Non-carboxylic Analogues of Aryl Propionic Acid: Synthesis, Anti-inflammatory, Analgesic, Antipyretic and Ulcerogenic Potential

Article abstract of DOI:10.1055/s-0033-1363251

As a part of ongoing studies in developing new potent anti-inflammatory and analgesic agents, a series of novel 6-methoxy naphthalene derivatives was efficiently synthesized and characterized by spectral and elemental analyses. The newly synthesized compounds were evaluated for their anti-inflammatory activities using carrageenin-induced rat paw edema model, analgesic activities using acetic acid induced writhing model in mice and anti-pyretic activity using yeast induced hyperpyrexia method as well as ulcerogenic effects. Among the synthesized compounds, thiourea derivative (6a, e) exhibited higher anti-inflammatory activity than the standard drug naproxen in reduction of the rat paw edema (88.71, 89.77%) respectively. All of the non-carboxylic tested compounds were found to have promising anti-inflammatory, analgesic and antipyretic activity, while were devoid of any ulcerogenic effects.

Full text of DOI:10.1055/s-0033-1363251

Original Article 485
Non-carboxylic Analogues of Aryl Propionic Acid:
Synthesis, Anti-inflammatory, Analgesic, Antipyretic
and Ulcerogenic Potential
1
1
2
Authors
S. I. Eissa , A. M. Farrag , A. A. A. Galeel
Affiliations
1
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azher University, Nasr City,Cairo, Egypt
2
Researcher, Pharmacology Department, National Research Center, Dokki, Cairo, Egypt
Key words
Abstract
model in mice and anti-pyretic activity using
●
▶ naproxen
▶ anti-inflammatory
▶ analgesic
▶ antipyretic
●
▶ ulcer effect
▼
yeast induced hyperpyrexia method as well
as ulcerogenic effects. Among the synthesized
compounds, thiourea derivative (6a, e) exhib-
ited higher anti-inflammatory activity than the
standard drug naproxen in reduction of the rat
paw edema (88.71, 89.77%) respectively. All
of the non-carboxylic tested compounds were
found to have promising anti-inflammatory,
analgesic and antipyretic activity, while were
devoid of any ulcerogenic effects.
●
As a part of ongoing studies in developing new
potent anti-inflammatory and analgesic agents,
a series of novel 6-methoxy naphthalene deriva-
tives was efficiently synthesized and character-
ized by spectral and elemental analyses. The
newly synthesized compounds were evaluated
for their anti-inflammatory activities using car-
rageenin-induced rat paw edema model, analge-
sic activities using acetic acid induced writhing
●
●
Introduction
▼
12]. It is demonstrated that the invention modi-
fied NSAIDs substantially reduce GI toxicity,
while exhibiting dose equivalent efficacy in anti-
inflammation activity in both acute and chronic
inflammation animal models [13–16]. Most
derivatives of NSAIDs have been prepared by
derivatization of the carboxyl group, depending
on the hypothesis that neutralization of carboxy-
late of NSAIDs would eliminate their ability to
inhibit COX-1 without significantly affecting
their COX-2 inhibitory properties [17].
Naproxen is one of the most popular NSAIDs that
inhibit nonselectively both major cyclooxygen-
ase (COX) isoform. It considered the only pure
stereospecific arylpropionic acid derivatives to
be used clinically as NSAID in the (S) configura-
tion [16].
The present work describes the synthesis and the
investigation of the analgesic, antipyretic and
anti-inflammatory properties of new 6 -methoxy
naphthalene derivatives. Our strategy for synthe-
sis of such derivatives is based on the modifica-
tion of the structure of the known potent non
selective NSAIDs. The strategy is intended to
obtain potent anti-inflammatory activity with-
out ulcerogenic effects using traditional medici-
nal chemistry techniques by both extending the
acetic acid side-chain and formation of bulky
Clinical use of the most available acidic non-steroi-
dal anti-inflammatory drugs (NSAIDs) is strongly
limited by their gastrointestinal (GI) side effects
which range in both severity and frequency from
relatively mild to more serious and potentially
life threating states. The GI complication of
NSAIDs is believed to be determined from the
mixed effect of irritation caused by blockage of
prostaglandin biosynthesis in GI tract, as their
mode of action is by non-selectively blocking
cyclooxygenase (COX-1 and COX-2), and direct
action of free carboxylic group in NSAIDs on the
epithelium of the GIT [1–5].
received 06 . 10 . 2013
accepted 25 . 11 . 2013
Bibliography
DOI http://dx.doi.org/
10.1055/s-0033-1363251
Published online:
January 20, 2014
Drug Res 2014;
64: 485–492
©
Georg Thieme Verlag KG
Therefore administration of NSAIDs, for example
to treat inflammatory diseases such as osteoar-
thritis or rheumatoid arthritis unavoidably leads
to a lack of the prostaglandins required for the
physiological functions mentioned above. As a
consequence long-term NSAID users suffer from
a high incidence of GI irritation or, in the worst
case from the development of life threatening GI
ulcers and bleeding. These lesions can lead to
increased morbidity in patients [6,7].
Considerable attention has been focused on the
development of new derivatives, such as to tem-
porarily mask the acidic group of NSAIDs as a
promising means of reducing or abolishing the GI
toxicity due to the local action mechanism [3,8–
Stuttgart · New York
ISSN 2194-9379
Correspondence
S . I. Eissa
Pharma ce utical Chemistry
Department
Faculty of Pharmacy (Girls)
A- lA zher University
Na sr City
Cairo
Po stal code 11787
Eg ypt
eT l.: +20/100/6364 634
aF x: +20/224/182 105
Sar az izo2005@yahoo.com
amide derivatives (● Fig. 1) .
▶
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

4
86 Original Article
and target compounds 3a–c, 6a–f, 9a–d, and
11a, b; aiming to mask the acidic group of NSAIDs
naproxen as a promising means of reducing or
abolishing the GI toxicity due to the local action
mechanism.
