Fluorine bearing sydnones with styryl ketone group: Synthesis and their possible analgesic and anti-inflammatory activities

Article abstract of DOI:10.3109/14756366.2011.586345

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2ai, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mgkg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.

Full text of DOI:10.3109/14756366.2011.586345

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(2): 241–248
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.586345
RESEARCH ARTICLE
Fluorine bearing sydnones with styryl ketone group: synthesis
and their possible analgesic and anti-inflammatory activities
Shreenivas Ramachandrarao Deshpande1 and Karkala Vasantakumar Pai2
1Department of Medicinal & Pharmaceutical Chemistry, HSK College of Pharmacy, Bagalkote, India and
2Department of Industrial Chemistry, Kuvempu University, Shankaraghatta, India
Abstract
In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone
group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a–i, was synthesized as better
analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-
4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated
at 100 mg\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed
good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in
mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect
at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice.
Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds
with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy
and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine
substitution.
Keywords: 3-(3-chloro-4-fluorophenyl)sydnone, styryl ketone, hot plate assay, writhing test, paw oedema,
ear oedema, ulcerogenicity
Introduction
substituted compounds of the above series i.e., 4-[1-
Structure activity relationship (SAR) is one of the tools
in drug design and development with which a medici-
nal chemist can explore the biological activity better by
effecting structural variation in a panel of compounds.
We undertook SAR studies of 4-[1-oxo-3-(substituted
aryl)-2-propenyl]-3-(3-different substituted phenyl)
sydnones as analgesic and anti-inflammatory agents on
the basis that molecules containing both the structural
features of sydnone and styryl ketone would be better
acting, because these compounds have been reported
separately in literature to exhibit analgesic and anti-
inflammatory activities1–6. As a part of this, we already
reported 3-(4-chlorophenyl) and 3-(4-methylphenyl)
substituted compounds of the said series for analge-
sic and anti-inflammatory activities7,8. In continuation
with it, we synthesized 3-(3-chloro-4-fluorophenyl)
oxo-3-(substituted
aryl)-2-propenyl]-3-(3-chloro-4-
fluorophenyl)sydnones 2a–i, and screened them for
analgesic and anti-inflammatory activities. e findings
of the study are presented in this paper.
Sydnones containing fluorine were planned to synthe-
size in an anticipation of good pharmacological profile
because fluorine, when present, can alter the biological
properties of a molecule. It affects lipophilicity thereby
enhancing absorption, transport, recognition and inter-
action of the molecule with the biological target in vivo,
thus increasing intrinsic activity, chemical and metabolic
stability9. In testimony of this, over 150 fluorinated drugs
are there in the market today making up to ~20% of all
pharmaceuticals. Some of the fluorinated molecules
which made their way to clinic include the antidepres-
sant fluoxetine, the cholesterol-lowering atorvastatin,
Address for Correspondence: Prof. Shreenivas R. Deshpande, Ph.D, Department of Medicinal and Pharmaceutical Chemistry,
HSK College of Pharmacy, BVVS Campus, Bagalkote 587 101, Karnataka, India. Tel.: +918354220008; Fax: +918354220008.
E-mail: srinidesh71@gmail.com
(Received 04 February 2011; revised 28 April 2011; accepted 04 May 2011)
241

