Synthesis and analgesic effects of 2-(2-carboxyphenylsulfanyl)-N-(4- substitutedphenyl)acetamide derivatives

Article abstract of DOI:10.1007/s00044-010-9300-y

This present study was undertaken to synthesize and investigate possible analgesic activities of some 2-(2-carboxyphenylsulfanyl)-N-(4-substitutedphenyl) acetamide derivatives that were designed by combining an analgesic drug thiosalicylic acid and the ma

Full text of DOI:10.1007/s00044-010-9300-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:152–157
DOI 10.1007/s00044-010-9300-y
ORIGINAL RESEARCH
Synthesis and analgesic effects of 2-(2-carboxyphenylsulfanyl)-
N-(4-substitutedphenyl)acetamide derivatives
¨
Umide Demir Ozkay Yusuf Ozkay
¨
¨
•
•
¨
Ozgu¨r Devrim Can
Received: 9 May 2009 / Accepted: 12 January 2010 / Published online: 2 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract This present study was undertaken to synthe-
size and investigate possible analgesic activities of some
2-(2-carboxyphenylsulfanyl)-N-(4-substitutedphenyl)acetam-
ide derivatives that were designed by combining an anal-
gesic drug thiosalicylic acid and the main pharmacophore
group of paracetamol, N-(4-substitutedphenylacetamide).
Chemical structures of synthesized compounds were elu-
neurological pathways on the central nervous system
(CNS) and peripheral nervous system (PNS) (Collina et al.,
2003).
Narcotic analgesic drugs, acting mainly by influencing
l-opioid receptors, are used for the treatment of severe
pain. For the treatment of inflammatory pain, several non-
steroidal anti-inflammatory drugs (NSAIDs) are used.
NSAIDs block cyclooxygenase (COX) enzyme and thus
inhibit the synthesis of prostaglandins. While these main
groups of analgesic drugs are commonly used to treat pain,
a significant proportion of patients do not achieve full pain
relief (Sałat et al., 2009).
1
cidated by IR, H-NMR, and Mass spectral data. Paracet-
amol, thiosalicylic acid and some of the synthesized
compounds in the series exhibited significant analgesic
activities in hot-plate, tail-clip, and acetic acid-induced
writhing tests. Compound 2d showed more potent analge-
sic activity than both paracetamol and thiosalicylic acid.
None of the compounds changed the responses of animals
recorded in Rota-Rod or activity cage tests with respect to
control values. Therefore, analgesic activities of the syn-
thesized compounds evaluated in this study were not
caused by motor impairments or neurosedative effects.
On the other hand, both opioid analgesics and NSAIDs
can cause serious adverse side effects. Therapeutic uses of
narcotic analgesics are limited by the common side effects,
such as sedation, respiratory depression, constipation, and
physical dependence etc. (Benyamin et al., 2008). Besides,
long-term clinical usage of NSAIDs is associated with
several significant side effects including gastrointestinal
lesions, bleeding, nephrotoxicity, and heart stroke (Habeeb
et al., 2001; Simon, 2001; Bertolini et al., 2002). There-
fore, discovery and development of more potent and safer
analgesic compounds remains a major challenge in phar-
maceutical field.
Keywords Paracetamol ꢀ Thiosalicylic acid ꢀ Hot-plate ꢀ
Tail-clip ꢀ Writhing test
Introduction
Salicylic acid derivatives such as thiosalicylic acid,
acetylsalicylic acid, gentisic acid, and diflunisal are well
known analgesic drugs that include free carboxyl group
(Fig. 1). They act via inhibition of prostaglandin synthesis
and preventing inflammation, pain, rise in temperature, and
related diseases (Vane, 1978; Meade et al., 1993; Wu and
Ercal, 2004). Paracetamol and phenacetine which contain
N-(4-substitutedphenyl)acetamide moiety on their scaffold
are also frequently used as safe analgesics (Fig. 1). The
mechanism by which paracetamol reduces fever and pain is
debated because unlike salicylic acid derivatives, it works
Analgesic drugs are crucial therapeutic agents for the
treatment of acute and chronic pain. They act in various
¨
¨
¨
U. Demir Ozkay ꢀ O. D. Can (&)
Faculty of Pharmacy, Department of Pharmacology, Anadolu
University, 26470 Eskis¸ehir, Turkey
e-mail: ozgurdt@anadolu.edu.tr
¨
Y. Ozkay
Faculty of Pharmacy, Department of Pharmaceutical Chemistry,
Anadolu University, 26470 Eskis¸ehir, Turkey
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Med Chem Res (2011) 20:152–157
153
COOH
OH
checked by thin layer chromatography (TLC) using silica gel
60G (Merck). IR spectra were recorded on Shimadzu, 8400
FTIR spectrometer as KBr pellets (m, cm-1). 1H-NMR
spectra were obtained from a Brucker UltraShield 500 MHz
spectrometer in deutoro dimethylsulfoxide (DMSO-d6).