Materials and Methods
2-(6-methoxynaphthalen-2-yl)-N'-(4-(2-oxo-2-phenylethoxy)
▼
benzylidene)propanehydrazide 3b: Yield 90%; mp 185–
Chemistry
187°C. IR: 3451 (NH), 1659 (CH CO), 1613 (CONH), 1510 (C=N),
2
−
1
Melting points were determined on open capillary tubes using
Griffin melting point apparatus and are uncorrected. Elemental
analyses (C, H, N) were performed by Micro Analytical Center,
The Regional Center for Mycology and Biotechnology, Al-Azher
University. The values were found to be within ±0.4% of the
theoretical ones unless otherwise indicated. Infrared spectra
were recorded on Thermo Electron Corporation IR 200, using
KBr discs, at Pharmaceutical Analysis Unit, Faculty of Pharmacy
1241 (C-O-C), cm . 1H NMR (DMSO-d6) δ: 1.46 (d, 3H, CH3),
3.83 (s,3H, OCH ), 4.75 (q, 1H, CH), 5.13 (s, 2H, O-CH ), 7.04, (d,
3
2
2H, AB system), 7.17, (d, 1H, aromatic-H-7), 7.29 (s, 1H, aro-
matic-H-5), 7.40 (d, 1H, aromatic-H-3), 7.43–7.57, (m,5H, aro-
matic-H), 7.64–7.78, (m, 3H, aromatic-H1,4,8), 7.83 (d, 2H, AB
system), 8.12 (s, 1H, N=CH), 11.16, (s, 1H, NH exchangeable with
+
D2O). MS (m/z): 465 (M −1, 0.04), Anal. Calcd for C29H26N O : C,
2
4
74.66; H, 5.62; N,6.00. Found: C, 74.73; H, 5.60; N, 6.13.
(Boys), Al-Azher University.1H NMR spectra were scanned on
Varian Gemini 300MHz spectrometers at Research Services
Unit, Faculty of Science, and Cairo University. DMSO-d6 was
used as a solvent (chemical shifts are given in part per million
2-((2-(2-(6-methoxynaphthalen-2-yl)propanoyl)hydrazono)
methyl)phenyl4-methylbenzenesulfonate 3c: Yield 85%; mp
−
1
169–171°C. IR: 3449 (NH), 1610 (C=O), 1547 (C=N) cm . 1H
(ppm) downfield from TMS).Mass spectra were made on a
NMR (DMSO-d6) δ: 1.45 (d, 3H, CH ), 2.62 (s, 3H, CH ), 3.83
3
3
DI-150 Unit of Shimadzu GC/MS-QP 5050A at the Regional Cen-
tre for Mycology and Biotechnology, AL-Azhar University. Ana-
lytical thin-layer chromatography (TLC) was performed on
precoated silica gel plates 60-F-254 (Merck; 0.25mm).
(s,3H, OCH3), 4.66 (q, 1H, CH), 7.06–7.18 (m, 4H, aromatic-H),
7.22, (d, 1H, aromatic-H-7), 7.29 (s, 1H, aromatic-H-5), 7.49 (d,
1H, aromatic-H-3), 7.59 (d, 2H, AB system), 7.66 (d, 2H, AB sys-
tem), 7.69–7.86, (m, 3H, aromatic-H1,4,8), 8.13 (s, 1H, N=CH),
+
1
1.31 (s, 1H, NH exchangeable with D O). MS (m/z): 502 (M ,
2
2-(6-methoxynaphthalen-2-yl)propanoicacidhydrazide2: C o m -
26.39), Anal. Calcd for C28H26N O S: C, 66.91; H, 5.21; N, 5.57.
2
5
pound 2 was previously reported [18,19].
Found: C, 66.03; H, 5.18; N, 5.65.
N-(aryl)-2-(6-methoxynaphthalen-2-yl)propanehydrazide
6-Methoxynaphthalen-2-yl)propanoyl chloride 4: Compound
4 was previously reported [18].
3
a–c: A mixture of 2-(6-methoxynaphthalen-2-yl) propanoic
acid hydrazide 2 (0.01 moles) and 0.01 moles of appropriate
aldehyde was dissolved in 30ml of ethanol. Then refluxed for 8h
and kept aside. The solid obtained was filtered, washed with
water, dried and recrystallized from ethanol.
2-(2-methoxynaphthalen-6-yl)propanoylisothiocyanate5: C o m -
pound 5 was previously reported [19].
N-(2-(6-methoxynaphthalen-2-yl)propanoyl)-3-(aryl)thiourea
6a–f: A mixture of 2-(2-methoxynaphthalen-6-yl)propanoyl
isothiocyanate 5 (0.01mol) and amine derivatives (0.01mol) in
dry acetone (40ml) was refluxed for 4h, allowed to cool, the
solid product that obtained was collected by filtration left to dry
and crystallized from suitable solvent.
N-(4-bromo-2-hydroxybenzylidene)-2-(6-methoxynaphtha-
len-2-yl)propanehydrazide 3a: Yield 85%; mp 160–162°C. IR:
-1
3
400–3225 (br) (OH, NH), 1612 (C=O), 1502 (C=N) cm . 1H
NMR (DMSO-d6) δ: 1.49 (d, 3H, CH ), 3.83 (s, 3H, OCH ), 4.66
3
3
(q,1H, CH), 6.83–7.11 (m, 3H aromatic-H), 7.17, (d, 1H, aromatic
H-7), 7.29 (s, 1H, aromatic H-5), 7.49 (d, 1H, aromatic H-3),
7
1
.64–7.79, (m, 3H, aromatic H1,4,8), 8.10 (s, 1H, N=CH), 10.28 (s,
H, NH exchangeable with D2O), 11.32 (s, 1H, Ph-OH exchange-
N-(2-(6-methoxynaphthalen-2-yl)propanoyl)-3-(4-chlorophe-
nyl)thiourea 6a: Crystallization solvent benzene, Yield 80%;
mp 100–101°C. IR: 3490, 3374 2(NH), 1690 (C=O), 1156 (C=S)
cm . 1H NMR (DMSO-d6) δ: 1.45 (s, 3H, CH3), 3.78 (s,3H,OCH3),
4.22 (q,1H, CH), 7.05 (d, 2H, AB system), 7.15, (d, 1H, aromatic-
H-7), 7.22 (s, 1H, aromatic-H-5), 7.41 (d, 2H, AB system), 7.49 (d,
1H, aromatic-H-3), 7.65–7.83, (m, 3H, aromatic-H1,4,8), 11.70
able with D2O). 13C NMR (DMSO-d6) δ: 17.3 & 54.3 (CH -CH),
3
−
1
55.8 (OCH3), 105–146 (imine carbon+aromatic carbons),
+
177(C=O). MS (m/z): 427 (M +1, 72.50), Anal. Calcd for
C21H19BrN O : C, 59.03; H, 4.48; N, 6.56. Found: C, 59.12; H,
2
3
4.51; N, 6.64.
