Thiazolidin-4-one and hydrazone derivatives of capric acid as possible anti-inflammatory, analgesic and hydrogen peroxide-scavenging agents

Article abstract of DOI:10.3109/14756366.2010.535796

Starting from capric acid, hydrazone and thiazolidin-4-one derivatives have been synthesized in the present investigation. Decanoic acid hydrazide was reacted appropriately to yield hydrazones, which were then cyclized to yield the corresponding thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by analytical and spectral methods. Anti-inflammatory, analgesic, and hydrogen peroxide-scavenging activity of the title compounds were evaluated. Among synthesized compounds, 2-hydroxyphenyl thiazolidinone with 44.90% inhibition of inflammation was the most potent anti-inflammatory agent. Similarly, 4-methoxybenzylidine hydrazide with 64.90% inhibition of writhing was observed to be the most potent analgesic agent of the synthesized compounds. All the synthesized compounds exhibited potent hydrogen peroxide-scavenging activity.

Full text of DOI:10.3109/14756366.2010.535796

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011; 26(4): 546–552
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2010.535796
ORIGINAL ARTICLE
iazolidin-4-one and hydrazone derivatives of capric acid
as possible anti-inflammatory, analgesic and hydrogen
peroxide-scavenging agents
Archana Sharma1, Vipin Kumar1, Sandeep Jain2, and Prabodh Chander Sharma1
1Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119 India, and 2Department of
Pharmaceutical Sciences, Guru Jambheshwar University of Science and Technology, Hisar, 125001 India
Abstract
Starting from capric acid, hydrazone and thiazolidin-4-one derivatives have been synthesized in the present
investigation. Decanoic acid hydrazide was reacted appropriately to yield hydrazones, which were then cyclized to
yield the corresponding thiazolidin-4-ones. The structures of the newly synthesized compounds were confirmed by
analytical and spectral methods. Anti-inflammatory, analgesic, and hydrogen peroxide-scavenging activity of the
title compounds were evaluated. Among synthesized compounds, 2-hydroxyphenyl thiazolidinone with 44.90%
inhibition of inflammation was the most potent anti-inflammatory agent. Similarly, 4-methoxybenzylidine hydrazide
with 64.90% inhibition of writhing was observed to be the most potent analgesic agent of the synthesized compounds.
All the synthesized compounds exhibited potent hydrogen peroxide-scavenging activity.
Keywords: Hydrazone, 4-thiazolidinone, capric acid, anti-inflammatory activity, analgesic activity, hydrogen
peroxide-scavenging activity
Introduction
related to many disorders such as arthritis, asthma,
and psoriasis, which require repeated or prolonged
In the recent past, there has been a considerable interest
and enthusiasm in developing novel and small hetero-
cyclic moieties possessing significant biological activi-
ties. e presence of thiazole moiety in the structure
of several naturally occurring molecules with impor-
tant antibiotic, immunosuppressive, and antitumour
activities has been well known for long.1 iazolidinone
derivatives have been reported to depict excellent
anticancer,2,3 anti-HIV,4 antitubercular,5 anti-inflamma-
tory and analgesic,6–8 antioxidant,9 antimicrobial,10–12
FSH agonists,13 CFTR inhibitory14 activities. Moreover,
hydrazones have been found to possess many bio-
logical actions such as antibacterial, anticonvulsant,
anti-inflammatory, antiprotozoal, and antitubercular.
erefore, synthesis, structure, and biological activities
of novel hydrazones prepared from fatty acid hydrazides
has been the focus of many researchers.15,16
treatment.17,18
Nonsteroidal anti-inflammatory
drugs (NSAIDs) are widely used for pain, fever, and
inflammation.19,20 Generally, undesired gastrointesti-
nal (GI) irritation21 and other side effects limit clinical
utility of most of the conventional NSAIDs. erefore,
discovery of new and safe anti-inflammatory agents
represents a challenging goal to medicinal chemists.
Recently, we have reported synthesis of novel 2,5-
disubstituted thiazolidinone derivatives from capric
acid with promising anti-inflammatory, analgesic, and
hydrogen peroxide-scavenging activities.22 In the lights
of these facts, we anticipated that the 2-substituted thi-
azolidinones and hydrazones derived from capric acid
may also possess commendable biological potential.
us, it was felt worthwhile to undertake biological
evaluation of these compounds and determine their
possible pharmacological significance. Hence, in the
present work, we report the synthesis with chemical
Inflammation is a multifactorial process. It reflects
the response of organisms to various stimuli and is
Address for Correspondence: Prabodh Chander Sharma, Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, 136119
India. E-mail: sharma_prabodh@rediffmail.com
(Received 08 September 2010; revised 25 October 2010; accepted 26 October 2010)
546

Thiazolidin-4-one and hydrazone derivatives of capric acid 547
characterization and biological activities of these
hydrazones and 2-substituted thiazolidin-4-ones.