242 S. R. Deshpande et al.
the anticancer agent 5-fluorouracil, the general anaes-
thetic halothane, the anti-inflammatory drug flumetha-
sone and the antibacterial ciprofloxacin10,11. erefore,
recently there is an increased interest in the synthesis of
fluorinated compounds as pharmaceuticals.
sodium caboxymethyl cellulose (Sod CMC). e ani-
mals in the vehicle control group were administered
0.5% Sod CMC 10 mL/kg b.w. p.o. All efforts were made
to minimize animal suffering and to reduce the num-
ber of animals used. e guidelines of institutional ani-
mal ethics committee constituted as per committee for
the purpose of control and supervision of experiments
on animals, Ministry of Environment and Forestry,
Government of India, were followed.
Methods
e analytical reagent grade chemicals were used with-
out further purification. Carrageenan was obtained
from Sigma (St. Louis, MO), croton oil from Paras per-
fumers (Delhi, India) and pentazocine from Pharma
Impex Laboratories (P) Ltd., (Kolkata, India). Embiotic
Laboratories (P) Ltd., (Bengaluru, India) gifted acetyl
salicylic acid (ASA), ibuprofen and indomethacin. e
completion of reaction and purity of products were
monitored by thin layer chromatography using silica gel
60 F254 pre-coated aluminium sheets (Merck, Darmstadt,
Germany) and benzene-ethyl acetate 8.5:1.5 by volume
as mobile phase. e spots were visualized by iodine
vapour.
Statistics
e data of animal experiments were expressed as mean
standard deviation (SD) and analyzed by Graph-pad
Prism (San Diego, CA). Statistical differences between
the treatments and the control were tested by analy-
sis of variance, followed by Dunnett’s multiple com-
parison test. Data with p value < 0.05 was considered
significant.
Synthesis of 2a–g: 4-[1-oxo-3- (4-N, N-dimethylamino
phenyl)-2-propenyl]-3-(3-chloro-4-fluoro phenyl)
sydnone 2f
Instrumentation
A mixture of 4-acetyl-3-(3-chloro-4-fluorophenyl)
Melting points were determined in Dolphin open cap-
illary tube apparatus (Mumbai, India) and are uncor-
rected. Ultra Violet-Visible (UV-Vis) spectra were taken
on Systronics V530 (Ahmedabad, India), Infrared (IR)
spectra on ermoNicolet 200 FT-IR (Madison, WI) by
potassium bromide pellet technique and mass spectra
(MS) on Finnegan-Mat1020 (electron impact, 70 ev)
(Bremen, Germany). Proton nuclear magnetic reso-
nance (1H-NMR) spectra in deuterochloroform were
recorded on BrukerAC200F (200 MHz) (Rheinstetten,
Germany), whereas 13C-NMR spectra were taken at
50 MHz. Chemical shifts were measured on δ scale in
parts per million downfield to tetramethylsilane. Peak
multiplicities are indicated as s (singlet), d (doublet), m
(multiplet) and br (broad); coupling constant (J) values