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

Original Article 487
(
s,1H, CSNH exchangeable with D O), 12.40 (s, 1H, CONH
benzene, Yield 55%; mp 90–92°C. IR: 3525 (NH), 3360–3300
(br) (2NH), 1667 (C=O), 1149 (C=S) cm . 1H NMR (DMSO-d6)
2
13
−1
exchangeable with D O): C NMR (DMSO-d6) δ: 17.1 & 53.2
2
(
CH -CH),55.4(OCH ),104–149(aromaticcarbons),177.2(amidic
δ: 1.51 (d, 3H, CH ), 3.85 (s,3H, OCH ), 3.99 (q, H, CH), 6.76 (d,
3
3
3
3
+
carbon), 183.2(thiourea carbon). MS (m/z): 398 (M , 2.06), Anal.
Calcd for C21H19ClN O S: C, 63.23; H, 4.80; N,7.02. Found: C,
6
1H,CH thiazole), 7.13, (d, 1H, aromatic-H-7), 7.15 (d, 2H, AB sys-
tem), 7.18 (s, 1H, aromatic-H-5), 7.47 (d, 1H,CH thiazole), 7.50
(d, 1H, aromatic-H-3), 7.72–7.78, (m, 3H, aromatic-H1,4,8), 7.80
2
2
3.41; H, 4.84; N, 7.14.
(
d, 2H, AB system), 7.12 (s, 1H, CONH exchangeable with D O),
2
N-(2-(6-methoxynaphthalen-2-yl)propanoyl)-3-(4-hydroxy-
phenyl)thiourea 6b: Crystallization solvent ethanol, Yield
10.35 (s,1H, CSNH exchangeable with D O), 12.49 (s, 1H, NHSO
2
2
+
exchangeable with D O). MS (m/z): 526(M , 1.65), Anal. Calcd
2
8
5%; mp 140–142°C. IR: 3450–3250 (br) (OH, 2NH), 1668
for C24H22N O S : C, 54.73; H, 4.21; N, 10.64. Found: C, 54.84; H,
4.16; N, 10.78.
4
4 3
−
1
(C=O), 1028 (C=S) cm . 1H NMR (DMSO-d6) δ: 1.48 (d, 3H,
CH ), 3.86 (s, 3H, OCH ), 4.21 (q, H, CH), 6.78 (d, 2H, AB system),
3
3
7
2
.15, (d, 1H, aromatic-H-7), 7.22 (s, 1H, aromatic-H-5), 7.49 (d,
H, AB system), 7.52 (d, 1H, aromatic-H-3), 7.79–7.91, (m, 3H,
Ethyl 4-(2-(6-methoxynaphthalen-2-yl)propanamido)benzoate
7: Compound 7 was previously reported [20].
aromatic-H1,4,8), 10.17(s,1H, CSNH exchangeable with D O),
2
1
1.57 (s, 1H, CONH exchangeable with D O), 12.70 (s, H, Ph-OH
N-(4-(Hydrazinecarbonyl)phenyl)-2-(6-methoxynaphthalen-
2-yl) propanamide 8: Compound 8 was previously reported
[20].
2
+
exchangeable with D O). MS (m/z): 380 (M , 0.03), Anal. Calcd
for C21H20N O S: C, 66.29; H, 5.30; N, 7.36. Found: C, 66.43; H,
2
2
3
5.24; N, 7.52.
2
-(6-methoxynaphthalen-2-yl)-N-(4-(2-(4-substituted
phenylsulfonyl)hydrazinecarbonyl)phenyl)propanamide
9a-d: mixture of N-(4-(Hydrazinecarbonyl)phenyl)-2-(6-
N-(2-(6-methoxynaphthalen-2-yl)propanoyl)-3-(4-sulfamoyl-
phenyl)thiourea 6c: Crystallization solvent ethanol, Yield
A
6
(
0%; mp 220–222°C. IR: 3200–3400 (br) (NH , 2NH), 1658
methoxynaphthalen-2-yl) propanamide 8 (0.01mol) and ben-
zene sulfonamide derivatives (0.01mol) in pyridine (20mL) was
2
C=O), 1163 (C=S) cm−1. 1H NMR (DMSO-d6) δ: 1.50 (d, 3H,
CH ), 3.86 (s, 3H, OCH ), 4.00 (q, 1H, CH), 7,13 (s, 1H, CSNH
stirred overnight at 25°C, poured into H O (50mL), and extracted
3
3
2
exchangeable with D O), 7.16, (d, 1H, aromatic-H-7), 7.22 (s, 1H,
aromatic-H-5), 7.28 (d, 2H, AB system), 7.49 (d, 2H, AB system),
with EtOAc. The combined organic layer was washed, dried, fil-
tered, and condensed. The product was crystallized from etha-
nol.
2
7.52 (d, 1H, aromatic-H-3), 7.74–7.79, (m, 3H, aromatic-H1,4,8),
7
,81 (s, 2H, NH2 exchangeable with D2O), 10.35 (s, 1H, CONH
+
exchangeable with D O). MS (m/z): 443 (M , 0.53), Anal. Calcd
2-(6-methoxynaphthalen-2-yl)-N-(4-(2-(phenylsulfonyl)
2
for C21H21N O S : C, 56.87; H, 4.77; N, 9.47. Found: C, 57.08; H,
hydrazinecarbonyl)phenyl)propanamide 9a: Yield 65%; mp
110–112°C. IR: 3450–3250 (br) (3NH), 1669 (CONH), cm . 1H
3
4 2
−
1
4.81; N, 9.63.
