Anti-inflammatory activity and PGE2 inhibitory properties of novel phenylcarbamoylmethyl ester-containing compounds

Article abstract of DOI:10.3390/molecules14020667

A variety of 4-(un)substituted phenylcarbamoyl methyl ester-containing compounds 3a-d, 5a-d and 7a-d were synthesized via reaction in N,N-dimethylformamide of (un)substituted chloroacetanilides 2a-d with the potassium salts of ibuprofen (1), naproxen (4)

Full text of DOI:10.3390/molecules14020667

Molecules 2009, 14, 667-681; doi:10.3390/molecules14020667
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Anti-inflammatory Activity and PGE2 Inhibitory Properties of
Novel Phenylcarbamoylmethyl Ester-Containing Compounds
Flora Barsoum, Hanan Georgey * and Nagwa Abdel-Gawad
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street,
Cairo 11562, Egypt; E-mails: ffbarsoum2@yahoo.com (F.B.), hamadido21@hotmail.com (N.A-G.)
* Author to whom correspondence should be addressed; E-mail: hanan-hanna@hotmail.com;
Tel.:002-02-24535200 or 002-017-5600699.
Received: 17 December 2008; in revised form: 2 February 2009 / Accepted: 6 February 2009 /
Published: 11 February 2009
Abstract: A variety of 4-(un)substituted phenylcarbamoyl methyl ester-containing
compounds 3a-d, 5a-d and 7a-d were synthesized via reaction in N,N-dimethylformamide
of (un)substituted chloroacetanilides 2a-d with the potassium salts of ibuprofen (1),
naproxen (4) and N-acetylanthranilic acid (6). Moreover, other 4-(un)substituted
phenylcarbamoylmethyl ester-containing compounds 10a-d were synthesized via the attack
of (un)substituted chloroacetanilides 2a-d on one of the carboxylic acid groups of the
potassium salt of 4-(2-carboxyethylcarboxamido)benzoic acid (8) in N,N-
dimethylformamide, with subsequent cyclization of the other one giving finally a
pyrrolidinone structure. Anti-inflammatory properties of the synthesized compounds were
evaluated in vivo utilizing a standard acute carrageenan-induced paw oedema method in
rats and the most promising prepared anti-inflammatory active agents were evaluated for
ulcerogenic liability in rats using ibuprofen and naproxen as reference standards in both
screenings. PGE2 inhibitory properties of the highly promising anti-inflammatory agents
synthesized and low gastric ulcerogenic liabilities were tested with a PGE2 assay kit
technique.
Keywords: Ibuprofen; Naproxen; 4-(Un)substituted phenylcarbamoylmethyl esters; Anti-
inflammatory; Ulcerogenic liability; PGE2.

Molecules 2009, 14
668
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and
inflammation. Most currently used NSAIDs suffer from limitations in their therapeutic uses, since they
cause gastrointestinal and renal side effects, which are inseparable from their pharmacological
activities. These compounds act via inhibition of the enzyme cyclooxygenase, thus preventing
prostaglandin synthesis [1]. They have greater selectivity to inhibit COX-1 (constitutively expressed
and providing cytoprotection in the gastrointestinal tract and necessary for normal platelet aggregation
and renal function) than COX-2 (inducible by inflammatory stimuli) [2-5]. Consequently, long-term
therapy with non-selective NSAIDs may cause gastrointestinal complications ranging from stomach
irritation to life-threatening gastrointestinal ulceration and bleeding [6]. Several lines of evidence have
suggested that modification of the carboxyl function of representative NSAIDs results in retained anti-
inflammatory activity and reduced ulcerogenic potential [7-9].
In the present work, we intended to investigate the synthesis of 4-(un)substituted
phenylcarbamoylmethyl ester-containing compounds adopting simple synthetic approaches and
utilizing easily accessible starting chemicals. These compounds are esters of well known NSAIDs
(ibuprofen and naproxen), N-acetylanthranilic acid (nitrogen isostere of salicyclic acid [10]) and 4-
(2,5-dioxopyrrolidin-1-yl)benzoic acid, in which the carboxylic function is altered to a substituted ester
prodrug residue hoping to circumvent the untoward ulcerogenic side effects of the free acid. Also,
(un)substituted phenylcarbamoylmethyl moieties were made to study the effect of such substituents on
the physicochemical properties of the compounds and consequently on their pharmacological activity,
to produce new hit compounds for a drug discovery program. The anti-inflammatory properties of the
synthesized compounds were screened. Ulcerogenic liabilities for the most active anti-inflammatory
compounds in each group would be considered. Additionally, PGE2 inhibitory properties for the most
active anti-inflammatory agents with less ulcerogenic liability in each group were determined since
PGE2 stimulates tumor cell proliferation and differentiaton [11,12] and cancer regression has been
documented in patients taking non-steroidal, anti-prostaglandin drugs such as ibuprofen [13]. The
interest for designing these compounds is attributed to the biological and pharmacological properties
associated with their structures. In addition to their anti-inflammatory activities [14,15], ibuprofen
affects the amyloid pathology in the brain [16] and its long-term use has been associated with reduced
risk of neurodegeneration [17]. Moreover, a variety of pyrrolidinone derivatives were reported to
possess antibacterial [18], anticonvulsant [19] and anticancer [20] activities.
Results and Discussion
Chemistry
Reaction of the potassium salts of ibuprofen (1), naproxen (4) and N-acetylanthranilic acid (6) with
(un)substituted chloroacetanilides 2a-d in N,N-dimethylformamide (Schemes 1, 2, and 3) afforded the
corresponding 4-(un)substituted phenylcarbamoylmethyl esters 3a-d, 5a-d, and 7a-d in good yields
(80-89%).

