 2, the only
change made is an isosteric replacement of oxygen to sulfur in isochromen-1-one by
Lawesson’s reagent, with, no changes in its proton from its previous compound. It is
confirmed with their 13C NMR Spectra which show a carbonyl group peak at 197.06
(Supplementary Fig. 8), while the carbonyl group of isocoumarine peak shifted
from 163.00 (in the previous compound) to 190.56 in thioanalogue is confirmed for
thionation i.e. carbonyl to thiocarbonyl, in the isochromen-1-thione ring (Supple-
mentary Fig. 8) and further confirmed through its mass spectra with the molecular
ion peak at 371.2 (Supplementary Fig. 7).
The compound 2 was thionated to get compound 3 which was confirmed by the
13C NMR spectrum. In compound 2, the carbonyl peak appears at d 163.11 ppm
which was shifted to the downfield at d 190.56 ppm, due to the thiocarbonyl group,
which confirms the formation of the product 3. The formation of compound 3 is
further supported by the mass m/z at 371.2.
In compound 4, the carboxylic acid carbonyl peak appeared at d 178.95 and the
thionated carbonyl of benzophenone moiety shows the peak at d 234.06. The
compound 4 was converted to acid chloride and then further reacted with
homophthalic acid to get isocoumarin. The acid group carbonyl shifted to the
downfield region and appeared at d 189.31 ppm which confirms the formation of the
isocumarin 5.
All the three compounds synthesized were screened for their pharmacological
activities, using in vitro anti-inflammatory membrane stabilization and anti-
denaturation methods [18, 19]), and their anti-oxidant properties and were compared
with those of ketoprofen, 1. The stabilization of the RBC membrane is followed by
observing the inhibiting effect on heat-induced hemolysis at different concentra-
tions. Anti-inflammatory agents provide membrane stabilization avoiding the
release of lysosomal content of neutrophil, the prime causes of inflammation [20]. In
the anti-denaturation assay, the ability of the active compound to inhibit heat-
induced protein denaturation at different concentration was observed, as the
denaturation of proteins is one of the causes of inflammation.
Fresh whole human blood (10 mL) was collected from a healthy volunteer and
transferred to the heparinized centrifuged tubes. The tubes were centrifuged at
3,000 rpm for 10 min and washed three times with equal volume of normal saline. It
was then reconstituted as 10 % v/v RBC suspension with normal saline.
Equal volumes of test samples (2, 3 and 5) of various concentrations (50, 75 and
100 lg/mL) and 10 % v/v RBC suspension [20] were taken in centrifuge tubes.
Normal saline solution was prepared and used as control and the anti-inflammatory
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A. A. Napoleon et al.
Table 1 Membrane stabilization activity of isochrome-1-one and their thioanalogues derived from
ketoprofen
Sample
no.
Conc. in
lg/mL
% Inhibition
for 2
% Inhibition
for 5
% Inhibition
for 3
% Inhibition for standard
(ketoprofen)
1
2
3
50
75
52.43 1.81 43.65 0.88 49.08 0.48 55.06 1.84
55.44 1.63 47.97 1.79 51.84 0.35 59.75 1.99
58.68 2.00 51.97 0.66 55.72 0.73 64.49 1.33
100
drug ketoprofen (bulk drug) was used as standard. The reaction mixture was
incubated at 56 °C in a waterbath for 30 min, cooled, and centrifuged again at
2,500 rpm for 5 min. Absorbance of supernatant liquid was taken at 560 nm using
UV spectrophotometer (Shimadzu 1602). The anti-inflammatory activities for
various concentrations of each sample are recorded and compared with the standard
[21]. The experiment was carried out in triplicate. Percentage membrane
stabilization activity was calculated by the formula below (see Table 1);
ðAbs of control ꢁ Abs of sampleÞ
% Inhibition of denaturation ¼
ꢂ 100:
Abs of control
Anti-denaturation assay
The ability of the synthesized compound to inhibit heat-induced protein denatur-
ation at different concentrations was studied through this assay. The method of
Williams et al. [22] was used for this antidenaturation assay.
A solution of 0.2 % W/V of BSA was prepared in tris buffer saline and pH was
adjusted to 6.8 using glacial acetic acid. A methanolic solution (50 lL) of test
samples of various concentrations (50, 75 and 100 lg/mL) was taken in Eppendorf
tubes, to which was added 5 mL of 0.2 %W/V BSA [22]. The control consisted of
5 mL of 0.2 W/V BSA solutions with 50 lL methanol. Ketoprofen in methanol
with 5 mL of 0.2 % W/V BSA solution is used as standard. The test tubes were
heated at 72 °C for 5 min and cooled for 10 min. The absorbance of these solutions
was determined by using UV spectrophotometer (Shimadzu 1602) at a wavelength
of 660 nm. The percentage inhibition of precipitation [23] (denaturation of the
protein) was determined on a % basis relative to the control using the following
formula (see Table 2):
Table 2 Albumin denaturation activity of isochromen-1-one and thioanalogues derived from ketoprofen
Sample
no.