NMR (DMSO-d6) δ: 1.48 (d, 3H, CH ), 3.38 (s,3H, OCH ), 4.10 (q,
3
3
N-(2-(6-methoxynaphthalen-2-yl) propanoyl)-3-(4-(pyrimidin-
-ylsulfamoyl) phenyl) thiourea 6d: Crystallization solvent
1H, CH), 7.12, (d, 1H, aromatic-H-7), 7.15 (d, 2H, AB system),
7.26 (s, 1H, aromatic-H-5), 7.47–7.50, (m, 5H, aromatic-H1),
7.57 (d, 2H, AB system), 7.60 (d, 1H, aromatic-H-3), 7.75–7.82,
2
benzene, Yield 80%; mp 110–111°C. IR: 3500–3375 (br) (3NH),
1
3
655 (C=O), 1163 (C=S) cm− . 1H NMR (DMSO-d6) δ: 1.51 (d,
1
(m, 3H, aromatic-H1,4,8), 9.86, 10.32,10.45 (s, 3H, 3NH
+
H, CH ), 3.84 (s,3H, OCH ), 4.20 (q,1H,CH), 7.00–7.15, (m, 3H,
exchangeable with D O). MS (m/z): 503 (M , 0.29), Anal. Calcd
3
3
2
aromatic H), 7.16, (d, 1H, aromatic-H-7), 7.22 (s, 1H, aromatic-
H-5), 7.29 (d, 2H, AB system), 7.50 (d, 2H, AB system), 7.82 (d,
for C27H25N O S: C, 64.40; H, 5.00; N, 8.34. Found: C, 64.53; H,
4.98; N, 8.47.
3
5
1H, aromatic-H-3), 7.86–7.98, (m, 3H, aromatic-H1,4,8), 10.52
(
s, 1H, CSNH exchangeable with D O), 11.79 (s, 1H, CONH
N-(4-(2-(4-bromophenylsulfonyl)hydrazinecarbonyl)phenyl)-
2
exchangeable with D O), 12.61 (s, 1H, NHSO exchangeable with
2-(6-methoxynaphthalen-2-yl)propanamide 9b: Yield 70%;
mp 199–200°C. IR: 3450–3200 (br) (3NH), 1670 (CONH), cm .
2
2
+
−1
D O). MS (m/z): 522 (M +1, 11.17), Anal. Calcd for C25H23N O S :
2
5
4 2
C, 57.57; H, 4.44; N, 13.43. Found: C, 57.64; H, 4.48; N, 13.61.
1H NMR (DMSO-d6) δ: 1.47 (d, 3H, CH3), 3.85 (s, 3H, OCH3), 3.99
q, 1H, CH), 7.01 (d, 2H, AB system), 7.19, (d, 1H, aromatic-H-7)
(
N-(2-(6-methoxynaphthalen-2-yl) propanoyl)-3-(4-(5-methi-
soxazole-3-yl) sulfamoyl)phenyl) thiourea 6e: Crystallization
solvent ethanol, Yield 65%; mp 160–162°C. IR: 3400–3200 (br)
7.27 (s, 1H, aromatic-H-5), 7.50 (d, 1H, aromatic-H-3), 7.61 (d,
2H, AB system), 7.64 (d, 2H, AB system), 7.72–7.78, (m, 3H, aro-
matic-H1,4,8), 7.81 (d, 2H, AB system), 10.10, 10.36, 10.60 (s, 3H,
(
3NH), 1658 (C=O), 1166 (C=S) cm−1. 1H NMR (DMSO-d6) δ:
3NH exchangeable with D O). MS (m/z): 582 (M +1, 0.26), Anal.
+
2
1
.36 (d, 3H, CH ), 2.26 (s, 3H, CH ), 3.85 (s,3H, OCH ), 4.10
Calcd for C27H24BrN O S: C, 55.68; H, 4.15; N, 7.21. Found: C,
3
3
3
3
5
(
q,1H,CH), 6.09 (s, 1H, isoxazole H), 6.80 (s, 1H, CSNH exchange-
55.79; H, 4.19; N, 7.34.
able with D O), 7.12 (d, 2H, AB system), 7.15, (d, 1H, aromatic-
2
H-7), 7.26 (s, 1H, aromatic-H-5), 7.42 (d, 2H, AB system), 7.70 (d,
2-(6-methoxynaphthalen-2-yl)-N-(4-(2-tosylhydrazinecarbo-
1
H, aromatic-H-3), 7.72–7.81, (m, 3H, aromatic-H1,4,8), 10.53
nyl)phenyl)propanamide 9c: Yield 60%; mp 200–202°C. IR:
−
1
(
s, 1H, CONH exchangeable with D O), 11.31 (s, 1H, NHSO
3380–3250 (br) (3NH), 1672 (COMH), cm . 1H NMR (DMSO-
d6) δ: 1.47 (d, 3H, CH3), 2.33 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 3.98
(q, 1H, CH), 7.12 (d, 2H, AB system), 7.16, (d, 1H, aromatic-H-7)
7.28 (s, 1H, aromatic-H-5), 7.31 (d, 1H, aromatic-H-3), 7.48 (d,
2
2
+
exchangeable with D O). MS (m/z): 524 (M , 1.65), Anal. Calcd
for C25H24N O S : C, 57.24; H, 4.61; N, 10.68. Found: C, 57.38; H,
2
4
5 2
4.68; N, 10.90.