Molecules 2009, 14
669
Scheme 1. Synthetic Pathway for Compounds 3a-d.
R
NHCOCH2Cl
2a-d
2a R =H
2b R =OCH3
2c R =Cl
COOH
i
COOK
ii
2d R =SO2NH2
1
R
COOCH2CONH
3a R =H
3a-d
3b R =OCH3
3c R =Cl
3d R =SO2NH2
Reaction conditions: i) KOH, ethanol, ii) DMF
Scheme 2. Synthetic Pathway for Compounds 5a-d.
COOH
2a-d
i
COOK
ii
MeO
MeO
4
COOCH2CONH
R
5a R =H
5b R =OCH3
5c R =Cl
MeO
5a-d
5d R =SO2NH2
Reaction conditions: i) KOH, ethanol, ii) DMF
Scheme 3. Synthetic Pathway for Compound 7a-d.
O
O
O
2a-d
OCH2CONH
R
OK
OH
ii
NHCOCH3
NHCOCH3
NHCOCH3
7a R =H
7b R =OCH3
7a-d
6
7c R =Cl
7d R =SO2NH2
Reaction conditions: i) KOH, ethanol, ii) DMF
1
The structures of 3a-d, 5a-d and 7a-d were established through spectroscopic (IR, H-NMR, MS)
as well as elemental analyses data. The IR spectra of 3a-d, 5a-d and 7a-d revealed the presence of a
strong band (at ν = 1758-1740 cm-1 for 3a-d, at ν = 1749-1736 cm-1 for 5a-d and at ν = 1709-1658
cm-1 for 7a-d, respectively), assignable to their carbonyl ester functions, in addition to the NH amidic