Mass analysis was carried out within an Agilent 1100 Series
LC/MSD Trap VL&SL spectrometer.
COOH
COOH
OCOCH3
COOH
OH
SH
HO
Salicylic acid
Acetylsalicylic acid
NHCOCH3
Thiosalicylic acid
Gentisic acid
NHCOCH3
COOH
OH
F
2-Chloro-N-(4-phenylacetamide) derivatives (1a–1f)
were prepared according to literature procedures demon-
strating acetylation reaction between aromatic amines and
chloroacetyl chloride (Kaplancikli et al., 2004; Turan-Zi-
touni et al., 2004).
F
OH
OCH2CH3
Diflunisal
Paracetamol
Phenacetine
Fig. 1 Analgesic agents derived from salicylic acid and N-
phenylacetamide
General synthesis procedure for the title compounds
(2a–2f)
as a weak prostaglandin biosynthesis inhibitor on PNS and
shows very low anti-inflammatory activity (Jackson et al.,
1984). In addition, paracetamol can offer a significant
additive analgesic effect to the opiates in severe pain. It has
been reported that paracetamol selectively inhibits prosta-
glandin production in the CNS, which could be responsible
of its analgesic action (Ramwell, 1981; Jackson et al.,
1984; Cranswick and Coghlan, 2000).
For synthesis of the each title compounds, appropriate
2-chloro-N-(4-substitutedphenyl)acetamide derivative (0.025 mol),
thiosalicylic acid (0.025 mol), and triethylamine (0.025 mol)
were dissolved in acetone. Reaction mixture was stirred for
3 h at room temperature. Acetone was removed then residue
was washed with cold water and dried. Products were re-
crystallized from absolute ethanol. Synthesis procedure for
the compounds was outlined in Fig. 2.
Pharmacological evaluation of newly synthesized com-
pounds containing one or more pharmacophore groups is the
most popular strategy in new drug development avenue.
From this point, our research group focused on structural
attributes of analgesic drugs mentioned above, so thiosali-
cylic acid and N-(4-substitutedphenyl)acetamide were
combined on the same chemical skeleton. Thus, we obtained
six compounds bearing two different analgesic agents resi-
dues. No pharmacologic observation including the title
compounds in back studies prompted us to investigate their
probable central or peripheral analgesic activities.
2-(2-Carboxyphenylsulfanyl)-N-phenylacetamide (2a)
m.p: 221°C. Yield: 74%. IR (KBr) mmaks(cm-1): 3352
(N–H st), 3227 (O–H st), 1728 (C=O st, carboxyl), 1674
(C=O st, amide), 1612–1445 (C=C st and C=N st), 836–753
1
(Ph deformation bands). H-NMR (DMSO-d6) d(ppm): 4.22
(2H; s; –CH2), 6.82–7.38 (8H; m; Ar–H), 8.17 (H; d; thio-
saliyclic acid C6–H), 10.66 (H; br, N–H), 12.19 (H; s;
–COOH). ES-MS (m/e): M ? 1: 288.2, M ? 2: 289.3.
2-(2-Carboxyphenylsulfanyl)-N-(4-
chlorophenyl)acetamide (2b)
Materials and methods
m.p: 195°C. Yield: 81%. IR (KBr) mmaks(cm-1): 3359
(N–H st), 3223 (O–H st), 1716 (C=O st, carboxyl), 1679
(C=O st, amide), 1608–1446 (C=C st and C=N st), 832–758
(Ph deformation bands). 1H-NMR (DMSO-d6) d(ppm): 4.23
(2H; s; –CH2), 6.75–7.39 (7H; m; Ar–H), 8.18 (H; d; thio-
saliyclic acid C6–H), 10.62 (H; br, N–H), 12.13 (H; s;
–COOH). ES-MS (m/e): M ? 1: 322.6, M ? 2: 323.7.