2H, AB system), 7.51–7.69, (m, 3H, aromatic-H1,4,8), 7.75 (d, 2H,
N-(2-(6-methoxynaphthalen-2-yl) propanoyl)-3-(4-(5-thiazole-
-yl) sulfamoyl)phenyl) thiourea 6f: Crystallization solvent
AB system), 7.81 (d, 2H, AB system), 9.83, 10.34, 10.52 (s, 3H,
3
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

4
88 Original Article
3
NH exchangeable with D O). 13C NMR (DMSO-d6)δ: 17.5 &
with the guide for care and use of laboratory animals and in
accordance with the animal procedures were performed in
accordance with the Ethics Committee of the National Research
Centre and followed the recommendations of the National Insti-
tutes of Health Guide for Care and Use of Laboratory Animals
2
53.7 (CH -CH), 24.3 (Ph-CH ) 55.4 (OCH ), 104–149 (aromatic
3
3
3
carbons), 172.3(amidic carbon), 164.7(CONHNH). MS (m/z): 517
(M+, 2.54), Anal. Calcd for C28H27N O S: C, 64.97; H, 5.26; N,
3
5
8.12. Found: C, 65.06; H, 5.29; N, 8.21.
(Publication No. 85–23, revised 1985).
N-(4-(2-(4-fluorophenylsulfonyl)hydrazinecarbonyl)phenyl)-
All the tested compounds were dissolved in dimethylformamide
(DMF) before subcutaneous injection in the tested animals. The
control group was similarly injected with DMF.
2
-(6-methoxynaphthalen-2-yl)propanamide 9d: Yield 55%;
−
1
mp 300–302°C. IR: 3400–3300 (br) (3NH), 1665 (CONH), cm
.
1
H NMR (DMSO-d6) δ: 1.49 (d, 3H, CH ), 3.84 (s, 3H, OCH ), 4.08
3
3
(q, 1H, CH), 7.12 (d, 2H, AB system), 7.15, (d, 1H, aromatic-H-7)
Anti-inflammatory activity
7
2
.26 (s, 1H, aromatic-H-5), 7.27 (d, 1H, aromatic-H-3), 7.54 (d,
H, AB system), 7.70 (d, 2H, AB system), 7.75–7.80, (m, 3H, aro-
The anti-inflammatory effect of the newly synthesized com-
pounds was evaluated in correspondence to the carrageenan-
induced paw edema method [22]. 15 groups of animals each
consisting of 6 rats weighing 130–150g were selected. The 1st
group was treated with the vehicle and left as control while the
2nd one was given Naproxen by subcutaneous injection in a
dose of 10mg kg1 (standard). Other animals were pretreated
with drugs 1h before injection of carrageenan (0.1ml of 1%).
Carrageenan was injected into the sub plantar tissue of left hind
paw of each rat. Swellings of carrageenan-injected foot were
measured at 0, 1, 2, 3 and 4h using Plethysmometer (UGO Basile,
Italy) [22,23]. Edema volume of control (Vc) and volume of
treated (Vt) were used to calculate percentage (%) inhibition and
(%) edema volume by using the following formula: % Inhibi-
tion=[1− (Vt/Vc)]×100% Edema volume=100×(Edema volume
after drug treatment/Initial volume). Carrageenan-induced hind
paw edema is the standard experimental model of acute inflam-
mation. Carrageenan is the phlogistic agent of choice for testing
anti-inflammatory drugs as it is not known to be antigenic and is
devoid of apparent systemic effects.
matic-H1,4,8), 7.87 (d, 2H, AB system), 9.84, 10.51, 10.72 (s, 3H,
+
3NH exchangeable with D O). MS (m/z): 521 (M , 0.20), Anal.
2
Calcd for C27H24FN O S: C, 62.18; H, 4.64; N, 8.06. Found: C,
3
5
62.31; H, 4.66; N, 8.17.
2
-(6-methoxynaphthalen-2-yl) propanoyl azide 10: C o m -
pound 10 was previously reported [21].
substituted 2-(6-methoxynaphthalen-2-yl)propanoylcarbamate
1
with different alcohols (60ml) for 3h, the separated crystalline
product were filtered, left to dry and recrystallized from suitable
solvent.
1a, b: A solution of compound 10 (0.01mol) was refluxed
Methyl 2-(6-methoxynaphthalen-2-yl)propanoylcarbamate 11a:
Crystallization solvent methanol, Yield 88%; mp 120–122°C. IR:
3
389 (NH), 1695, 1628 (2C=O),1250 (C-O-C) cm− . 1H NMR
1
(DMSO-d6) δ: 1.35 (d, 3H, CH ), 3.29 (s, 3H, C=O-OCH ), 3.86 (s,
3
3
3
H, OCH ), 4.81 (q,1H,CH), 6.36 (s, 1H, NH), 7.11, (d, 1H, aro-
3
matic-H-7) 7.15 (s, 1H, aromatic-H-5), 7.28 (d, 1H, aromatic-
H-3), 7.65–7.78, (m, 3H, aromatic-H1,4,8), MS (m/z): 289 (M +2,
Analgesic activity
+
Acetic acid induced writhing test in male mice (n=6) weighing
20–25g were used. All animals were withdrawn from food 2h
before the start of experiment and were divided in different
groups. Group I was injected with normal saline (10ml/kg) as
control, Group II received standard drug naproxen (10mg/kg)
while the remaining groups were injected with 10mg/kg p.o. of
test compounds. 30min later, the animals were treated intra
peritoneal with 0.1ml of 1% acetic acid. The numbers of abdom-
inal constrictions (writhes) were counted after 5min of acetic
acid injection for the period of 20min [23].
0
.22), Anal. Calcd for C16H17NO : C, 66.89; H, 5.96; N, 4.88.
4
Found: C, 66.96; H, 5.98; N, 5.02.
Ethyl 2-(6-methoxynaphthalen-2-yl)propanoylcarbamate11b:
Crystallization solvent ethanol, Yield 75%; mp 140–142°C. IR:
3
−
1
394 (NH), 1694, 1618 (2C=O), 1236 (C-O-C) cm . 1H NMR
(DMSO-d6) δ: 1.12 (t, 3H, CH CH ), 1.38 (d, 3H, CH ), 3.86 (q, 2H,
2
3
3
CH CH ), 3.94 (s, 3H, OCH ), 4.77 (q, H, CH), 6.39 (s, 1H, NH),
7
1
NMR (DMSO-d6) δ: 16.7 & 42.7 (CH -CH),. 58.4 &13.8 (CH -CH )
5
bon), 175.2(CONH), MS (m/z): 300 (M −1, 10.73), Anal. Calcd for
2
3
3
.12, (d, 1H, aromatic-H-7) 7.15 (s, 1H, aromatic-H-5), 7.28 (d,
H, aromatic-H-3), 7.65–7.78, (m, 3H, aromatic-H1,4,8). 13C
The abdominal constriction response induced by acetic acid is a
sensitive procedure to establish peripherally acting analgesics.