Molecules 2009, 14
670
stretching vibration band (at ν = 3400-3206 cm-1 for 3a-d, at ν = 3389-3249 cm-1 for 5a-d and at ν =
3424-3285 cm-1 for 7a-d, respectively).
The 1H-NMR spectra of 3a-d and 5a-d reveal the presence of the methylene group as two doublet
signals (at δ = 4.47-4.52, 4.90-4.93, J = 15.3-15.9 for 3a-d and at δ = 4.44-4.47, 4.92-5.03, J = 15.3-
15.9 for 5a-d, respectively), due to their mutual coupling with each other since there is a chiral center
and the two protons are non-equivalent. In contrast, in the case of 7a-d this methylene residue appears
as a sharp singlet signal at δ = 4.94-5.00 due to the absence of chirality. The mass spectra of 3a-d, 5a-
d and 7a-c exhibited the expected parent molecular ion peaks, thus confirming the assumed structures.
Meanwhile, 4-(un)substituted phenylcarbamoylmethyl esters 10a-d were obtained through reaction
of (un)substituted chloroacetanilides 2a-d with the potassium salt of 4-(2-carboxyethyl-
carboxamido)benzoic acid 8 in N,N-dimethylformamide. The reaction was assumed to take place at
both carboxylic acid groups giving two phenylcarbamoylmethyl ester moieties. However, different
spectroscopic data reveal that the chloroacetanilides attacked only one of the carboxylic acid groups,
with subsequent cyclization of the other one finally gave the pyrrolidinone structure in spite of the use
of 2 moles KOH and 2 moles of (un)substituted chloroacetanilides 2a-d per mole of the starting
material 8 (Scheme 4).
Scheme 4. Synthetic Pathway for Compound 10a-d.
O
O
O
OH
iv
O
OK
HO
N
H
KO
N
O
H
8
O
i
O
v
2a-d
COOH
N
O
9
ii
O
O
O
O
H
N
2b
iii
N
COOK
N
O
O
10
R
O
10a R =H
10b R =OCH3
10c R =Cl
10d R =SO2NH2
Reaction conditions: i) (CH3CO)2O ii) KOH, DMF, iii) DMF, iv) KOH, ethanol, v) DMF
1
The structures of 10a-d were confirmed through spectroscopic (IR, H-NMR, MS) as well as
elemental analyses data. The IR spectra of 10a-d exhibit strong carbonyl bands at ν = 1778-1782,
1706-1719, 1605-1690 cm-1, corresponding to the pyrrolidinone (cyclic amide), ester and acyclic

Molecules 2009, 14
671
1
amide moieties, respectively. The H-NMR spectra of 10a-d strongly support the presumed cyclized
structures, exhibiting only one D2O exchangeable amino signal at δ = 10.05-10.56, a sharp singlet
signal at δ = 2.81-2.82 corresponding to the two pyrrolidinyl methylene protons besides a singlet signal
of one methylene ester function at δ = 4.91-4.99. The 13C-NMR (APT) spectrum of 10b excludes any
other possible structure, revealing the presence of carbonyl groups corresponding to two cyclic amides
at δ = 177.19, one ester at δ = 165.46 and an acyclic amide at δ = 165.54, confirming the cyclization
reaction process. The mass spectra of 10a-d exhibiting the parent molecular ion peaks confirmed the
assumed structures. To further confirm the cyclization reaction, a chloroacetanilide, i.e. 2b, was
reacted with the potassium salt of 4-(2,5-dioxopyrrolidin-1-yl)benzoic acid (9) in N,N-
dimethylformamide to give the same compound 10b.
Anti-inflammatory Activity
The anti-inflammatory activity of all synthesized compounds 3a-d, 5a-d, 7a-d and 10a-d was
determined by the standard carrageenan-induced paw oedema method in rats [21-23], at a dose of 50
mg/kg body weight, and compared with ibuprofen and naproxen as reference drugs. From the results
obtained (Table 1), it appears that all ibuprofen containing compounds 3a-d show slightly enhanced
anti-inflammatory activities (78.2-89.5% inhibition of oedema) comparable to that of the reference
drug ibuprofen (76.1%). Similarly, all naproxen containing compounds 5a-d also exhibit better
activities (83.6-88.3%) relative to the reference drug naproxen (75.3%). On the contrary, all N-acetyl
anthranilic acid derivatives 7a-d possess anti-inflammatory activities (54.2-67.3%) lower than both
ibuprofen and naproxen. Moreover, among compounds having the pyrrolidinone ring, 10b and 10d
exhibit better anti-inflammatory activity (84.1% and 79.4%, respectively) than both ibuprofen (76.1%)
and naproxen (75.3%).
Table 1. Anti-inflammatory Activity of the Tested Compounds Using Acute Carrageenan-
Induced Paw Oedema in Rats.
Compound
Mean swelling volume "mL"
0.742 ± 0.096b,c
0.177 ± 0.065a
% Inhibition of oedema
Control
00.0
76.1
75.3
78.2
89.5
87.9
82.2
88.3
84.8
87.9
83.6
67.3
67.0
56.9
Ibuprofen
Naproxen
0.183 ± 0.023a
3a
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
0.162 ± 0.103a
0.078 ± 0.073a,b,c
0.090 ± 0.068a
0.132 ± 0.055a
0.087 ± 0.031a,c
0.113 ± 0.043a
0.090 ± 0.058a
0.122 ± 0.074a
0.243 ± 0.101a
0.245 ± 0.107a
0.320 ± 0.078a,b,c