Chemistry
All chemicals used for the synthesis of the compounds were
supplied from Merck (Germany). Melting points (m.p) of
target compounds were determined in open capillaries on an
Electrothermal 9001 Digital Melting Point Apparatus and
wereuncorrected. Thepurityofthecompoundswasroutinely
Fig. 2 Synthesis of the
compounds 2a–2f
R
NH2
NHCOCH2Cl
COOH
COOH
O
SH
S
ClCOCH2Cl
TEA
N
+
H
Acetone
TEA / Benzene
2a-2f
R
R
R: -H, -Cl, -Br, -CH3, -OCH3, -COOH
1a-1f
123

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Med Chem Res (2011) 20:152–157
2-(2-Carboxyphenylsulfanyl)-N-(4-
bromophenyl)acetamide (2c)
room with controlled temperature (24 1°C) for 12 h
light/12 h dark cycle. All animals were acclimatized to the
laboratory environment at least 48 h before the experi-
mental session. Twelve hours before each experiment
animals received only water in order to avoid food inter-
ference with substance absorption. The experimental pro-
tocols have been approved by the Local Ethical Committee
on Animal Experimentation of Eskis¸ehir Osmangazi Uni-
versity, Turkey (Approval No: 07.35.35-1)
m.p: 208°C. Yield: 83%. IR (KBr) mmaks(cm-1): 3348 (N–
H st), 3231 (O–H st), 1725 (C=O st, carboxyl), 1684 (C=O
st, amide), 1610–1452 (C=C st and C=N st), 837–755 (Ph
deformation bands). 1H-NMR (DMSO-d6) d(ppm): 4.20
(2H; s; –CH2), 6.79–7.38 (7H; m; Ar–H), 8.21 (H; d;
thiosaliyclic acid C6–H), 10.65 (H; br, N–H), 12.11 (H; s;
–COOH). ES-MS (m/e): M ? 1: 367.3, M ? 2: 368.1.
Administration of test compounds
2-(2-Carboxyphenylsulfanyl)-N-(4-
methylphenyl)acetamide (2d)
All administrations to mice (n = 6 in each group) were
made by single injections via intraperitoneal (i.p) route.
Response latencies were measured 30 min after the appli-
cations. Physiological saline was injected to control group,
as all compounds were dissolved in it. Thiosalicylic acid,
paracetamol, and synthesized compounds were applied at
100 mg/kg doses.
m.p: 146°C. Yield: 76%. IR (KBr) mmaks(cm-1): 3361 (N–
H st), 3247 (O–H st), 1712 (C=O st, carboxyl), 1674 (C=O
st, amide), 1609–1453 (C=C st and C=N st), 841–746 (Ph
deformation bands). 1H-NMR (DMSO-d6) d(ppm): 2.28
(3H; s; –CH3), 4.21 (2H; s; –CH2), 6.74–7.35 (7H; m;
Ar–H), 8.20 (H; d; thiosaliyclic acid C6–H), 10.63 (H; br,
N–H), 12.23 (H; s; –COOH). ES-MS (m/e): M ? 1: 302.5,
M ? 2: 303.4.
Assessment of analgesic activity
Hot-plate test The supraspinal component of antinoci-
ceptive action in mice was evaluated by hot-plate test as
described previously (Kaplancikli et al., 2008). Mouse was
placed in a glass beaker, which was set at a fixed tem-
perature of 55 0.5°C in a water bath and the latency time
for paw licking or jumping was determined by a stopwatch
2-(2-Carboxyphenylsulfanyl)-N-(4-
methoxyphenyl)acetamide (2e)
m.p: 171°C. Yield: 79%. IR (KBr) mmaks(cm-1): 3352 (N–
H st), 3227 (O–H st), 1728 (C=O st, carboxyl), 1674 (C=O
st, amide), 1612–1445 (C=C st and C=N st), 836–753 (Ph
deformation bands). 1H-NMR (DMSO-d6) d(ppm): 3.86
(3H; s; –OCH3), 4.19 (2H; s; –CH2), 6.73–7.39 (7H; m;
Ar–H), 8.16 (H; d; thiosaliyclic acid C6–H), 10.74 (H; br,
N–H), 12.20 (H; s; –COOH). ES-MS (m/e): M ? 1: 318.2,
M ? 2: 319.3.