This response is thought to involve local peritoneal receptors.
3
2
3
5.8 (OCH ), 105.3–160 (aromatic carbons & carboxylate car-
3
+
C17H19NO : C, 67.76; H, 6.36; N, 4.65. Found: C, 67.89; H, 6.39; N,
Gastric ulceration studies
4
4
.69.
All the animals were subjected to this experimental process.
They were sacrificed immediately after the last measurement,
under ether anaesthesia and stomachs were removed, opened
through the greater curvature, washed and fixed in 5% formalin
solution. The stomachs were then examined for lesion under a
dissecting microscope [24].
Pharmacological screening
Animals
Wistar rats (130–150g) and Albino mice (20–25g) were obtained
from the animal house colony of the National research centre,
Dokki, Giza, Egypt. Animals were housed in groups of five at an
ambient temperature of 25±1°C with free access to food and
water. Animals were deprived of food but not water four hours
before the experiment. For screening of anti-inflammatory, anti-
pyretic activity and analgesic effect; the first group served as a
control group. The second group was used as reference standard.
Other groups received test compounds at doses (10mg/kg p.o.).
All experimental procedures were conducted in accordance
Antipyretic activity
To induce hyperpyrexia, 10mg/kg b.w. of an aqueous suspension
of brewer’s yeast (20% in normal saline) was injected subcuta-
neously in the back below the nape of the rat, in consistent with
the yeast-induced hyperpyrexia method [25]. The animals were
fasting during the experiment, but they were given water ad
libitum. Control temperatures were recorded with a thermom-
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

Original Article 489
F ig. 2 Reagents a Et OH/H2 SO4 c onc.,reflux/
NH2 NH2 /E tOH,reflux; b R C6 H4 CHO/EtOH, reflux:
c S O2 Cl /b ezene,reflux; d N H4 SCN/dry
H
N
Cl
OH
NH2
O
c
O
a
O
O
O
O
acetone,reflux; e N H2 C6 H4R/dry acetone, reflux.
4
1
2
d
e
b
N
C
S
H
N
O
O
N
R
O
5
O
3a-c
3
R
H
N
H
N
Br
OH
O
S
O
R
a
,
6a-f
6
R
a
b
c
X=Cl
OH
b
O
SO NH
2
2
N
O
HN
SO2
d
N
O
O
O
O
N
S
c
e
SO2
SO2
N
H
H
N
f
S
N
H
N
N
Cl
NH2 NH2 /E tOH, reflux; c X -C6 H4 SO2 Cl/pyridine,
reflux; d N aN /a ce tone, stirring.
d
a
O
O
O
O
O
O
O
1
0
7
O
4
e
b
H
N
OR
H
N
O
O
H
N
O
O
8
O
NH
1
1a,b
O
R: a=CH , b=C H
c
H
N
O
S
O
H
O
N
O
N
H
O
x
9a-d
x: a=H, b=Br, c=CH , d=F
eter (Model BAT-12, Physitemps, Sensortek inc. USA) before the
yeast injection and 18h later to evaluate the pyretic response.
The temperature measurements in fevered animals prior to drug
administration were used as the pre-drug control. Test com-
pounds and naproxen (10mg/kg b.w.), which served as the refer-
ence drug, were given orally 18h after the yeast injection. The
temperatures were recorded at 1, 2 and 3h after the drugs
administration.
Result and Discussion
▼
Chemistry
The target compounds were conducted according to the
sequence of reactions depicted in● Fig. 2, 3. The required Schiff
▶
analogous 3a-c were synthesized by condensation of amino
group of acid hydrazides [21, 26] with various aryl aldehydes
[27] in refluxing ethanol for 2–4 h. The structures of new
compounds N-(aryl)-2-(6-methoxynaphthalen-2-yl)propane-
hydrazide 3a-c were confirmed by spectral data. The main
features characterizing their IR spectra are the disappearance
Statistical analysis
Values were expressed as means±S.E. Comparisons between
means were carried out using one way ANOVA followed by Tukey
multiple comparisons test.
of the band corresponding to the NH group and the detection
of a strong C=N stretching band at 1580–1645cm evidenced
2
−
1
the formation of Schiff base. Moreover 1H-NMR; of the synthe-
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

4
90 Original Article
sized compounds revealed besides the parent expected signals a
singlet at around δ 10.28ppm attributed to NH, another singlet
characterized the H-NMR spectra at approximately δ 8.12ppm
4
h post carrageenan injection, in doses equal to 10mg/kg and Naproxen
1
(10mg/kg) in rats (n=6).
corresponding to the imine hydrogen. The 13C-NMR spectrum
of compound 3a displayed new downfield signals at δ 124.9ppm
due to imine carbon in addition to the new aromatic carbons.
On the other hand naproxen acid chloride 4 was synthesized
according to the reported procedure [14,18,19], using thionyl
chloride in dry benzene. It was reacted with ammonium thiocy-
anate in acetone under refluxing condition to afford the corre-
sponding naproxenoyl isothiocyanate[19,28] 5 in a good yield.
The reactivity of isothiocyanate 5 toward some nucleophilic rea-
gents was discussed [19]. Thus, interaction of isothiocyanate 5
with some amino compounds gave the novel thiourea deriva-
Groups
Paw size (mm)(mean±S.E.M)
Reduction %
Carrageenan
Na proxin
146. 5± 9.9
17. 4± 1.4*
31. 5± 3*a
20. 2± 1.9
–
88.14
78.49
86.19
77.92
88.71
77.28
80.84
82.74
89.77
86.26
82.87
83.38
86.25
82.75
80.34
80.20
3a
3b
3c
6a
6b
6c
32. 4± 3*a
16. 5± 1.5*
3 3± 1.4*a
28. 6± 0.7*a
25. 3± 2.4*a
6d
6e
6f
1 5± 1.3
tives 6a–f (●
▶
Fig. 2) .