(3H, t, –CH3), 1.24–1.58 (14H, m, (CH2)7), 2.18–2.59 (2H,
t, COCH2), 7.38–7.63 (5H, m, aromatic proton), 9.97 (1H,
s, NCH), 11.02–11.14 (H, s, NH).
Decanoic acid (2-nitro benzylidene)hydrazide (4b).
Yield 67.33%; m.p. 101–102ºC; IR (cm−1, KBr): 3257 (N–H
of –CONH), 3045 (C–H str of aromatic), 2982-2845 (C–H
str of alkane), 1650 (C=O of –CONH), 1610-1490 (C=C aro-
matic), 1552 (N–O of –NO2) 1455 (C=N). 1H NMR, δ ppm
(CDCl3): 0.81 (3H, t, –CH3), 1.22–1.57 (14H, m, (–CH2)7),
2.21–2.48 (2H, t, COCH2), 7.68–8.65 (4H, m, aromatic pro-
ton), 10.12 (1H, s, NCH), 10.54–10.98 (H, s, NH).
Decanoic acid (4-chloro benzylidene)hydrazide (4c).
Yield 79.73%; m.p. 107–108ºC; IR (cm−1, KBr): 3255 (N–H
of –CONH), 3020 (C–H str of aromatic), 2910-2865 (C–H
str of alkane), 1656 (C=O of –CONH), 1610-1490 (C=C
aromatic) 1458 (C=N). 1H NMR, δ ppm (CDCl3): 0.83
(3H, t, –CH3), 1.23–1.59 (14H, m, (–CH2)7), 2.2–2.49 (2H, t,
COCH2), 7.60–8.56 (4H, m, aromatic proton), 10.02 (1H,
s, NCH), 11.01–11.21 (H, s, NH).
Materials and methods
Chemistry
Chemicals and all solvents used in this study were
procured from Merck AG (Mumbai, India), SD Fines
(Mumbai, India), and Qualigens (Navi Mumbai, India).
Melting points were obtained on a Labindia MR-VIS
visual melting range apparatus (Mumbai, India) and are
uncorrected. e infrared (IR) spectra were recorded on
a Perkin Elmer (Waltham, MA), IR spectrophotometer
(potassium bromide disk). 1H NMR spectra were recorded
using Bruker 400 (Fallanden, Switzerland) spectrom-
eter and chemical shifts are expressed as δ (ppm) with
tetramethylsilane as an internal standard. Mass spectra
were obtained on Waters Q-TOF micro mass spectrom-
eter (Manchester, UK), using electron spray ionization
method.
Decanoic acid (4-fluoro benzylidene)hydrazide (4d).
Yield 87.06%; m.p. 94–96ºC; IR (cm−1, KBr): 3258 (N–H of
–CONH), 3050 (C–H str of aromatic), 2920-2880 (C–H str
of alkane), 1650 (C=O of –CONH), 1610-1490 (C=C aro-
General procedure for the preparation of compounds
Synthesis of methyl ester of capric acid (2). A mixture
of decanoic acid (0.25M) (1) and excess of methanol
(250mL) with 1mL of sulphuric acid was refluxed for
3–4h. e solution was cooled and poured into crushed
ice. Sodium bicarbonate was added to remove excess acid
and then product was extracted with ether. e ether layer
was evaporated to get a thick concentrated ester (2).
Decanoic acid hydrazide (3). e ester (0.2 M) (2)
obtained in earlier step and excess of hydrazine hydrate
(0.30 M)weresuspendedinethanol(250 mL)andrefluxed
for about 3 h and cooled. e solid was separated by fil-
tration and recrystallized from ethanol to afford decanoic
acid hydrazide (3).
Hydrazones (4a–i). A mixture of decanoic acid hydraz-
ide (0.025 M) (3) and respective aromatic aldehyde
(0.025 M) was refluxed in methanol (50 mL) in the pres-
ence of small amount of glacial acetic acid for about 2 h.
e mixture was cooled and poured in ice-cold water.
e solid thus obtained was separated by filtration and
recrystallized from methanol to give the corresponding
hydrazone (4a–i).
1
matic) 1459 (C=N). H NMR, δ ppm (CDCl3): 0.87 (3H,
t, –CH3), 1.37–1.86 (14H, m, (–CH2)7), 2.84–2.87 (2H, t,
COCH2), 7.37–7.80 (4H, m, aromatic proton), 8.13–9.85
(1H, s, NCH), 10.78–11.03 (H, s, NH).
Decanoic acid (4-methoxy benzylidene)hydrazide (4e).