´
(De Fatima Arrigoni-Blank et al., 2004). A sensitivity test
was carried out before the experiments and only the ani-
mals reacting within 15 s were chosen for the tests (Shinde
et al., 1999). Maximum cut-off time was established as
´
30 s to prevent tissue damage (De Fatima Arrigoni-Blank
et al., 2004). Effects of the synthesized compounds on the
nociception were calculated by converting hot-plate
latencies to percentage analgesic activity according to the
following equation (Asongalem et al., 2004):
2-(2-Carboxyphenylsulfanyl)-N-(4-
carboxyphenyl)acetamide (2f)
Analgesic activity %
m.p: 264°C. Yield: 72%. IR (KBr) mmaks(cm-1): 3366 (N–
H st), 3228 (O–H st), 1719 (C=O st, carboxyl), 1671 (C=O
st, amide), 1610–1448 (C=C st and C=N st), 836–753 (Ph
deformation bands). 1H-NMR (DMSO-d6) d(ppm): 4.18
(2H; s; –CH2), 6.79–7.48 (5H; m; Ar–H), 8.08 (2H; d; N-
(4-carboxyphenyl)acetamide C3,5), 8.18 (H; d; thiosaliyclic
acid C6–H), 10.70 (H; br, N–H), 12.17 (2H; s; 2 x–COOH).
Ms (Es) (m/e): M ? 1: 332.2, M ? 2: 333.4.
¼ ½ðpostdrug latency ꢁ predrug latencyÞ=
predrug latencyꢂ ꢃ 100
Tail-clip test The mechanical antinociceptive activities of
the compounds were measured by tail-clip test in mice as
described elsewhere (D’Amour and Smith, 1941; Aydin
et al., 2003). Animals that did not response to the clamp
within 10 s were discarded from the experiments before the
experimental session (Adeyemi et al., 2004). Cut-off time
for the tail-clip tests was chosen as 10 s to avoid possible
tissue damage (Ozturk et al., 2002). Analgesia was
expressed as a percentage of the maximum possible effect
(MPE %), according the following equation (Gabra and
Sirois, 2003):
Pharmacology
Animals
Adult Swiss albino female mice weighing 30–35 g were
used for the experiments. The animals were housed in a
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Med Chem Res (2011) 20:152–157
155
Differences between data sets were considered as signifi-
MPE % ¼ ½ðpostdrug latency ꢁ predrug latencyÞ=
ðcut-off time ꢁ predrug latencyÞꢂ ꢃ 100
cant when p-value was less than 0.05.
Acetic acid-induced writhing responses Acetic acid-
induced writhing test was applied for the investigation of
peripheral component of analgesic activity (Koster et al.,
1959). Mice were treated with an aqueous solution of
acetic acid (0.6% v/v, i.p) at a dose of 10 ml/kg to induce
contractions. Five minutes after the injection of acetic acid
solution, the number of abdominal contractions and stret-
ches during the following 10 min was recorded. After pre-
treatment with reference or synthesized compounds, sig-
nificant reduction in the number of writhing was consid-
ered as positive analgesic response. The percentage
protection against writhing was calculated according to
following equation (Gu¨lc¸in et al., 2004):
Results and discussion
Chemistry
In this study, some 2-(2-carboxyphenylsulfanyl)-N-(4-
substitutedphenyl)acetamide derivatives were synthesized
(Fig. 2). Structure elucidations of the final compounds
1
were performed with IR, H-NMR, and ES-MS methods.
Literature surveys demonstrated that treatment of thio-
saliyclic acid with alkyl halides under basic conditions
gives S-alkylation reaction. Thus, in final reaction step,
esterification of carboxyl group of thiosalicylic with
2-chloro-N-phenyl acetamide derivatives is unexpected
(Mironov et al., 2004; Volonterio and Zanda, 2005).
Besides, spectral data are in accordance with the chemical
structure of the compounds 2a–f.
Protection %
¼ ½ðcontrol mean ꢁ treated meanÞ=control meanꢂ ꢃ 100
Assessment of neurosedative activity
Characteristic stretching absorption of amide and car-
boxylic acid carbonyl (C=O) groups were observed at
1671–1684 cm-1 and 1712–1728 cm-1, respectively. The
stretching absorption at about 3348–3366 cm-1 and
3223–3257 cm-1 were recorded for amide N–H and car-
boxylic acid O–H bonds, respectively. Disappearance of
stretching absorption for S–H bond at about 2550 cm-1
could be commented as evidence for target compounds.