Molecules 2009, 14
672
Table 1. Cont.
7d
0.340 ± 0.105a,b,c
54.2
72.0
84.1
54.4
79.4
10a
10b
10c
0.208 ± 0.080a
0.118 ± 0.085a
0.338 ± 0.123a,b,c
0.153 ± 0.119a
10d
a
b
Significantly different from the control value at p < 0.05; significantly different from the
ibuprofen value at p < 0.05; c significantly different from the naproxen value at p < 0.05; results are
means of six experiments ± SE.
Ulcerogenic Liability
The ulcerogenic liability for the most active anti-inflammatory compounds (3b, 3c, 5a, 5c, 7a and
10 b) in each series was determined in albino rats following the previously reported method [23,24].
From the data obtained (Table 2), it has been observed that all the tested compounds possess less
ulcerogenic potentialities (ulcer indexes of 11.60-16.69), compared with that of the standard drugs
ibuprofen and naproxen (ulcer indexes of 22.90 and 23.15, respectively).
Table 2. Ulcergenic Liability of Selected Compounds.
Number of
animals
with ulcers
Average
number of
ulcers
0.00
% incidence
divided by 10
Average
severity
Compound
Ulcer index
Control
0/5
5/5
5/5
5/5
4/5
4/5
5/5
5/5
4/5
0.00
10
10
10
8
0.00
1.90
1.75
1.10
1.00
1.00
1.29
1.00
1.70
0.00
Ibuprofen
11.00
11.40
2.00
22.90
23.15
13.10
11.60
12.20
16.69
14.40
15.30
Naproxen
3b
3c
2.60
5a
8
3.20
5c
10
10
8
5.40
7a
3.40
10b
5.60
PGE2 Inhibitory Properties
PGE2 inhibitory properties were studied for compounds 3c, 5a, 7a and 10b, which showed the
highest anti-inflammatory and lowest ulcerogenic properties in each series. This was evaluated in vivo,
utilizing the previously reported six-day-old air pouch method [25,26]. PGE2 was measured using
ELISA kit specific for rats, provided by R&D Systems (Minneapolis, USA & Canada), and the results
were compared with indomethacin chosen as a reference drug according to the instructions of the kit.
From the obtained results (Table 3), it has been observed that all the tested compounds reduce PGE2
levels, however, the ibuprofen and naproxen containing compounds (3c and 5a) showed remarkable
inhibitions (50.83, 63.83 pg/mL, respectively) compared to indomethacin (98.33 pg/mL). Although
compounds 7a and 10b exhibited inhibitions of 127.33 and 103.50 pg/mL, respectively, which is lower

Molecules 2009, 14
673
than indomethacin (98.33 pg/mL), it is remarkably high compared to the control (533.33 pg/mL),
indicating the anti-inflammatory activities of these two compounds.
Table 3. PGE2 Concentration of Selected Compounds.
Compound
Mean concentration "pg/ml"
533.33±19.26
Control
Indomethacin
98.33±3.33*
3c
5a
50.83±3.86*
63.83±3.87*
7a
127.33±2.53*
10b
103.50±2.29*
*Significantly different from the control value at p < 0.05.
Results are means of 6 experiments ± SE.
Conclusions
The synthesis of 4-(un)substituted phenylcarbamoylmethyl ester-containing compounds 3a-d, 5a-d,
7a-d and 10a-d was undertaken. The structure of the newly synthesized compounds was established by
1
microanalytical and spectral (IR, H-NMR, mass) data. They were tested for their anti-inflammatory
activity. Further the ulcerogenic liability and PGE2 inhibitory properties for the most active
compounds were determined. Results showed that all the tested compounds exhibited promising anti-
inflammatory activity, compared to ibuprofen and naproxen, with marked decreases in the ulcerogenic
side effects. Moreover, esterification of both ibuprofen and naproxen derivatives led to increases in the
anti-inflammatory activity, compared to the parent drugs, and this was enhanced in the case of the 4-
methoxyphenylcarbamoyl methyl ester 3b and the phenylcarbamoylmethyl ester 5a of ibuprofen and
naproxen, respectively. On the other hand, there is a significant change in the pharmacological activity
amongst the different ester substituted derivatives of N-acetylanthranilic acid 7a-d and 4-(3-
carboxypropionylamino)benzoic acid 10a-d in which the 4-chloro derivatives 7c and 10c, together
with the 4-sulphamoyl derivative 7d showed a marked decrease in the anti-inflammatory activity.
Finally, the results of the in vivo anti-inflammatory activity by the standard acute carrageenan-induced
paw oedema method in rats revealed remarkable activities that largely coincide with the results
observed using a PGE2 assay kit technique.
Experimental
General
Melting points are uncorrected and recorded on a Gallenkamp melting point apparatus. IR spectra
1
(KBr) were recorded on a Bruker Vector 22 spectrophotometer. H-NMR spectra were recorded on a
Varian MERCURY 300 (300 MHz) spectrometer. Mass spectra were recorded on GCMS-QP 1000
EX, Gas chromatograph-Mass spectrometer, at 70 eV. Compounds 2a-d [27,28], 6 [29], 8 [30] and 9
[31] were prepared according to the previously reported procedures. Ibuprofen and naproxen were
purchased from Sigma Chemical Co. (St. Louis, MO, USA) in the form of racemic mixtures.