Yield 89.55%; m.p. 75–78ºC; IR (cm−1, KBr): 3262 (N–H
of –CONH), 3040 (C–H str of aromatic), 2925-2880 (C–H
str of alkane), 1660 (C=O of –CONH), 1615-1492 (C=C
aromatic) 1458 (C=N). 1H NMR, δ ppm (CDCl3): 0.83 (3H,
t, –CH3), 1.24–1.57 (14H, m, (–CH2)7), 2.15–2.59 (2H, t,
COCH2), 3.22–3.77 (3H, t, OCH3), 6.94–7.56 (4H, m, aro-
matic proton), 9.73 (1H, s, NCH), 10.99–11.18 (H, s, NH).
Decanoic acid (3-nitro benzylidene)hydrazide (4f).
Yield 76.43%; m.p. 123–125ºC; IR (cm−1, KBr): 3255 (N–H
of –CONH), 3046 (C–H str of aromatic), 2980-2840 (C–H
str of alkane), 1655 (C=O of –CONH), 1610-1492 (C=C aro-
matic), 1550 (N–O of –NO2) 1465 (C=N). 1H NMR, δ ppm
(CDCl3): 0.85 (3H, t, –CH3), 1.38–1.85 (14H, m, (–CH2)7),
2.84–2.88 (2H, t, COCH2), 7.18–7.37 (4H, m, aromatic pro-
ton), 8.55 (1H, s, NCH), 10.87–11.05 (H, s, NH).
2-Substituted thiazolidin-4-one (5a–i). Synthesized
hydrazone (0.02 M) (4) and appropriate quantity of
thioglycolic acid (0.02 M) in dimethyl formamide (DMF)
(50 mL), containing a pinch of anhydrous ZnCl2 were
refluxed for about 6 h. e reaction mixture was cooled
and poured on to crushed ice. e solid thus obtained
Decanoic acid (2-hydroxy benzylidene)hydrazide (4g).
Yield 76.55%; m.p. 106–110ºC; IR (cm−1, KBr): 3250 (N–H
of –CONH), 3195 (O–H str), 3059 (C–H str of aromatic),
2910-2876 (C–H str of alkane), 1656 (C=O of –CONH),
1
1610-1490 (C=C aromatic) 1457 (C=N). H NMR, δ ppm
(CDCl3): 0.83 (3H, t, –CH3), 1.23–1.59 (14H, m, (–CH2)7),
2.2-2.49 (2H, t, COCH2), 7.60–8.56 (4H, m, aromatic pro-
ton), 8.04 (1H. s, –OH), 10.02 (1H, s, NCH), 11.03–11.26
(H, s, NH).
was filtered, washed with water, and the product (5a–i
)
was recrystallized from ethanol.
Syntheticpathwayfortheformationoftitlecompounds
is depicted in Figure 1.
Decanoic acid benzylidene-hydrazide (4a). Yield
85.33%; m.p. 75–77ºC; IR (cm−1, KBr): 3256 (N–H of
–CONH), 3020 (C–H str of aromatic), 2910-2870 (C–H
str of alkane), 1660 (C=O of –CONH), 1610-1490 (C=C
aromatic) 1449 (C=N); 1H NMR, δ ppm (CDCl3): 0.83
Decanoic acid (4-dimethylamino benzylidene)
hydrazide (4h). Yield 81.20%; m.p. 115–118ºC; IR (cm−1,
KBr): 3255 (N–H of –CONH), 3025 (C–H str of aromatic),
2910-2875 (C–H str of alkane), 1660 (C=O of –CONH),
1
1610-1490 (C=C aromatic) 1447 (C=N). H NMR, δ ppm
(CDCl3): 0.84 (3H, t, –CH3), 1.24–1.56 (14H, m, (–CH2)7),
© 2011 Informa UK, Ltd.

548 A. Sharma et al.
2.13–2.15 (2H, t, COCH2), 3.12 (6H, s, N–(CH3)2), 6.69–7.46
(4H, m, aromatic proton), 8.19 (1H, s, NCH), 10.76–10.88
(H, s, NH).
Decanoic acid (4-hydroxy-3,5-dimethoxy benzylidene)
hydrazide (4i). Yield 75.51%; m.p. 134–136ºC; IR (cm−1,
KBr): 3250 (N–H of –CONH), 3192 (O–H str), 3051 (C–H
str of aromatic), 2910-2876 (C–H str of alkane), 1656
(C=O of –CONH), 1610-1497 (C=C aromatic) 1450 (C=N).