20. 1± 1.6
25. 1± 2*a
The structures of the N-(2-(6-methoxynaphthalen-2-yl)
propanoyl)-3-(aryl)thiourea were established by IR spectra
which showed a new strong absorption band in the region
9a
9
b
c
24. 4± 2
9
20. 1± 1.6
9d
1a
1b
25. 3± 1.4*a
28. 8± 2.4*a
2 9± 2.4*a
−
1
3
200–3400cm assigned to 2NH stretching of the tiourea moi-
1
1
1
ety. The H-NMR spectra of 6a as a representative example,
revealed besides the expected 6-methoxynaphthale propanoyl
signals, 2 new singlets at δ 11.70 and 12.40 assigned to CSNH
*Significantly different from control group at P<0.05. ª significantly different from
naproxen group at P<0.05
13
and CONH respectively. C-NMR spectrum of compound 6a dis-
played 21 carbon signals. The most important signal appeared at
δ 181.2ppm characteristic for thiourea carbon (●
●
▶
Fig. 2) .
ard carrageenan-induced paw edema in rats [22], at a dose of
10mg/Kg body weight, and compared with naproxen as a refer-
ence drug. All the tested compounds and the standard drug
naproxen produced significant reduction of a paw size as com-
▶
Fig. 3; describes the synthesis of N-(4-(2-(4-substitutedben-
zenesulfonyl)hydrazinecarbonyl)phenyl)-2-(6-methoxynaph-
thalen-2-yl)propanamide 9a–d via reaction of acid chloride 4
with 4-aminoethylbenzoate via nucleophilic addition, followed
by hydrazinolysis of the prepared ‘ester 7 to afford hydrazide
derivative 8 [29], which was ‘allowed to react with different sul-
fonyl chlorides [20] to yield the corresponding aryl amide deriv-
atives 9a–d. The structures of the latter products were confirmed
by IR spectra which showed the characteristic bands for the con-
jugated C=O and their 3NH stretching. The HNMR spectra of 9c
as an example showed besides the expected signals of the parent
compound 8, a new singlet at δ 2.33ppm attributed to the CH of
methyl sulfonyl phenyl moiety, in addition to the new aromatic
protons.
Finally, naproxen acid chloride 4 was also reacted with sodium
azide in refluxing acetone to furnish the novel acid azide deriva-
tive 101 [12,30], the latter yield carbamates 11a, b by boiling
with different alcohols. It has been found that the elemental
analysis and spectral data was in consistent with the proposed
carbamates structures. The IR showed a new band around 3394
for NH stretching, in addition to the characteristic bands for 2
pared to the control group (●
▶
Table 1, ● Fig. 2). For 6-methoxy-
▶
naphthalenhydrazide series 6a–c, compound 6b showed potent
anti-inflammatory activity (86.25% reduction) while the 2 other
derivatives of the same series 6a, 6c showed moderate anti-
inflammatory activity (78.49, 77.92% reduction) respectively
when compared to the reference standard naproxen (88.14%
reduction) and the control group. Our attempt is to optimize the
naproxen anti-inflammatory activity by extending the propa-
noic side chain while at the same time increase the number of
heteroatom attached directly to the 6-methoxynaphthalen ring.
We proposed to synthesize N-(2-(6-methoxynaphthalen-2-yl)
propanoyl)-3-(aryl)thiourea series 6a–f, and it is worth men-
tioning here, that two compounds of this series 6a,e exhibited
more potent anti-inflammatory than our reference standard
naproxen with reduction % (88.71, 89.77) respectively. The
other derivatives of the same series showed anti-inflammatory
activity ranging from very good to moderate as shown by com-
pounds 4f, 4d, 4c, and 4b (86.26, 82.74%, 80.84, 77.28% reduc-
tion) respectively.
1
3
1
conjugated C=O. The HNMR for 11b showed new triplet and
quartet signals at δ 1.12 and 3.86 attributed to CH and CH pro-
The above result revealed that, increasing the number of hetero
atom that can act as hydrogen bond donor or acceptor might
show good anti-inflammatory activity. For that reason, the
intermediate naproxenoyl chloride 4 was chemically trans-
formed to the respective aryl amide derivatives 9a–d hoping to
get potent anti-inflammatory activity as well. Unexpectedly,
among this latter series only compound 9c showed potent anti-
inflammatory activity with reduction % (86.28). In our exten-
sion strategy, to test the relation between the activity and the
presence of the aromatic functionalities, we planned to synthe-
size N-(2-alkyloxyacetyl)-2(6-methoxynaphthalen-2-yl)propan-
amide 11a, b, and it has been observed that, both compounds
exerted nearly the same moderate anti-inflammatory activity
3
2
13
tons of ethyl group respectively. Also the C-NMR spectrum of
compound 6a revealed the appearance of the new 2 signals of
the 2 ethyl carbons at δ 13.8and 58.5ppm, and new downfield
signal of (–COO) carbon.
In the current study we started with (S) naproxen and the prod-
ucts showed single spots in TLC. This prompted us to assume
that these derivatives produced are also in (S) configuration.
X-ray studies will be planned for these compounds (● Fig. 3) .
▶
Pharmacology
Anti-inflammatory activity
All final new compounds 3a–c, 6a–f, 9a–d and 11a, b were
tested for their in-vivo anti-inflammatory activity using stand-
(80.34, 80.20% reduction) (● Table 1) .
▶
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

Original Article 491
Anal gs iec activity
The tabulated results showed that almost all compounds signifi-
cantly decreased the temperature of pyretic rats at 1, 2, and 3h
after compounds administration (● Table 3) .