Molecules 2009, 14
674
Synthesis of 4-(un)substituted phenylcarbamoylmethyl esters 3a-d, 5a-d and 7a-d
A mixture of equimolar amounts of 1, 4, or 6 and an ethanolic solution of potassium hydroxide (5
mmol) in absolute ethanol (30 mL) was stirred at room temperature (25-30 °C) for 15 minutes. The
residue after evaporation under reduced pressure was treated with the appropriate chloroacetanilides
2a-d (5 mmol) in N,N-dimethylformamide (5 mL) in a boiling water bath for 12 hours. The reaction
mixture was then cooled, poured onto ice-cooled water and the separated solid was collected, dried and
crystallized from a suitable solvent affording 3a-d, 5a-d and 7a-d as colourless crystals.
4-(2-Methylpropyl)-α-methylbenzene acetic acid phenylcarbamoylmethyl ester (3a): m.p. 78-80 °C
(from methanol); yield 83%; IR νmax/cm-1: 3330 (NH), 2950, 2922, 2866 (CH aliph.), 1740 (C=O
1
ester), 1685 (C=O amide), 1603, 1546 (C=C); H-NMR δ/ppm (CDCl3): 0.92 (d, 6H, 2CH3, J = 6.6
Hz), 1.59 (d, 3H, CH-CH3, J = 7.2 Hz), 1.85-1.90 (m, 1H, CH-CH2), 2.49 (d, 2H, CH-CH2, J = 7.2 Hz),
3.85 (q, 1H, CH-CH3, J = 7.2 Hz), 4.49 (d, 1H, upfield H of COOCH2, J = 15.6 Hz), 4.92 (d, 1H,
downfield H of COOCH2, J = 15.9 Hz), 7.07-7.30 (m, 10H, arom. H + NH); MS: m/z (%) = 339 (M+,
20), 247 (6), 188 (96), 161 (100), 93 (37); Anal. Calcd. For C21H25NO3 (339.42): C, 74.31; H, 7.42; N,
4.13%. Found: C, 74.17; H, 7.63; N, 3.94%.
4-(2-Methylpropyl)-α-methylbenzene acetic acid (4-methoxyphenylcarbamoyl)methyl ester (3b): m.p.
122-124 °C (from 2:1 v/v ether-petroleum ether); yield 87%; IR νmax/cm-1: 3400 (NH), 2960, 2869,
2842 (CH aliph.), 1746 (C=O ester), 1694 (C=O amide), 1600, 1538 (C=C); 1H-NMR δ/ppm (CDCl3):
0.90 (d, 6H, 2CH3, J = 6.6 Hz), 1.58 (d, 3H, CH-CH3, J = 7.2 Hz), 1.83-1.88 (m, 1H, CH-CH2), 2.48
(d, 2H, CH-CH2, J = 7.2 Hz), 3.79 (s, 3H, OCH3), 3.84 (q, 1H, CH-CH3, J = 7.2 Hz), 4.48 (d, 1H,
upfield H of COOCH2, J = 15.6 Hz), 4.90 (d, 1H, downfield H of COOCH2, J = 15.3 Hz), 6.77-7.29
(m, 9H, arom. H + NH); MS: m/z (%) = 369 (M+, 49), 188 (14), 161 (59), 123 (100); Anal. Calcd. For
C22H27NO4 (369.45): C, 71.52; H, 7.37; N, 3.79%. Found: C, 71.76; H, 7.15; N, 3.56%.
4-(2-Methylpropyl)-α-methylbenzene acetic acid (4-chlorophenylcarbamoyl)methyl ester (3c): m.p. 69-
71 °C (from 2:1 v/v ether-petroleum ether); yield 82%; IR νmax/cm-1: 3396 (NH), 2958, 2927, 2869
(CH aliph.), 1745 (C=O ester), 1704 (C=O amide), 1595, 1531 (C=C); 1H-NMR δ/ppm (CDCl3): 0.92
(d, 6H, 2CH3, J = 6.6 Hz), 1.58 (d, 3H, CH-CH3, J = 7.2 Hz), 1.84-1.89 (m, 1H, CH-CH2), 2.49 (d, 2H,
CH-CH2, J = 7.2 Hz), 3.86 (q, 1H, CH-CH3, J = 7.2 Hz), 4.47 (d, 1H, upfield H of COOCH2, J = 15.9
Hz), 4.93 (d, 1H, downfield H of COOCH2, J = 15.6 Hz), 7.08-7.29 (m, 9H, arom. H + NH); MS: m/z
(%) = 375 (M+2, 20), 373 (M+, 62), 247 (18), 188 (93), 161 (100), 127 (30); Anal. Calcd. For
C21H24ClNO3 (373.86): C, 67.46; H, 6.47; N, 3.75%. Found: C, 67.70; H, 6.20; N, 3.90%.
4-(2-Methylpropyl)-α-methylbenzene acetic acid (4-sulfamoylphenylcarbamoyl)methyl ester (3d): m.p.
163-165 °C (from methanol); yield 89%; IR νmax/cm-1: 3388, 3303, 3206 (NH, NH2), 2953, 2924, 2868
(CH aliph.), 1758 (C=O ester), 1685 (C=O amide), 1595, 1539 (C=C); 1H-NMR δ/ppm (CDCl3): 0.91
(d, 6H, 2CH3, J = 6.6 Hz), 1.58 (d, 3H, CH-CH3, J = 7.2 Hz), 1.86-1.91 (m, 1H, CH-CH2), 2.49 (d, 2H,
CH-CH2, J = 7.2 Hz), 3.88 (q, 1H, CH-CH3, J = 7.2 Hz), 4.52 (d, 1H, upfield H of COOCH2, J = 15.6
Hz), 4.90 (d, 1H, downfield H of COOCH2, J = 15.9 Hz), 5.04 (br.s, 1H, D2O exchangeable NH),