1H NMR, δ ppm (CDCl3): 0.81 (3H, t, –CH3), 1.23–1.55
(14H, m, (–CH2)7), 2.20–2.41 (2H, t, COCH2), 3.75 (6H,
s, –OCH3), 7.76–8.26 (2H, m, aromatic proton), 8.05 (1H,
s, –OH), 10.01 (1H, s, NCH), 11.03–11.26 (H, s, NH).
Decanoic acid (4-oxo-2-phenyl-thiazolidin-3yl)amide
(5a). Yield 84.01%; m.p. 160–165ºC; IR (cm−1, KBr): 3251
(N–H of –CONH), 3025 (C–H str of aromatic), 2910-2870
(C–H str of alkane), 1755 (C=O of thiazolidinone), 1650
(C=O of CONH), 1614-1485 (C=C aromatic), 1144, 690
(C–S of thiazolidinone). 1H NMR, δ ppm (DMSO-d6):
0.85–0.88 (3H, t, –CH3), 1.25–1.43 (14H, m, (–CH2)7),
1.70–1.77 (2H, t, COCH2), 2.08–2.11 (2H, s, SCH2),
CH3(CH2)8COOH
Capric Acid (1)
ROH H2SO4
CH3(CH2)8COOCH3
Methyldecylate (2)
N2H4.OH2
CH3OH
CH3(CH2)8CONHNH2
Decanoic acid hydrazide (3)
ArCHO
CH3(CH2)8CONH–N=CHAr
Schiff's base (4a-i
)
SHCH2COOH
O
O
S
NH
N
CH3(CH2)8C
Ar
2-Substituted thiazolidin-4-one (5a-i
)
S. No.
4/5a
−Ar
S. No.
4/5f
−Ar
NO2
HO
O2N
4/5b
4/5c
4/5g
4/5h
Cl
F
N(CH3)2
H3CO
OH
4/5d
4/5e
4/5i
OCH3
OCH3
Figure 1. Synthetic protocol for the preparation of hydrazones and thiazolidinones.
Journal of Enzyme Inhibition and Medicinal Chemistry

Thiazolidin-4-one and hydrazone derivatives of capric acid 549
7.26–7.41 (5H, m, aromatic proton), 7.87 (1H, s, SCHN),
10.41 (1H, s, NH).
ppm (DMSO-d6): 0.87–0.89 (3H, t, –CH3), 1.16–1.29 [14H,
m, (CH2)7], 1.60–1.92 (2H, t, –COCH2), 2.30–3.02 (2H, s,
–SCH2), 6.89–7.26 (4H, m, aromatic proton), 7.73 (1H, s,
–SCHN), 8.04–8.73 (1H, s, –OH), 9.57 (1H, s, –NH).
Decanoic acid [4-oxo-2-(2-nitro phenyl)-thiazolidin-
3yl]amide (5b). Yield 70.34%; m.p. 145–150ºC; IR (cm−1,
KBr): 3260 (N–H of CONH), 3040 (C–H str of aromatic),
2930-2870 (C–H str of alkane), 1757 (C=O of thiazolidi-
none), 1665 (C=O of CONH), 1610-1485(C=C aromatic),
1544 (N–O of NO2), 1149, 696 (C–S of thiazolidinone).
1H NMR, δ ppm (DMSO-d6): 0.84–0.86 (3H, t, –CH3),
1.26–1.45 (14H, m, (–CH2)7), 1.70–1.76 (2H, t, COCH2),
2.08–2.11 (2H, s, SCH2), 8.84–7.45 (m, 4H, aromatic pro-
ton), 7.87 (1H, s, SCHN), 10.41 (1H, s, NH).
Decanoic acid [4-oxo-2-(4-chloro phenyl)-thiazolidin-
3yl]amide (5c). Yield 78.46%; m.p. 170–172ºC; IR (cm−1,
KBr): 3252 (N–H of CONH), 3058 (C–H str of aromatic),
2919-2848 (C–H str of alkane), 1756 (C=O of thiazolidi-
none), 1653 (C=O of CONH), 1610-1485 (C=C aromatic),
1147, 695 (C–S of thiazolidinone). 1H NMR, δ ppm
(DMSO-d6): 0.87–0.89 (3H, t, CH3), 1.25–1.41 [14H, m,
(–CH2)7], 1.69–1.76 (2H, t, –COCH2), 2.73–2.77 (2H, s,
–SCH2), 7.34–7.61 (4H, m, aromatic proton), 7.86 (1H, s,
–SCHN), 10.77 (1H, s, –NH).