Conc. in
lL/mL
% Inhibition
for 2
% Inhibition
for 5
% Inhibition
for 3
% Inhibition for
standard (ketoprofen)
1
2
3
50
75
60.31 1.58
63.20 1.57
66.05 1.16
48.42 0.50
54.15 1.80
56.31 0.98
52.48 1.37
54.79 0.45
57.81 0.65
66.43 1.42
69.59 1.43
75.83 1.93
100
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Pharmacological evaluation of isochromen-1-one and their thioanalogues
1347
ðAbs of control ꢁ Abs of sampleÞ
% Inhibition of denaturation ¼
ꢂ 100:
Abs of control
The synthesized isochromen-1-ones were effective in inhibiting heat-induced
albumin denaturation at different concentrations as shown in Table 2. Among the
synthesized isochromen-1-ones, 2 showed a better albumin denaturation property.
Maximum inhibition of 66.05 1.16 was observed at 100 lg/mL. Ketoprofen, an
anti-inflammatory drug taken as standard, showed the maximum inhibition,
75.83 1.93 at the concentration of 100 lg/mL.
In vitro antioxidant studies
Anti-oxidant studies of the synthesized isochromen-1-ones and their thioanalogues
derived from ketoprofen was carried out by two methods, DPPH and H2O2
scavenging.
The free radical scavenging activity of all the synthesized Isochromen-1-ones
was determined by the 1,1-diphenyl-2-picryl-hydrazil (DPPH). This activity was
measured by following the methodology described by Blois [27] where, in the
bleaching rate of a stable free radical, DPPH is monitored at a characteristic
wavelength in the presence of the sample. In its radical form, DPPH absorbs at
517 nm [24, 25], but upon reduction by an antioxidant or a radical species, its
absorption decreases. A methanol solution of the stable nitrogen-centered free
radical DPPH (0.1 mM) was incubated with the test compounds 2, 3 and 5 in
different concentrations (25, 50, 75 and 100 lg/mL) for 30 min, and the absorbance
was measured at 517 nm in a UV spectrophotometer. Butylated hydroxy toluene
(BHT), a good antioxidant, is taken as a standard in this study. The scavenging
activities for various concentrations of each sample were recorded and the results
were compared with the standard (see Table 3). The experiment was performed in
triplicate. The capability of the scavenging DPPH radical was calculated by the
following equation [26]
ðAbs of control ꢁ Abs of sampleÞ
DPPH Scavenging effect ð%Þ ¼
ꢂ 100:
Abs of control
The results reveal a significant decrease in the concentration of DPPH radical due
to the scavenging ability of tested isochromen-1-ones and their derivatives
compared to that of the standard. The compound 2 is found to be exhibiting better
DPPH scavenging activity at various concentrations, among the tested compounds.
Table 3 DPPH scavenging activity of isochromen-1-ones and thioanalogues derived from ketoprofen
Sample
no.
Conc.
in lg/mL
% Scavenging
effect for 2
% Scavenging
effect for 5
% Scavenging
effect for 3
% Scavenging effect
for standard (BHT)
1
2
3
4
25
50
26.13 1.77
37.60 1.20
51.05 2.25
59.90 1.26
20.17 1.09
31.35 2.10
47.92 1.00
52.69 1.93
13.70 2.32
22.91 1.10
31.77 1.52
43.37 1.27
46.89 1.58
69.65 1.26
74.63 1.01
77.12 0.56
75
100
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A. A. Napoleon et al.
Table 4 H2O2 scavenging activity of isochromen-1-ones and thioanalogues derived from ketoprofen
Sample
no.
Conc.
in lg/mL
% Scavenging
effect of 2
% Scavenging
effect of 5
% Scavenging
effect of 3
% Scavenging
effect of standard
(ascorbic acid)
1
2
3
4
25
50
20.78 0.84
31.89 1.63
47.79 1.90
54.05 1.23
13.20 0.36
24.15 1.75
38.04 1,63
44.78 0.83
13.59 1.23
18.82 0.64
29.08 1.16
36.92 1.03
51.17 1.57
70.30 0.65
78.89 0.30
81.40 1.35
75
100
H2O2 scavenging activity
Hydrogen peroxide can be formed in vivo by many oxidizing enzymes such as
superoxide dismutase. It can cross membranes, and may slowly oxidize a number of
compounds in our body. The ability of the compound to scavenge hydrogen
peroxide was determined.