Molecules 2009, 14
675
7.17-7.77 (m, 10H, arom. H + NH2); MS: m/z (%) = 418 (M+, 4), 247 (4), 188 (79), 161 (100); Anal.
Calcd. For C21H26N2O5S (418.50): C, 60.27; H, 6.26; N, 6.70%. Found: C, 60.50; H, 6.11; N, 6.67%.
6-Methoxy-α-methylnaphthalene-2-yl acetic acid phenylcarbamoylmethyl ester (5a): m.p. 111-113 °C
(from ethanol); yield 85%; IR νmax/cm-1: 3387 (NH), 1741 (C=O ester), 1702 (C=O amide), 1535
1
(C=C); H-NMR δ/ppm (CDCl3): 1.69 (d, 3H, CH3, J = 7.2 Hz), 3.96 (s, 3H, OCH3), 4.02 (q, 1H, CH,
J = 7.2 Hz), 4.47 (d, 1H, upfield H of CH2, J = 15.3 Hz), 4.94 (d, 1H, downfield H of CH2, J = 15.9
Hz), 6.75-7.78 (m, 12H, arom. H + napth. H + NH); MS: m/z (%) = 363 (M+, 37), 212 (100), 185 (95);
Anal. Calcd. For C22H21NO4 (363.40): C, 72.71; H, 5.83; N, 3.85%. Found: C, 72.63; H, 5.88; N,
3.76%.
6-Methoxy-α-methylnaphthalene-2-yl acetic acid (4-methoxyphenylcarbamoyl)methyl ester (5b):
Crystallization from benzene; m.p. 137-139 °C; yield 88%; IR νmax/cm-1: 3251 (NH), 1740 (C=O
ester), 1661 (C=O amide), 1556, 1508 (C=C); 1H-NMR δ/ppm (CDCl3): 1.69 (d, 3H, CH3, J = 7.2 Hz),
3.73 (s, 3H, arom.OCH3), 3.95 (s, 3H, napth. OCH3), 4.02(q, 1H, CH, J = 7.2 Hz), 4.46 (d, 1H, upfield
H of CH2, J = 15.6 Hz), 4.92 (d, 1H, downfield H of CH2, J = 15.6 Hz), 6.57-7.77 (m, 11H, arom. H +
napth. H + NH); MS: m/z (%) = 393 (M+, 25), 213 (13), 185 (100); Anal. Calcd. For C23H23NO5
(393.42): C, 70.21; H, 5.89; N, 3.56%. Found: C, 70.36; H, 6.00; N, 3.70%.
6-Methoxy-α-methylnaphthalene-2-yl acetic acid (4-chlorophenylcarbamoyl)methyl ester (5c): m.p.
132-134 °C (from methanol); yield 84%; IR νmax/cm-1: 3389 (NH), 1749 (C=O ester), 1700 (C=O
1
amide), 1598, 1527 (C=C); H-NMR δ/ppm (CDCl3): 1.68 (d, 3H, CH3, J = 7.2 Hz), 3.96 (s, 3H,