Decanoic acid [4-oxo-2-(4-fluoro phenyl)-thiazolidin-
3yl]amide (5d). Yield 78.42%; m.p. 175–176ºC; IR (cm−1,
KBr): 3255 (N–H of CONHN), 3050 (C–H str of aromatic),
2910-2868 (C–H str of alkane), 1752 (C=O of thiazoli-
dinone), 1660 (C=O of –CONH), 1615-1490 (C=C aro-
matic), 1145, 692 (C–S of thiazolidinone). 1H NMR, δ
ppm (DMSO-d6): 0.85–0.87 (3H, t, CH3), 1.25–1.39 [14H,
m, –CH2)7], 1.69–1.76 (2H, t, –COCH2), 2.75–2.79 (2H, s,
–SCH2), 7.64–7.85 (4H, m, aromatic proton), 7.80 (1H, s,
–SCHN), 10.71 (1H, s, –NH).
Decanoic acid [4-oxo-2-(4-N dimethyl amino phenyl)-
thiazolidin-3yl]amide (5h). Yield 65.16%; m.p. 150–153ºC;
IR (cm−1, KBr): 3261 (N–H of CONH), 3020 (C–H str of
aromatic), 2914-2872 (C–H str of alkane), 1760 (C=O of
thiazolidinone), 1655 (C=O of CONH), 1614-1485 (C=C
1
aromatic), 1144, 690 (C–S of thiazolidinone). H NMR, δ
ppm (DMSO-d6): 0.85–0.88 (3H, t, –CH3), 1.25–1.43 (14H,
m, (–CH2)7), 1.70–1.77 (2H, t, COCH2), 2.08–2.11 (2H, s,
SCH2), 3.10 (6H, s, N–(CH3)2), 7.26–7.41 (H, m, aromatic
proton), 7.87 (1H, s, SCHN), 10.41 (1H, s, NH).
Decanoic acid [4-oxo-2-(4-hydroxy-3,5-dimethoxy
phenyl)-thiazolidin-3yl]amide (5i). Yield 66.11%; m.p.
248–251ºC; IR (cm−1, KBr): IR (cm−1, KBr): 3265 (N–H of
CONH), 3190 (O–H str), 3040 (C–H str of aromatic), 2930-
2865 (C–H str of alkane), 1760 (C=O of thiazolidinone),
1668 (C=O of CONH), 1615–1480 (C=C aromatic), 1149,
696 (C–S of thiazolidinone). 1H NMR, δ ppm (DMSO-d6):
0.87–0.89 (3H, t, –CH3), 1.16–1.30 [14H, m, (CH2)7], 1.62–
1.95 (2H, t, –COCH2), 2.30–3.02 (2H, s, –SCH2), 3.71 (6H,
s, –OCH3), 7.10–7.41 (H, m, aromatic proton), 8.01 (1H, s,
–OH), 7.73 (1H, s, –SCHN), 9.57 (1H, s, –NH).
Pharmacological screening
Methods
Wistar rats weighing 180–250 g and Swiss albino mice
weighing25–30 gwerehousedinaroommaintainedunder
controlled room temperature 22 2°C, relative humidity
60–70%, and provided with food and water ad libitum. All
the experimental procedures and protocols used in the
study were reviewed by the Institutional Animal Ethics
Committee (Regn. No. 563/02/a/CPCSEA) and were in
accordance with the guidelines of the CPCSEA, Ministry
of Forests and Environment, Government of India. e
animals were deprived of food for 24 h before experimen-
tation but allowed free access to water throughout.
Decanoic
acid
[4-oxo-2-(4-methoxy
phenyl)-
thiazolidin-3yl]amide (5e). Yield 78.18%; m.p. 226–228ºC;
IR (cm−1, KBr): 3250 (N–H of –CONH), 3050 (C–H str of
aromatic), 2918-2852 (C–H str of alkane), 1760 (C=O of
thiazolidinone), 1659 (C=O of CONH), 1485-1610 (C=C
1
aromatic), 1150, 695 (C–S of thiazolidinone). H NMR, δ
ppm (DMSO-d6): 0.87–0.89 (3H, t, –CH3), 1.16–1.29 [14H,
m, (CH2)7], 1.60–1.92 (2H, t, –COCH2), 2.30–3.02 (2H, s,
–SCH2), 3.63 (3H, s, –OCH3), 7.10–7.41 (4H, m, aromatic
proton), 7.73 (1H, s, –SCHN), 9.57 (1H, s, –NH).
Anti-inflammatory activity
e anti-inflammatory activity of synthesized compounds
using carrageenan-induced paw oedema was studied
according to method of Winter et al.23 e animals were
divided into different groups each consisting of six rats.
Control group received normal saline:Tween 80 (95:5), the
standard group received standard drug diclofenac sodium
50mg/kg body weight, and the test groups received the
synthesized compounds at the dose of 50mg/kg body
weight. irty minutes after administration of test and
standard drugs, 0.1mL of 1% w/v of carrageenan suspen-
sion in normal saline was injected to all animals in the
left hind paw (plantar region). e paw volume, up to the
tibiotarsal articulation, was measured using a plethys-
mometer (Model 7140, Ugo Basile, Italy). Results of anti-
inflammatory screening are presented in Table 1.