are given in Hz. Eddy’s Hot Plate (Kshitij International,
Ambala, India) and digital micrometer (Digitrik mark II,
NSK, Japan) were used in biological activities.
sydnone 1 (2.6 g, 0.01 mol), sodium hydroxide aque-
ous solution (0.6 g, 0.015 mol, 3 mL) and ethanol (95%,
20 mL) was cooled (5–10°C) and to this was added
4-N,N-dimethylaminobenzaldehyde (2 g, 0.012 mol)
while being stirred. e reaction mixture was stirred
further for 1 h. e precipitate obtained was filtered
washed with cold water and re-crystallised from etha-
nol (95%) and ethyl acetate (1:1) to give the title com-
pound (1.67 g, 0.0043 mol, 43%): mp 109–110°C; IR cm−1
1755 (C=O, sydnone), 1660 (C=O, styryl ketone); 1H-
NMR δ 3.08 (s, 6H, N(CH3)2), 6.74–6.77 (m, 3H, ArH and
olefinic αH), 7.36–7.49 (m, 2H, ArH), 7.78–7.83 (m, 4H,
ArH and olefinic βH); 13C-NMR δ 40.06, 106.03, 111.01,
118.2, 121.48, 124.2, 125.11, 131.97, 133.26, 134.20,
136.50, 154.39, 157.66, 162.77, 168.61, 190.31; MS m/z
387.59 (M+).
Remaining compounds were prepared similarly using
respective aryl aldehydes.
Animals
Adult healthy Albino mice (20–25 g b.w.) and Sprague-
Dawley rats (100–150 g b.w.) of either sex, bred at the
animal house facility of HSK College of Pharmacy,
Bagalkote, were used. e animals were maintained
on standard pellet diet and free access to water and
housed in polypropylene cage (4 per cage) on paddy
husk bedding under laboratory conditions at 22 3°C
temperature, 60 10% humidity and 12-h light/dark
cycle. ey were acclimatized for 7 days. e food was
withdrawn 18 h before the experiment, but free access
to water was allowed. e experiments were performed
on randomly formed groups during the light phase of
the cycle and the animals were used for once experi-
ment only. e test compounds and standard drugs
were administered p.o., as aqueous suspension in 0.5%
4-[1-oxo-3-(phenyl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)
sydnone 2a IR cm−1 1753 (C=O, sydnone), 1662 (C=O,
styryl ketone); 1H-NMR δ 6.73 (d, 1H, J= 10.00, olefinic αH),
7.2–7.61 (m, 5H, ArH), 7.64–7.72 (m, 4H, ArH and olefinic
βH); 13C-NMR δ 106.31, 117.12, 120.83, 121.45, 125.16,
128.22, 128.63, 131.37, 135.48, 135.68, 145.36, 158.96,
167.35, 187.53; MS m/z 344.63 (M+).
4-[1-oxo-3-(2-furyl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)
sydnone 2b IR cm−1 1765 (C=O, sydnone), 1676 (C=O,
styryl ketone); 1H-NMR δ 6.92 (d, 1H, J= 11.76, olefinic αH),
7.03 (t, 1H, J= 11.76, furyl-4H), 7.26–7.42 (m, 2H, ArH),
7.73–7.96 (m, 3H, ArH, furyl-3H, and olefinic βH), 8.25 (d,
1H, J= 7.05, furyl-5H); 13C-NMR δ 105.18, 112.68, 113.93,
117.26, 120.88, 121.25, 125.37, 127.48, 131.24, 135.68,
Journal of Enzyme Inhibition and Medicinal Chemistry