For examining possible sedative activity due to the com-
pounds 2a–f, which may interfere with the test results to
give false positives, activity cage test was performed. The
horizontal and vertical locomotor activities of the mice
were recorded by the activity cage apparatus (Ugo Basile,
No.7420, Varese, Italy). Interruptions of light beams to the
photocells during horizontal and vertical movements of the
animals were automatically recorded for 4 min (Votava
et al., 2005).
1
In H-NMR spectra, aromatic carboxyl group protons
were observed at 12.11–12.23 ppm as a singlet. N–H and
CH2 protons of acetamide group gave peaks at
10.62–10.74 ppm as a broad and at 4.18–4.23 ppm as a
singlet, respectively. Aromatic protons of phenyl groups
were observed at 6.73–7.48 ppm as multiplet. Only the
aromatic protons belong to 6th position of thiosalicylic acid
and 3rd and 5th positions of N-(4-carboxyphenyl)acetamide
moieties (for compound 2f) could be separated from other
aromatic protons and were observed at 8.16–8.21 ppm and
8.08 ppm as doublets, respectively.
Assessment of motor coordination
For examining possible motor coordination deficits due to
synthesized compounds, which may interfere with the test
results, Rota-Rod test was performed. Before the experi-
mental session, three trials were given for three consecutive
days on the Rota-Rod apparatus (Ugo Basile 7560, Milano,
Italy) set at a rate of 16 revolutions per minute. Mice that
were able to remain on the rod longer than 180 s were
selected for the test. Latency to fall from the rotating mill
was recorded (Adzu et al., 2002; Tabarelli et al., 2004).
M ? 1 and M ? 2 peaks in MS agreed well with the
calculated molecular weight of the target compounds.
Pharmacology
Statistical analyses
As well as peripherally mediated analgesic actions, cen-
trally mediated analgesic activities of NSAIDs have been
reported previously (Vanegas, 2002; Anderson, 2008).
Therefore, both central and peripheral analgesic action
potentials of the synthesized compounds were studied in
this present study. Hot-plate and tail-clip tests were per-
formed for examining centrally mediated, whereas acetic
acid-induced writhing tests were applied for investigating
peripherally mediated analgesic actions of the synthesized
The data used in statistical analyses were obtained from six
animals for each of the groups. Experimental data of all
tests were analyzed by one-way ANOVA, following by
Tukey’s test. Statistical analyses of the experimental data
were performed using GraphPad Prism 3.0 software
(GraphPad Software, San Diego, CA, USA). The results
were expressed as mean standard error of mean (S.E.M).
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Med Chem Res (2011) 20:152–157
Table 1 Effects of reference and synthesized compounds on
response latencies of mice in hot-plate tests
Table 3 Effects of synthesized compounds on response latencies of
mice in acetic acid-induced writhing tests
Treatment
Analgesia %
Treatment
Number of writhing Protection %
Control
1.32 3.47
Control
29.50 2.20
20.83 0.60*
–
Paracetamol (100 mg/kg)
Thiosalicylic acid (100 mg/kg)
2a (100 mg/kg)
51.61 6.50***
62.49 11.91***
79.98 10.75***
65.73 9.84***
8.48 5.91
Paracetamol (100 mg/kg)
29.38
33.89
54.80
49.72
9.04
Thiosalicylic acid (100 mg/kg) 19.50 1.73*
2a (100 mg/kg)
2b (100 mg/kg)
2c (100 mg/kg)
2d (100 mg/kg)
2e (100 mg/kg)
2f (100 mg/kg)
13.33 1.28***
14.83 1.19***
26.84 2.12
2b (100 mg/kg)
2c (100 mg/kg)
2d (100 mg/kg)
89.37 11.58***, a,b
7.00 1.29***,c
76.27
27.68
20.34
2e (100 mg/kg)
35.12 11.57
21.34 2.32
2f (100 mg/kg)
18.07 13.82
23.50 2.88
Values are given as mean S.E.M. Significance against control
values, *** p \ 0.001; Significance against thiosalicylic acid,
p \ 0.05; Significance against paracetamol, p \ 0.01. One-way
ANOVA, post-hoc Tukey test, n = 6
Values are given as mean S.E.M. Significance against control
values, * p \ 0.05; *** p \ 0.001; Significance against thiosalicylic
acid and paracetamol, p \ 0.001; One-way ANOVA, post-hoc
Tukey test, n = 6
a
b
c
abdominal contractions and stretches in acetic acid-induced
writhing test pointed out the analgesic activities of the
compounds against chemical noxious stimuli. Therefore,
analgesic actions of compounds 2a, 2b, and 2d in this study
seem to be related with all thermal, mechanical, and
chemical neuronal pathways.