Decanoic acid [4-oxo-2-(3-nitro phenyl)-thiazolidin-
3yl]amide (5f). Yield 74.41%; m.p. 203–208ºC; IR (cm−1,
KBr): 3260 (N–H of –CONH), 3042 (C–H str of aromatic),
2930-2860 (C–H str of alkane), 1757 (C=O of thiazolidi-
none), 1665 (C=O of CONH), 1610-1485 (C=C aromatic),
1544 (N–O of NO2), 1150, 696 (C–S of thiazolidinone).
1H NMR, δ ppm (DMSO-d6): 0.84–0.86 (3H, t, –CH3),
1.26–1.45 (14H, m, (–CH2)7), 1.70–1.76 (2H, t, COCH2),
2.08–2.11 (2H, s, SCH2), 8.84–7.45 (m, 4H, aromatic pro-
ton), 7.87 (1H, s, SCHN), 10.41 (1H, s, NH).
Decanoicacid[4-oxo-2-(2-hydroxyphenyl)-thiazolidin-
3yl]amide (5g). Yield 63.21%; m.p. 199–201ºC; IR (cm−1,
KBr): 3265 (N–H of CONH), 3196 (O–H str), 3050 (C–H str
of aromatic), 2925-2860 (C–H str of alkane), 1760 (C=O
of thiazolidinone), 1665 (C=O of CONH), 1610-1485(C=C
e percentage protection of oedema (inhibition of
inflammation) was calculated according to the formula,
1
aromatic), 1149, 696 (C–S of thiazolidinone). H NMR, δ
© 2011 Informa UK, Ltd.

550 A. Sharma et al.
percentage anti-inflammatory activity=100×(1 − Vt/Vc)
where Vt and Vc are the volume of oedema in test com-
pounds and control groups, respectively. It is pertinent
to mention here that maximum activity was obtained at
90min and thus percentage inhibition was calculated at
90min.
were added to a hydrogen peroxide solution (0.6 mL,
40 mM). e absorbance of hydrogen peroxide at 230 nm
was determined after 10 min against a blank solution
containing phosphate buffer without hydrogen perox-
ide. e percentage scavenging of hydrogen peroxide of
synthesized compounds and standard compounds were
calculated using the following formula:
Analgesic activity
Percentagescavenging[H2O2 ]=[(A0 − A1 )/A0 ]×100
e analgesic activity was measured against chemical
stimulus. For analgesic activity, the animals were divided
into groups consisting of six mice each. e control group
received normal saline:Tween 80 (95:5). e standard
group received diclofenac sodium 50 mg/kg body weight
and the test groups received the synthetic compounds
at a dose of 50 mg/kg body weight. irty minutes later,
nociception was induced by an intraperitoneal (IP)
injection of acetic acid (1.0%), 0.1 mL/10 g. e number
of stretching or writhing was recorded from 5 to 15 min.
e percentage protection was calculated by following
formula:
where A0 was the absorbance of the blank, and A1 was
the absorbance in the presence of the sample and stan-
dards.24 Percentage scavenging of hydrogen peroxide
by synthesized compounds at 100, 300, and 500 μg/mL
concentration was observed. Results are summarized in
Table 3.
Results and discussion
Synthetic chemistry
In the present investigation, synthesis of hydrazones
and thiazolidinones has been carried out starting from
a long chain fatty acid that is capric acid. Hydrazide (3)
was obtained by reaction of the methyl ester of capric
acid (2) with hydrazine hydrate and was further reacted
with different aromatic aldehydes to yield correspond-
ing hydrazones (4a–i). e hydrazones thus obtained
were then reacted with mercapto acid in DMF and in
presence of small amount of ZnCl2 to yield 2-substituted
thiazolidin-4-ones (5a–i). Synthesis of hydrazones and
thiazolidinones was confirmed by spectral analysis. IR
Percentage protection =100 −
(No.of writhes in test/No. of writhes in control) ×100.
Results of this study have been summarized in Table 2.
Hydrogen peroxide-scavenging activity
A solution of hydrogen peroxide (40 mM) was prepared in
phosphate buffer (pH 7.4). Different concentrations (100,
300, and 500 µg/mL) of all the synthesized compounds
Table 1. Anti-inflammatory activity of the synthesized
compounds.
Table 2. Analgesic activity of synthesized compounds.