Fluorine bearing sydnones 243
143.78, 152.26, 159.15, 166.83, 187.28; MS m/z 334.46
Compound 2i was prepared similarly using
2-hydroxyquinolin-3-carboxaldehyde.
(M+).
4-[1-oxo-3-(4-cholrophenyl)-2-propenyl]-3-(3-chloro-4-
fluorophenyl)sydnone 2c IR cm−1 1763 (C=O, sydnone),
1671(C=O, styryl ketone); H-NMR δ 6.81 (d, 1H, J= 10.52,
olefinic αH), 7.28–7.43 (m, 2H, ArH), 7.6 (d, 2H, J= 5.26,
ArH), 7.73–7.82 (m, 4H, ArH and olefinic βH); 13C-NMR
δ 105.37, 117.32, 120.93, 121.35, 124.98, 128.98, 129.17,
131.48, 133.52, 135.73, 145.68, 159.47, 167.28, 186.79; MS
m/z 379.18 (M+).
4-[1-oxo-3-(2-hydroxy-3-quinolinyl)-2-propenyl]-3-(3-chlo-
ro-4-fluorophenyl)sydnone 2i IR cm−1 1757 (C=O, sydnone),
1672 (C=O, styryl ketone); H-NMR δ 6.76 (d, 1H, J= 12.30,
olefinic αH) 7.27–7.39 (m, 2H, ArH), 7.57–7.8 (m, 2H, ArH
and olefinic βH), 7.81–8.14 (m, 4H ArH), 8.42 (s, 1H, ArH),
11.47 (s, br, 1H, OH); 13C-NMR δ 106.18, 117.61, 121.13,
122.24, 124.30, 125.26, 125.60, 127.31, 127.86, 128.63,
130.75, 131.89, 136.12, 136.65, 145.74, 146.58, 159.38,
166.37, 174.92, 187.64; MS m/z 411.48 (M+).
1
1
4-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-3-(3-chlo-
ro-4-fluorophenyl)sydnone2d IRcm−1 1752(C=O, sydnone),
1657 (C=O, styryl ketone); 1H-NMR δ 3.93 (s, 9H, OCH3), 6.82
(d, 1H, J= 10.52, olefinic αH), 6.87 (s, 2H, ArH), 7.21–7.38
(m, 2H, ArH), 7.81 (t, 2H, J= 10.52, ArH and olefinic βH);
13C-NMR δ 55.97, 61.00, 104.16, 105.48, 117.32, 120.86,
121.74, 125.53, 126.84, 132.10, 136.21, 138.63, 153.46,
159.28, 166.58, 187.33; MS m/z 434.53 (M+).
Acute toxicity
Mice and rats were divided into groups of four each and
the test compounds were administered p.o. to different
groups in increasing dose levels of 250, 500, 750 and
1000 mg/kg b.w. ey were observed continuously for
3 h, for neurological (ptosis, drowsiness, gait, tremors
and convulsions), autonomic (salivation, lacrimation,
perspiration, piloerection, urinary incontinence and def-
ecation) and general behavioural profiles and then every
30 min for next 3 h and finally for lethality after 24 h12.
4-[1-oxo-3-(4-nitrophenyl)-2-propenyl]-3-(3-chloro-4-fluo-
rophenyl)sydnone 2e IR cm−1 1755 (C=O, sydnone), 1667
(C=O, styryl ketone); 1H-NMR δ 7.38 (d, 1H, J= 11.56, olefinic
αH), 7.42–7.56 (m, 2H, ArH), 7.76 (m, 1H, ArH), 7.93 (d,
1H, J= 11.56, olefinic βH), 8.69 (d, 2H, J= 5.78, ArH), 8.93
(d, 2H, J= 5.78, ArH); 13C-NMR δ 106.15, 117.28, 120.92,
121.36, 124.18, 125.38, 129.13, 130.96, 135.57, 141.46,
145.37, 147.14, 158.84, 167.35, 187.46; MS m/z 389.49
(M+).
Analgesic activity
It was assessed in mice by chemically as well as thermally
induced pain using acetic acid-induced writhing13 and
hot plate assay14, respectively.
Acetic acid-induced writhing
4-[1-oxo-3-(2-nitrophenyl)-2-propenyl]-3-(3-chloro-4-
fluorophenyl)sydnone 2 g IR cm−1 1759 (C=O, sydnone),
1662 (C=O, styryl ketone); H-NMR δ 6.98 (d, 1H, J= 11.56,
olefinic αH), 7.32–7.48 (m, 2H, ArH), 7.78–8.21 (m, 4H,
ArH), 8.30–8.33 (m, 2H, ArH and olefinic βH); 13C-NMR
δ 105.82, 117.30, 121.18, 121.63, 123.97, 125.46, 127.48,
129.00, 131.35, 134.68, 135.74, 145.56, 147.98, 159.12,
165.94, 188.20; MS m/z 389.52 (M+).
A sensitivity test was carried out a day prior to drug
administration wherein the mice were injected 0.2–
0.25 mL of 0.6% acetic acid i.p. Mice showing writhing
within 30 min were chosen for study. Groups of six mice
each were dosed with the test compounds or with ASA at
a dose of 100 mg/kg b.w. p.o., 1 h before the i.p. injection
of 0.6% acetic acid (10 mL/kg b.w.). After 5 min of acetic
acid injection, they were observed for 20 min and the total
number of writhes was recorded. e percent reduction
of the number of writhes was calculated.
1
Synthesis of 2h and 2i: 4-[1-oxo-3-(4-hydroxy-
3-methoxy phenyl)-2- propenyl]-3-(3-chloro-4-
fluorophenyl)sydnone 2 h
Mean number of writhes
in Control Group−Mean number
of writhes inTreated Group
Mean number of