Table 2 Effects of reference and synthesized compounds on
response latencies of mice in tail-clip tests
Treatment
MPE % (Maximum
possible effect %)
Control
0.70 3.38
Paracetamol (100 mg/kg)
Thiosalicylic acid (100 mg/kg)
2a (100 mg/kg)
32.02 4.77**
40.37 8.98***
52.10 6.98***
43.94 3.87***
13.71 3.02
Hot-plate test is known to predominantly measures
responses organized supraspinally, while tail-clip test
mainly measures spinal reflexes (Wong et al., 1994; Gabra
and Sirois, 2003). As the compounds 2a, 2b, and 2d
showed significant analgesic activities in both hot-plate and
tail-clip tests (Tables 1, Table 2), it may be suggested that
these analgesic activities may related to both supraspinal
and spinal mechanisms. Furthermore, protections of ani-
mals from writhing behavior in the writhing tests (Table 3),
indicating that peripheral mechanisms may also play a role
in the analgesic actions.
2b (100 mg/kg)
2c (100 mg/kg)
2d (100 mg/kg)
72.31 4.85***,b,c
2e (100 mg/kg)
25.01 6.32
2f (100 mg/kg)
17.05 5.86
Values are given as mean S.E.M. Significance against control
values, ** p \ 0.01; *** p \ 0.001; Significance against thiosalicylic
b
c
acid, p \ 0.01; Significance against paracetamol, p \ 0.001;
One-way ANOVA, post-hoc Tukey test, n = 6
On the other hand, none of the applied compounds sig-
nificantly changed horizontal or vertical spontaneous
locomotor activities in activity cage measurements or fall-
ing latencies in Rota-Rod tests (data not shown). None of
the animals died at 100 mg/kg dose. Unchanged responses
in activity cage and Rota-Rod tests exhibited the absence of
neurosedative activity or motor coordination deficits, which
may interfere with the test results to give false positives.
Therefore, analgesic actions of paracetamol, thiosalicylic
acid, and compounds 2a, 2b, and 2d observed in this study
were not caused by neurological deficits.
compounds. In this study, paracetamol and thiosalicylic
acid increased the reaction times of mice in hot-plate
(Table 1) and tail-clip (Table 2) and decreased the num-
bers of abdominal contractions in acetic acid-induced
writhing tests (Table 3), therefore these reference com-
pounds were exhibited significant analgesic activities in all
applied tests.
Among the synthesized compounds, 2a, 2b, and 2d
caused statistically significant increase in reaction times of
mice in hot-plate (Table 1) and tail-clip (Table 2) tests.
These compounds decreased the number of abdominal
contractions in acetic acid-induced writhing tests (Table 3).
Significant increase in reaction times of animals in hot-
plate and tail-clip tests indicated the analgesic actions of
the compounds against thermal and mechanical noxious
stimuli, respectively. Besides, decrease in the number of
Bromo, methoxy, and carboxy substituted derivatives (2c,
2e, and 2f, respectively) in the series did not show analgesic
activities. Among the synthesized compounds, methyl
substituted derivative 2d, non-substituted derivative 2a, and
chloro substituted derivative 2b exhibited statistically sig-
nificant analgesic effects. Compound 2d had the highest
analgesia values (%) than other synthesized compounds and
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Med Chem Res (2011) 20:152–157
157
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was statistically more potent than both paracetamol and
thiosalycilic acid in all analgesia tests (Tables 1, 2, 3).
Obtained results had shown that variation of substitution
on the chemical structure caused significant difference on
analgesic activity. Methyl substitution on para position of
N-phenylacetamide may be suggested to increase the
analgesic activity. It can be hypothesized that different
alkyl substitution on phenyl ring at para position may also
increase the analgesic activity of title compounds.
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combined compounds exhibit strong supraspinal, spinal,
and peripheral analgesic activities. Compound 2d carrying
methyl substituted phenyl ring showed more potent anal-
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