Abdominal writhing method
Anti-inflammatory activity
Dose
(mg/kg)
Mean number of
writhing SEM
Inhibition
(%)
Dose
Oedema (ΔT)
(mm) SEM
Activity
(% at 90min)
Compound
Compound (mg/kg)
4a
4b
4c
4d
4e
4f
4g
4h
4i
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50.87
43.15
62.80
62.80
64.90
37.54
41.05
54.03
38.60
49.50
40.22
61.40
47.36
52.63
50.87
62.10
52.28
57.89
69.80
4a
4b
4c
4d
4e
4f
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
0.71 0.03
28.29
27.28
24.25
24.25
31.32
30.30
44.70
37.76
21.43
38.78
33.68
26.52
31.32
41.84
30.30
44.90
44.70
30.28
51.51
14.0 0.6**
16.20 1.18**
10.60 0.75**
10.60 0.92**
10.00 0.63**
17.8 0.4
0.72 0.07**
0.75 0.09**
0.75 0.06**
0.68 0.01**
0.70 0.01**
0.55 0.06**
0.61 0.05
4g
4h
4i
16.8 0.4**
13.1 0.7
17.50 0.76**
14.40 0.90**
17.10 0.21**
11.03 0.97**
15.70 0.69**
13.50 0.56**
14.10 0.92**
10.8 1.0**
0.77 0.09**
0.60 0.03
5a
5b
5c
5d
5e
5f
5a
5b
5c
5d
5e
5f
0.65 0.01**
0.73 0.04**
0.68 0.05**
0.57 0.02**
0.70 0.05**
0.54 0.04**
0.55 0.06**
0.69 0.08**
0.49 0.09**
5g
5h
5i
5g
5h
5i
13.6 1.3**
12.06 0.75**
8.90 0.28**
Diclofenac
sodium
Diclofenac
sodium
Values of paw thickness are mean SEM from six animals in each
group, P<0.05, **P<0.01, compared with control.
Values are mean SEM from six animals in each group, P<0.05,
**P<0.01, compared with control.
Journal of Enzyme Inhibition and Medicinal Chemistry

Thiazolidin-4-one and hydrazone derivatives of capric acid 551
spectra of hydrazones (4a–i) depicted bands in the region
3262-3250, 1660-1650, and 1465-1447 attributed to N–H
of CONH, C=O of CONH, and C=N stretching of com-
pounds respectively. In the IR spectra of 2-substituted
thiazolidinones bands of 3265-3250, 1760-1752, 1665-
1650 cm−1 regions were attributed to N–H of CONH, C=O
of thiazolidinone and C=O of CONH stretching of com-
pounds (5a–i). e peaks of 1760-1752 (C=O of thiazoli-
dinone) confirms the formation of thiazolidinone ring
from the hydrazones. In the NMR spectra of hydrazones
(4a–i), signal at δ 8.19–10.12 shows presence of CH=N in
the compounds. Lack of this signal in the spectra of title
compounds (5a–i), that is, thiazolidinones provides the
confirmatory evidence for ring closure from the cor-
responding Schiff’s bases. Presence of a peak at δ 7.87
confirmed formation of 1H singlet of –SCHN. Presence of
analgesic, hydrogen peroxide-scavenging activity
evaluation.
Anti-inflammatory screening
e anti-inflammatory activity of synthesized com-
pounds was determined using carrageenan-induced
paw oedema method. e paw volume, up to the tibi-
otarsal articulation, was measured using a plethysmom-
eter (Model 7140). e measures were determined at five
time intervals, that is, 0 h and 30, 60, 90, and 120 min after
drug/test compound treatment. Compounds have exhib-
ited significant anti-inflammatory activity. Compound 5g
with a hydroxyl group present depicted the most potent
activity of 44.90% (P-value <0.01). Compounds 4g and 5h
depicted the equivalent activity of 44.70%. Interestingly,
compound 4g was also having a hydroxyl group at ortho
position and was most active among the synthesized
hydrazones. Standard drug diclofenac sodium exhibited
51.51% inhibition (P-value <0.01) of inflammation.
1
a singlet peak at δ 10.54–11.26 in the H NMR spectra of
hydrazones signifies the presence of 1H of –NH(–CONH).
However, in thiazolidin-4-ones, the same signal was seen
at δ 9.57–10.77. Moreover, a singlet of 2H of –SCH2 was
also seen in the δ values ranging from 2.08 to 3.02 in NMR
spectra of thiazolidinones.