To the suspension of compound 1 (2.6 g, 0.01 mol) and
vanillin (1.8 g, 0.012 mol) in 20 mL ethanol (95%) was
passed dry hydrogen chloride gas for 0.5 h under cooling
(5°C). e reaction mixture was left overnight at room
temperature and poured into cold water. e separated
precipitate was filtered, washed, dried in air and re-crys-
tallised from ethanol (95%) to give the title compound
(2.18 g, 0.0056 mol, 56%): mp 158–160°C; IR cm−1 1758






%Reduction=
×100
writhes in Control Group
Hot plate assay
Groups of six mice each were administered with the
test compounds at a dose of 100 mg/kg b.w. p.o. or
with pentazocine (5 mg/kg b.w. p.o.) 1 h before the test.
e animals were placed on hot plate maintained at
55 1°C and the basal reaction time taken to cause a
discomfort (licking of paw or jumping response which-
ever appeared first) was recorded at zero min. Cut-off
period of 15 s was established to prevent damage to the
1
(C=O, sydnone), 1660 (C=O, styryl ketone); H-NMR δ
3.97 (s, 3H, OCH3), 5.98 (s, br, 1H, OH), 6.79–6.88 (m, 2H,
ArH and olefinic αH), 7.32–7.68 (m, 4H, Ar-H), 7.76–7.78
(m, 2H, ArH and olefinic βH); 13C-NMR δ 55.93, 105.73,
112.08, 117.32, 120.96, 121.48, 123.31, 125.83, 128.36,
131.89, 136.15, 146.10, 148.63, 149.76, 159.38, 166.48,
188.56; MS m/z 390.50 (M+).
© 2012 Informa UK, Ltd.

244 S. R. Deshpande et al.
paws. e reaction time in seconds was re-investigated
at 30, 60, and 120 min. e activity was expressed as
percent protection.
the rats were sacrificed, the stomachs removed, opened
along the greater curvature and observed for gastric
lesions on the mucosa. e lesion index for each group
was determined by counting the number of lesions (x) in
each of five size classes (y) which were defined as y= 1
(pinpoint lesion), y = 2 (lesions < 1 mm diameter), y = 3
(lesions 1–2 mm diameter), y = 4 (lesions 2–4 mm diam-
eter) and y = 5 (lesions >4 mm diameter).17
Average reaction time
in Control Group− Average reaction
time inTreated Group










%Protection=
×100
Averagereaction
time in Control Group
5
Lesionindex = x y
∑
i
i
i=1
Anti-inflammatory activity
Acute systemic and local anti-inflammatory activities
were carried out by carrageenan-induced paw oedema
in rats15 and croton oil induced ear oedema in mice16,
respectively.
Results and discussion
e starting material, 4-acetyl-3-(3-chloro-4-fluoro-
phenyl)sydnone 1, was prepared by the action of glacial
acetic acid on 3-(3-chloro-4-fluorophenyl)sydnone in
presence of phosphorous pentoxide18; the 3-(3-chloro-
4-fluorophenyl)sydnone itself was synthesized by lit-
erature protocol from 3-chloro-4-fluoroaniline19. e
IR spectrum of compound 1 showed sydnone C=O and
acetyl C=O stretching at 1772 and 1671 cm−1, respec-
tively, and in 1H-NMR spectrum, it showed a singlet
at δ 2.54 corresponding to three hydrogens of COCH3
and a multiplet at 7.61–7.89 accounting three aromatic
protons (data not shown). Claisen-Schmidt reaction of
compound 1 with different aryl aldehydes in presence
of either alkali or acid afforded the title compounds
2a–i (Figure 1). e UV-Vis spectra of compounds
2a–i exhibited considerable bathochromic shifts due
to π-π* (343–601 nm) in comparison to 321 nm for
compound 1 indicating the extension of conjugation
due to formation of α,β-unsaturated ketone. In their
IR spectra, compounds 2a–i showed sydnone C=O
and styryl ketone stretching at 1753–1765 cm−1 and
1660–1676 cm−1, respectively. Compounds 2a–i in their
1H-NMR spectra displayed, apart from other hydrogens,
doublets due to α protons of α,β-unsaturated ketone
moiety at δ 6.73–6.98, whereas β protons were seen
merged with aromatic protons at δ 7.64–8.33 in most
instances. e 13C-NMR spectra of compounds 2a–i
exhibited α-carbons of α,β-unsaturated ketone at δ
121.36–127.86, β-carbons at δ 146.10–159.47, carbons
of styryl ketone at δ 186.79–190.31, the sydnone C=O
at δ 165.94–168.61 and sydnone C-4 at δ 105.18–106.31
amidst other carbons. e mass spectra of compounds
2a–i showed the M+ ion peak at their respective m/z val-
ues which are consistent with their molecular weight.
e physical data of compounds 2a–i are presented in
Table 1.
Carrageenan-induced paw oedema
Groups of six rats were dosed at 100 mg/kg b.w. p.o. with
the test compounds or ibuprofen 1 h before 0.05 mL of a
1% suspension of carrageenan in saline was injected into
the sub plantar region of the right hind paw. An equal
volume of saline was injected into the other hind paw
and served as control. Paw volumes were measured by
plethismograph immediately after carrageenan injection
and again after 1, 2, 3 and 5 h later. Data were reported as
percent oedema inhibition.
AveragePaw volumein
ControlGroup−AveragePaw volume
inTreatedGroup