All the newly synthesized compounds were subjected to testing
their analgesic activity using the acetic acid–induced writhing
method [23]. Significant protection against writhing was
observed in animals treated with compounds 6a, c, 3c and 9c, d
where number of writhes were 6.3±0.4, 8±2.8, 6±0.6, 7±0.33,
and 6±0.6 respectively compared to 42.6±0.85 in the control
▶
Structure activity relationship
Firstly, it is interesting to point out that from the above–obtained
results, most of our optimized compounds obtained via the
extending strategy for the naproxen propanoic acid side chain
showed good pharmacological profile. The following assump-
tions about the structural activity relationship (SAR) can be
demonstrated;
▶ The number and setting of heteroatom that acts as either
hydrogen bond donor and /or acceptor proved crucial for the
anti-inflammatory activity, as it may cause the anchoring of
these compounds to the target receptor.
group (● Table 2) .
▶
as tGr ic ulceration studies
The stomachs of the animals were also examined for gastric
ulceration and in spite of high gastric ulcer incidence with the
reference compound naproxen the synthesized active com-
pounds generally showed negligible ulcerogenic effect.
Ant yi pr etic activity
The antipyretic activity was evaluated for newly prepared com-
pounds by using the yeast- induced hyperpyrexia method [25].
▶ In most cases, increase lipophilic properties of the substitu-
ent might increase the activity profile. This is obvious when
comparing the anti-inflammatory activity of 3a and 6b with
other lipophilic substituents bearing compounds.
Table 2 Analgesic effect (represented by number of writhes) of the new
▶ Replacing the Schiff aldehyde of 3b by other function 3a, c
markedly decreased the anti-inflammatory activity.
synthesized compounds in doses equal to 10mg/kg and Naproxen (10mg/
kg) in mice using acetic acid-induced writhing method (n=6).
▶
Aromatic extension might favor the anti-inflammatory activ-
ity rather than aliphatic extension. This obvious upon the
replacement of a big size aromatic group by the smaller
methyl or ethyl ones, resulting in biologically active com-
pounds which was less potent than the other aromatic con-
taining compounds, except for only compounds 3a, c which
were quite less potent than the others and this may be due to
the steric effect of the substituent.
Groups
No. of writhes in 20min after acetic acid
treatment (mean±S.E.M)
Co ntrol
42. 6± 0.85
4. 2± 0.5
2 3± 0.9
2 0± 0.9
6± 0.6
Na proxin
3
3
3
6
6
6
6
6
6
9
9
9
9
a
b
c
a
b
c
d
e
f
6. 3± 0.4
1 0± 0.57
8± 2.8
▶ Aromatic substituents might be enhancing analgesic activity.
▶ For (aryl) thiourea derivatives 6a–f, aromatic substitution by
electron withdrawing groups such as (aryl sulphonamide)
and (Cl), favored the activity rather than electron donating
1 8± 0.7
1 0± 0.6
1 1± 0.6
1 2± 0.6
17. 8± 0.5
7± 0.33
6± 0.6
one (NH ). The order of anti-inflammatory activity was
2
6e >6a >6f >6d >6c >6b; in general. The presence of electron
a
b
c
d
withdrawing moieties resulted in the highest activity among
all the compounds investigated in this study.
▶
These observations together with experimental results may
provide a good explanation for the design of potent anti-
inflammatory and analgesic drugs possessing 2-propanoyl-6-
methoxynaphthalene framework.
1
1a
1b
2 2± 0.9
2 1± 1.0
1
T able 3 Antipyretic effect of the new synthesized compounds and Naproxen in doses equal to 10mg/kg in hyperthermic rats (n=6).
Rectal temperature (°C) before drug administration
Decrease of rectal temperature after drug administration
1st 2nd 3rd
H
Time/H
−18H
0H
H
H
Co ntrol
37.0 4± 0.11
3 7± 0.06
39. 9± 0.3
39. 5± 0.12
39.1 2± 0.1
39.2 2± 0.11
39. 1± 0.10
39. 5± 0.2
39. 8± 0.24
38. 7± .06
40. 5± 0.2
37.9 6± 0.05
37.6 8± 0.09
37.6 6± 0.08
37.7 4± 0.07
38.0 6± 0.04
37. 6± 0.03
37.7 4± 0.09
37.6 8± 0.08
37.5 4± 0.05
37. 8± 0.08
37. 8± 0.09
37.6 4± 2
40. 3± 0.1
37.1 2± 0.05
37.3 2± 0.05
37.0 8± 0.08
37. 1± 0.06
37. 5± 0.04
37.0 6± 0.04
37.1 4± 0.07
37.1 2± 0.09
37.4 4± 0.05
37.1 8± 0.07
37. 4± 0.09
37.0 4± 0.11
37. 2± 0.08
37. 1± 0.03
37.6 8± 0.06
37.1 6± 0.08
Na proxin
3
3
3
6
6
6
6
6
6
9
9
9
9
a
b
c
a
b
c
d
e
f
37.1 8± 0.07
37. 1± 0.06
37.1 2± 0.14
37.1 2± 0.05
36.9 8± 0.06
37. 1± 0.06
37.0 8± 0.09
37.0 6± 0.08
3 7± 0.06
38. 3± 0.08
38. 4± 0.12
38.2 4± 0.08
38. 6± 0.07
38.3 4± 0.11
38.5 4± 0.1
38. 4± 0.11
38. 2± 0.05
38.6 4± 0.11
38. 6± 0.6
39. 3± 0. 2
39.4 0± 0.2
39.3 6± 0.05
39. 2± 0.11
39. 4± 0.10
39. 8± 0.24
39. 1± 0.11
39. 4± 0.07
3 9± 0.05
a
b
c
d
37.0 4± 0.11
3 7± 0.08
38.34±0.
37.1 4± 0.1
37. 2± 0.1
38. 6± 0.09
38. 3± 0.03
38. 8± 0.22
38.4 4± 0.11
37. 9± 0.07
37. 8± 0.04
38.1 4± 0.08
37.7 6± 0.11
1
1a
1b
37.0 6± 0.15
37.0 6± 0.1
39.9 4± 0.23
39. 4± 0.2
1
Eissa SI et al. Aryl Propionic Acid Derivatives… Drug Res 2014; 64: 485–492

4
92 Original Article
1
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▼
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3
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The authors declare that they have no conflict of interest with
6-methoxynaphthalene derivatives with potential anticancer activity.
respect to this paper.
Der Pharma Chemica 2012; 4: 1552–1566
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