Analgesic screening
Determination of analgesic activity was done by adopt-
ing acetic acid-induced abdominal writhing test. Swiss
albino mice weighing 25–30 g were used for carrying the
evaluation. For abdominal writhing test, nociception was
induced by an intraperitoneal (IP) injection of acetic acid
and diclofenac sodium was used as a standard drug. e
number of stretching or writhing was recorded from 5 to
15 min.25–27 All the compounds exhibited significant anal-
gesic activities. Most of the hydrazones (4) have shown
significant activities in this test with compound 4e being
the most potent compound of series (percentage inhibi-
tion 64.90, P-value <0.01) followed by compounds 4c and
4d (percentage inhibition 62.80, P-value <0.01). Among
thiazolidin-4-ones compound 5g and 5c were observed to
be most active and depicted 62.10% and 61.40% inhibi-
tion of writhing (P-value <0.01), respectively. e stan-
dard drug diclofenac sodium exhibited 69.80% inhibition
at a dose of 50 mg/kg.
Pharmacology
Keeping in view the biological potential of thiazolidin-
4-ones, it was decided to perform biological evalua-
tion of all the newly synthesized thiazolidinones, that
is, compounds 5a–j. Since hydrazones have also been
exhibiting potent pharmacological activities, it was con-
sidered useful to screen all the hydrazones (4a–i) also for
their pharmacological potential. Hence, all the synthe-
sized compounds were subjected to anti-inflammatory,
Table 3. Hydrogen peroxide-scavenging activity of synthesized
compounds.
Scavenging of hydrogen peroxide
at different concentrations (%)
S. No.
100 µg
51.63
51.35
68.51
50.78
54.04
49.21
43.97
40.00
49.21
49.79
39.86
53.33
61.28
45.39
53.90
41.70
41.70
50.01
64.60
49.30
300 µg
54.04
49.50
71.35
52.91
49.79
50.64
39.86
50.35
50.21
54.47
40.43
49.79
64.40
39.72
56.74
39.57
39.57
50.21
66.40
53.00
500 µg
39.72
49.36
75.32
53.12
49.79
50.50
45.82
39.72
49.50
53.90
40.00
49.50
60.85
39.29
54.89
39.57
39.57
50.07
67.20
56.00
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
Antioxidant screening
Evaluation of antioxidant activities was done by method of
scavenging of hydrogen peroxide. For this purpose, a solu-
tion of hydrogen peroxide (40mM) was prepared in phos-
phate buffer (pH 7.4) and different concentrations (100,
300, and 500 µg/mL) of all the synthesized compound were
added to a hydrogen peroxide solution (0.6mL, 40mM).
Absorbance of hydrogen peroxide at 230nm was deter-
mined after 10min against a blank solution containing
phosphate buffer without hydrogen peroxide. e percent-
age scavenging of hydrogen peroxide of synthesized com-
pounds and standard compound were calculated. Among
synthesized compounds, 4c, 5d, and 5i were observed to be
most active. However, all the compounds have exhibited
potent antioxidant activities in general.
5h
5i
BHA
In conclusion, the present investigation describes
preparation of a series of hydrazones and thiazolidin-4
-ones from capric acid and evaluation of their potential
Ascorbic acid
© 2011 Informa UK, Ltd.

552 A. Sharma et al.
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Acknowledgements
Prof. Om Prakash, Director, Institute of Pharmaceutical
Sciences,andLt.Gen(Dr.)D.D.S.Sandhu,ViceChancellor,
Kurukshetra University, Kurukshetra-136119, India, are
duly acknowledged for providing necessary facilities.
14. Sonawane, N.D., Verkman, A.S. iazolidinone CFTR inhibitors
with improved water solubility identified by structure–activity
analysis. Bioorg. Med. Chem. 2008, 16, 8187–8195.
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antimicrobial activity of long chain hydrazones. Acta Chim. Slov.
2008, 55, 448–452.
16. Deep, A., Jain, S., Sharma, P.C., Verma, P., Kumar, M., Dora, C.P.
Design and biological evaluation of biphenyl-4-carboxylic acid
hydrazide hydrazone for antimicrobial activity. Acta Pol. Pharm.
Drug Res. 2010, 67, 255–259.
17. Kharab, R., Sharma, P.C., Yar, M.S. Pharmacological significance
of triazole scaffold. J. Enz. Inhib. Med. Chem. 2010, (DOI No.
10.3109/14756360903524304).
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significant nucleus. In: Proceeding of the 1st Rashtriya Yuva
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19. Rajak, H., Kharya, M.D., Mishra, P. Synthesis of some novel
oxadiazole and oxadiazoline analogues for their antiinflammatory
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20. Rajak, H., Veerasamy, R., Kharya, M., Mishra, P. Design, synthesis,
and pharmacological evaluation of novel oxadiazole and
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21. Sharma, P.C., Yadav, S., Pahwa, R., Kaushik, D., Jain, S. Synthesis
and evaluation of novel prodrugs of naproxen. Med. Chem. Res.
2010, DOI No. 10.1007/s00044-010-9364-8.
Declaration of interest
e authors report no conflicts of interest. e authors
alone are responsible for the content and writing of the
paper.
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