%Edema
=
×100
inhibition
AveragePaw volume
inControlGroup
Topical ear oedema
Groupsofsixmicereceivedtopicalapplication(5 mg/ear)
of test compounds or indomethacin dissolved in dim-
ethyl sulfoxide (DMSO) on the anterior surface of the
right ear while 0.05 mL croton oil (4 parts of croton oil
and 96 parts of DMSO) was instantly applied on the pos-
terior surface of the same ear. Control animals received
an equivalent volume of DMSO. e ear thickness was
measured by digital micrometer 4 h after challenge of
croton oil to assess an increase in oedema. e % inhi-
bition of oedema was calculated using the following
relation.
Average ear thickness in
Control Group− Average ear thickness
inTreated Group










After 24 h of administration up to 1000mg/kg b.w.,
compounds 2a–i produced no mortality in both rats and
mice in acute toxicity testing. But few changes in the
behavioural response like alertness, touch and restless-
ness were noticed. ere were no significant changes
in neurological and autonomic profiles. Hence, 1/10th
of the maximum tolerated dose i.e., 100 mg/kg b.w. was
chosen for the pharmacological studies.
%Inhibition=
×100
Average ear thickness
in Control Group
Ulcerogenic assay
Groups of six rats were administered test compounds
or ibuprofen at a dose of 100 mg/kg b.w. p.o. After 4 h,
Journal of Enzyme Inhibition and Medicinal Chemistry

Fluorine bearing sydnones 245
Compound 2b, 2e and 2c showed good activity with
46, 44 and 40% reduction in writhes, respectively, in
writhing test (Table 2). e presence of chloro and nitro
groups at para position enhanced the activity. e furyl
analogue was equiactive to that of phenyl. e presence
of trimethoxy group on the phenyl ring sustained activ-
ity, whereas N, N-dimethylamino group at para posi-
tion did not. It is noteworthy that compounds 2a–i were
O
N
+
R
Ar
Ar'
N
O
O
3-(substituted phenyl)sydnone
Styryl ketone
Cl
Cl
O
Ar'
COCH3
OH− / H+
F
F
N
N
N
N
Ar'CHO
+
+
+
O
O
O
O
1
Sydnonyl styryl ketones (2a-i)
Figure 1. Design and synthesis of title compounds.
Table 1. Physical data and yields of compounds 2a–i.
Cl
O
Ar'
F
N
N
+
O
O
Comp
2a
Ar′
Mol. Formula
C17H10N2O3ClF
Mol. Wt.
344.5
Yield (%)
48
Mp (°C)
UV-Vis Abs. (nm)*
151–152
346, 246
2b
C15H8N2O4ClF
334.5
37
133–135
344, 246
O
2c
C17H9N2O3Cl2F
C20H16N2O6ClF
379
41
42
134–135
119–121
343, 249
Cl
2d
434.5
397, 309, 241
MeO
MeO
MeO
2e
2f
C17H9N3O5ClF
C19H15N3O3ClF
389.5
387.5
45
43
137–139
109–110
358, 245
344, 245
O2N
(CH3)2N
2g
2h
C17H9N3O5ClF
C18H12N2O5ClF
C20H11N3O4ClF
389.5
390.5
411.5
42
56
47
139–141
158–160
207–209
601, 247
356, 246
NO2
HO
MeO
2i
393, 290, 244
N
OH
*In CHCl3.
© 2012 Informa UK, Ltd.