A methanolic solution of test samples 2, 3 and 5 of various concentrations (25,
50, 75 and 100 lg/ml) were added to a hydrogen peroxide solution prepared in
phosphate buffer saline (pH 7.4). After 10 min, the absorbance was measured at
230 nm (Shimadzu 1602). Ascorbic acid, which is a good antioxidant, was taken as
a standard in this study. The scavenging activities for various concentrations of each
sample were recorded and compared with the standard (see Table 4). The
experiment was performed in triplicate. The capability of scavenging H2O2 was
calculated by the following equation;
ðAbs of control ꢁ Abs of sampleÞ
% Scavenging effect ¼
ꢂ 100:
Abs of control
The results illustrates that a significant increase in H2O2 scavenging activity of
the tested samples with an increase in concentration. Among the tested compounds,
2 showed maximum antioxidant property.
Experimental methods
The starting material ketoprofen required for the present study was procured from
Piramal Healthcare, Mumbai. Isochromen-1-ones can be synthesized by conden-
sation reaction [13, 14] between acid chloride derivative of the ketoprofen USP
99 % purity (Sigma Aldrich) using thionyl chloride 99 % purity; Rankem) and
homophthalic acid 98 % purity (Sigma Aldrich).
3-[1-(3-Benzoylphenyl) ethyl]-1H-isochromen-1-one, 2
Ketoprofen, 1 (6 mmol, 1.524 g) was taken in a RB flask, 3.5 mL of thionyl
chloride (99 % purity; Rankem) was added , mixed well and refluxed for 2 h in a
fume hood to give 2-(3-benzoylphenyl)propanoyl chloride. Completion of the
reaction was checked with the help of TLC and stoppage of SO2 gas. Excess of
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Pharmacological evaluation of isochromen-1-one and their thioanalogues
1349
thionyl chloride was distilled off in the fume hood under reduced pressure. The
carboxylic acid chloride formed was highly sensitive to moisture, hence further
reaction was carried out in situ.
The above acid chloride mixture, homophthalic acid, (1.5 mmol, 0.27 g) was
added and refluxed at 200 °C in oilbath in a fume hood for 4 h [15] to afford the
3-[1-(3-benzoylphenyl) ethyl]-1H-isochromen-1-one, 2. The completion of the
reaction was monitored by TLC. The desired product was extracted with ethyl
acetate and washed with sodium bicarbonate solution to remove unreacted acid and
then with water. Anhydrous sodium sulphate was added to ethyl acetate layer to
remove the moisture and the contents are filtered, concentrated and purified by using
silica gel column chromatography with petroleum ether (40–60 °C) and ethyl
acetate mixture.
3-(1-(3-Benzoylphenyl) ethyl)-1H-isochromen-1-thione, 3
Mixture of 3-(1-(3-benzoylphenyl)ethyl)-1H-isochromen-1-one 2 (2 mmol,0.74 g),
Lawesson’s reagent (3 mmol, 1.206 g) and toluene (10 mL) was taken in a RB
flask. It was mixed well and refluxed [16, 17] for 1 h to afford 3-(1-(3-
benzoylphenyl) ethyl)-1H-isochromene-1-thione, 3. The completion of the reaction
was monitored by TLC using petroleum ether:ethyl acetate solvent system. The
product obtained was dissolved in chloroform. The reaction mixture was concen-
trated and the purified product was obtained by column chromatography using
petroleum ether (40–60 °C) and ethyl acetate mixture.
3-{1-[3-(Benzothioyl) phenyl] ethyl}-1H-isochromen-1-one, 5
Ketoprofen, 1 (6 mmol, 1.524 g) was taken in a RB flask. To this were added
Lawesson’s reagent (3 mmol, 1.206 g) and toluene (20 mL), mixed well and
refluxed for 1 h to afford 2-[3-benzothioylphenyl]propanoic acid, 4. The completion
of the reaction was monitered by TLC using petroleum ether (40–60 °C):ethyl
acetate. The desired product was extracted with chloroform and purified using silica
gel column chromatography.
The 2-(3-benzothioylphenyl) propanoic acid, 4 (5 mmol, 1.350 g) was taken in a
round-bottom flask to which was added 3.0 mL of thionyl chloride, mixed well and
then refluxed in a fume hood for 2 h to afford 2-(3-benzothiophenyl)propanoyl
chloride, which was found to be highly moisture sensitive, hence the further reaction
was carried out in situ. The acid chloride [2-(3-benzothioylphenyl) propanoyl
chloride] was made to react with homophthalic acid at 200 °C in an oilbath for 4 h
to afford 3-(1-(3-benzothioylphenyl) ethyl)-1H-isochromen-1-one, 5. The comple-
tion of the reaction was monitored by TLC. The desired product was extracted with
ethyl acetate layer and washed with sodium bicarbonate solution in order to remove
the excess acid and then with water. Then, to the extract, anhydrous sodium sulfate
was added to remove the moisture, filtered, and concentrated. The purified
compound was obtained by silica gel column chromatography using petroleum ether
(40–60 °C) and ethyl acetate mixture.