246 S. R. Deshpande et al.
found to be more active than the corresponding 4-methyl
analogues reported by us earlier8. It is reported that
intraperitoneal administration of an agent that irritates
the serous membrane such as acetic acid results in the
release of prostaglandins like PGE2 and PGF2α and sym-
pathomimetic system mediators in the peritoneal fluid20.
It is speculated that the activity of the test compounds
could be due to inhibition of synthesis of prostaglandins
and or sympathomimetic system mediators. In hot plate
assay, centrally acting analgesics increase the reaction
time in laboratory animals21. Since none of the tested
compounds significantly increase the reaction time in
animals in hot plate test (Table 2), it can therefore be
concluded that compounds 2a–i do not possess centrally
mediated analgesic effect.
e hind paw inflammation oedema produced by
carrageenan is a biphasic event and the agents which
act on the first stage inhibit the chemical mediators
such as histamine, serotonin, and bradykinin, while the
second stage of the oedema is related to the arachidonic
acid metabolites since it is inhibited by aspirin, indo-
methacin, and other COX inhibitors22. In paw oedema
test, compounds 2a–i displayed very weak anti-inflam-
matory activity at 1 and 2 h than the corresponding
4-chloro analogues reported by us7 indicating none of
the compounds 2a–i is inhibiting the synthesis or action
of chemical mediators. Nitric oxide (NO) is known to
inhibit the adhesion of leucocytes to the endothelium,
preventing adhesion cascade and reduce inflammation
in initial stages23. e weak and slow release of NO by
sydnones24 may be responsible for the weak activity
shown by these compounds in the early stage of inflam-
mation. At 3 h, compounds 2a–i showed significant
activity with 2c and 2f showing highest activities with
56 and 55% oedema inhibition followed by 2e, 2h and
2d with 49, 45 and 43% oedema inhibition, respectively
(Table 3). ese compounds showed more activity than
the 4-chloro counterparts7 highlighting the effect of
fluorine substitution. e good activity shown by these
compounds in the second phase of inflammation may
be attributed to more availability of these compounds
at the site of action due to increased lipophilicity by
fluorine substitution. ey may act by inhibiting either
COX and or lipoxygenase enzyme thereby preventing
the formation of inflammatory prostaglandins and or
leukotrienes from the arachidonic acid cascade. At 5th
h, only compound 2c and 2f showed significant activity
with 20 and 18% oedema inhibition, respectively. e
chloro and N,N-dimethylamino substitution at para
position seems to favour the activity.
e good systemic anti-inflammatory activity dis-
played by title compounds and the paucity of data on
local anti-inflammatory activity of sydnone derivatives
prompted us to screen compounds 2a–i for topical
anti-inflammatory activity. It is known that the oedema-
tous inflammation induced by croton oil treated ears
is related to the activation of phopholipaseA2, which
releases arachidonic acid from the cell membrane that
in turn, is metabolized to proinflammatory prostaglan-
dins and leukotrienes25. Reduction in the thickness of the
croton oil induced ear oedema by any agent is an index
of its topical anti-inflammatory activity. Compound
2c, 2e, 2d, 2g and 2h exhibited significant topical anti-
inflammatory activity with 27, 25, 24, 23 and 22% oedema
inhibition, whereas standard drug indomethacin showed
69% oedema inhibition (Table 3). Here also, the chloro
derivative displayed good activity. However, the topical
anti-inflammatory activity of these compounds was not
pronounced compared to systemic activity. Again, their
topical anti-inflammatory activity could be due to inhibi-
tion of COX and or lipoxygenase enzymes.
e major drawback of non-steroidal anti-inflamma-
tory drugs is their propensity to cause gastric ulceration26,
and the three active compounds in the series 2c, 2e and
2f were tested for this effect. e compounds with elec-
tron attracting substituents such as 2c and 2e showed
ulcerogenic index of 11.12 and 14.38, respectively, that
was less than that of ibuprofen (Table 4). From this study,
compounds 2c and 2e have emerged to be the most
promising in terms of the ratio of efficacy and adverse
Table 2. Analgesic activity of compounds 2a–i.
Hot plate assay
Mean reaction time SD, sec (% protection)
Acetic acid writhing assay
Mean no. of writhes SD
(% reduction)
Comp
0 min
30 min
4.14 0.05 (3)
3.95 0.10 (2)
3.89 0.24 (3)
3.97 0.12 (1)
4.01 0.13 (0)
3.85 0.19 (5)
3.87 0.14 (4)
3.98 0.09 (1)
3.86 0.05 (4)
7.23 0.21** (80)
—
60 min
4.15 0.07 (4)
3.97 0.12 (0)
4.16 0.18 (4)
3.93 0.08 (1)
4.15 0.17 (4)
3.73 0.16 (6)
3.94 0.10 (1)
4.23 0.05 (6)
4.08 0.31 (2)
7.89 0.13** (98)
—
120 min
4.10 0.09 (3)
3.89 0.17 (2)
3.97 0.14 (1)
3.95 0.23 (1)
3.74 0.16 (6)
3.91 0.20 (2)
3.83 0.17 (4)
3.88 0.21 (3)
3.97 0.17 (1)
7.38 0.14** (85)
—
2a
3.87 0.04 (2)
3.83 0.41 (3)
3.82 0.36 (3)
3.78 0.24 (4)
3.79 0.31 (4)
3.90 0.41 (1)
3.95 0.52 (0)
3.85 0.07 (2)
3.92 0.24 (1)
3.94 0.04 (0)
—
47 05** (35)
46 08** (36)
40 11** (44)
48 10** (33)
44 05** (39)
58 06* (19)
55 08** (23)
53 07** (26)
52 06** (28)
—
2b
2c
2d
2e
2f
2g
2h
2i
Pentazocine
ASA
29 09** (60)
72 07
Control
3.96 0.03
4.02 0.38
3.98 0.03
3.99 0.05
*p<0.05, ** p<0.01 when compared to control.
Journal of Enzyme Inhibition and Medicinal Chemistry

Fluorine bearing sydnones 247
Table 3. Anti-inflammatory activity of compounds 2a–i.
Croton oil induced ear
oedema inflammation
Carrageenan-induced paw oedema inflammation
Mean oedema vol. SD, mL (% oedema inhibition)
Mean ear thickness SD, mm
(% oedema inhibition)
Compound
1 h
2 h
3 h
5 h
2a
0.34 0.04 (−)
0.33 0.02 (03)
0.30 0.01 (11)
0.31 0.04 (09)
0.32 0.05 (06)
0.30 0.02 (11)
0.34 0.03 (−)
0.32 0.03 (06)
0.33 0.05 (03)
0.28 0.03* (18)
—
0.43 0.02 (04)
0.42 0.01 (06)
0.31 0.03* (31)
0.37 0.05 (18)
0.36 0.04 (20)
0.33 0.04 (26)
0.40 0.02 (11)
0.34 0.03 (24)
0.41 0.01 (08)
0.26 0.04** (42)
—
0.42 0.04 (−)
0.40 0.02 (−)
0.31 0.03** (20)
0.36 0.03 (07)
0.35 0.04 (10)
0.32 0.05* (18)
0.41 0.04 (−)
0.36 0.02 (07)
0.41 0.05 (−)
0.27 0.03** (31)
—
0.44 0.03** (17)
0.43 0.05** (19)
0.23 0.02** (56)
0.30 0.03** (43)
0.27 0.04** (49)
0.24 0.01** (55)
0.38 0.03** (28)
0.29 0.03** (45)
0.41 0.05** (22)
0.16 0.06** (70)
—
0.156 0.002* (14)
0.153 0.004* (16)
0.133 0.006** (27)
0.138 0.003* (24)
0.136 0.005* (25)
0.147 0.002* (19)
0.132 0.004* (23)
0.142 0.004* (22)
0.158 0.003* (13)
—
2b
2c
2d
2e
2f
2g
2h
2i
Ibuprofen
Indomethacin
Control
0.056 0.002** (69)
0.182 0.006 (−)
0.34 0.01
0.45 0.04
0.53 0.04
0.39 0.02
*p<0.05, **p<0.01 when compared to control.
Declaration of interest
Table 4. Ulcerogenicity of selected compounds.
Compound
Lesion index ( SD)
e authors report no conflicts of interest.
2c
11.12 (1.93)**
14.38 (2.56)*
21.68 (2.15)*
19.16 (4.28)*
4.23 (0.76)
2e
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