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A. A. Napoleon et al.
Data
3-[1-(3-benzoylphenyl) ethyl]-1H-isochromen-1-one, 2: C24H18O3Yellow solid,
m.p. 144–148 °C, IR (KBr, tmax cm-1): 2,921.63 (aromatic C–H stretch),
1,747.19, 1,605.45 (C = O stretch), 1,161.9 (C–O stretch). H NMR (400 MHz,
1
DMSO-d6) d 8.29 (s,1H), 7.84–7.81 (d, J = 12 Hz, 3H), 7.74–7.72 (d, J = 8 Hz
2H), 7.61 (s,1H), 7.54–7.52 (d, J = 8 Hz 4H), 7.51 (s, 1H), 7.43–7.34 (d, J = 36 Hz
1H), 6.07 (t, 1H), 4.17 (q, 1H), 2.43 (s, 3H) ppm. 13C NMR (400 MHz, DMSO-d6)
d 18.57, 43.71, 100.18, 123.08, 125.36, 127.20, 128.51, 128.68, 128.91, 129.11,
129.52, 129.70, 130.28, 132.29, 132.64, 132.99, 133.30, 134.09, 134.59, 135.86,
136.26, 163.08, 163.11, 196.20 ppm. Mass, m/z: 355.1.
3-(1-(3-Benzoylphenyl) ethyl)-1H-isochromen-1-thione, 3: C24H18 SO2 Orange
solid, m.p. 164–168 °C, IR (KBr, tmax cm-1): 2,921.63 (aromatic C–H stretch),
1,747.19, 1,605.45 (C = O stretch), 1,161.9 (C–O stretch). H NMR (400 MHz,
1
DMSO-d6) d 8.29 (s,1H), 7.84–7.81 (d, J = 12 Hz, 3H), 7.74–7.72 (d, J = 8 Hz
2H), 7.61 (s,1H), 7.54–7.52 (d, J = 8 Hz 4H), 7.51 (s, 1H), 7.43–7.34 (d, J = 36 Hz
1H), 6.07 (t, 1H), 4.17 (q, 1H), 2.43 (s, 3H) ppm. 13C NMR (400 MHz, DMSO-d6)
d: 18.06, 43.29, 105.90, 125.79, 126.21, 127.20, 127.91, 128.64, 128.71, 128.91,
129.70, 129.88, 129.94, 130.28, 132.29, 132.64, 133.30, 133.59, 134.94, 138.19,
139.69, 167.28, 190.56, 197.06. Mass, m/z: 371.2
2-[3-Benzothioylphenyl] propanoic acid, 4: C16H14SO2 Light green solid m.p.
121–123 °C, IR (KBr, tmax cm-1): 2,921.63 (aromatic C–H stretch), 1,747.19,
1,605.45 (C = O stretch), 1,161.9 (C–O stretch). 13C NMR (400 MHz, DMSO-d6)
d: 17.33, 45.71, 125.22, 127.51, 128.46, 128.54, 128.61, 129.20, 130.39,
130.41.130.55, 142.05, 145.36, 148.44, 178.95, 234.06. Mass, m/z: 270.
3-{1-[3-(Benzothioyl) phenyl] ethyl}-1H-isochromen-1-one, 5: C24H18SO2 Off-
white solid, m.p. 101–104 °C, IR (KBr, tmax cm-1): 2,921.63 (aromatic C–H
stretch), 1,747.19, 1,605.45 (C = O stretch), 1,161.9 (C–O stretch). 13C NMR
(400 MHz, DMSO-d6): 24 peaks d: 18.57, 43.86, 104.70, 120.05, 124.01, 125.25,
126.09, 128.14, 128.54, 128.84, 129.19, 129.50, 129.60, 131.91, 132.42, 132.80,
132.86, 133.02, 133.09, 137.31, 142.35, 161.90, 189.31, 233.53. Mass, m/z: 402.
Conclusion
The isochromen-1-ones and their thio analogues 2, 3 and 5 were synthesized from
ketoprofen, an anti-inflammatory drug containing carboxylic acid group with good
1
yield, and were successfully characterized by IR, H NMR, 13C NMR and mass
spectral techniques. The in vitro studies results show that 3-[1-(3-benzoylphenyl)
ethyl]-1H-isochromen-1-one, 2 have better anti-oxidant activity and anti-inflam-
matory activity whereas 3-(1-(3-benzoylphenyl) ethyl)-1H-isochromene-1-thione, 3
and 3-(1-(3-benzothioylphenyl)ethyl)-1H-isochromen-1-one, 5 showed moderate
anti-oxidant activity and anti-inflammatory activity when compared to the starting
material (ketoprofen).
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1351
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