OCH3), 4.02 (q, 1H, CH, J = 7.2 Hz), 4.44 (d, 1H, upfield H of CH2, J = 15.6 Hz), 4.94 (d, 1H,
downfield H of CH2, J = 15.6 Hz), 6.63-7.76 (m, 11H, arom. H + napth. H + NH); MS: m/z (%) = 399
(M+2, 6), 397 (M+, 18), 213 (23), 185 (100); Anal. Calcd. For C22H20ClNO4 (397.84): C, 66.41; H,
5.07; N, 3.52%. Found: C, 66.45; H, 5.04; N, 3.37%.
6-Methoxy-α-methylnaphthalene-2-yl acetic acid (4-sulfamoylphenylcarbamoyl)methyl ester (5d): m.p.
202-204 °C (from methanol); yield 89%; IR νmax/cm-1: 3325, 3287, 3249 (NH, NH2), 1736 (C=O
ester), 1696 (C=O amide), 1600, 1540 (C=C); 1H-NMR δ/ppm (CDCl3): 1.69 (d, 3H, CH3, J = 7.2 Hz),
3.98 (s, 3H, OCH3), 4.02 (q, 1H, CH, J = 7.2 Hz), 4.44 (d, 1H, upfield H of CH2, J = 15.6 Hz), 5.03 (d,
1H, downfield H of CH2, J = 15.6 Hz), 6.75-7.78 (m, 13H, arom. H + napth. H + NH + NH2); MS: m/z
(%) = 442 (M+, 34), 212 (49), 185 (100); Anal. Calcd. For C22H22N2O6S (442.48): C, 59.71; H, 5.01;
N, 6.33%. Found: C, 60.02; H, 4.84; N, 6.30%.
2-Acetylaminobenzoic acid phenylcarbamoylmethyl ester (7a): m.p. 209-210 °C (from ethanol); yield
80%; IR νmax/cm-1: 3285 (NH), 1689, 1688 (C=O), 1598 (C=C); 1H-NMR δ/ppm (DMSO-d6): 2.13 (s,
3H, CH3), 4.97 (s, 2H, CH2), 7.06-8.29 (m, 9H, arom. H), 10.25 (br.s, 1H, D2O exchangeable NH),
10.42 (br.s, 1H, D2O exchangeable NH); MS: m/z (%) = 312 (M+, 26), 220 (13), 162 (57), 120 (100);
Anal. Calcd. For C17H16N2O4 (312.32): C, 65.37; H, 5.16; N, 8.97%. Found: C, 65.28; H, 5.24; N,
8.77%.
2-Acetylaminobenzoic acid (4-methoxyphenylcarbamoyl)methyl ester (7b): m.p. 200-202 °C (from
1
ethanol); yield 85%; IR νmax/cm-1: 3337, 3264 (NH), 1704, 1686, 1668 (C=O), 1590 (C=C); H-NMR

Molecules 2009, 14
676
δ/ppm (DMSO-d6): 2.13 (s, 3H, COCH3), 3.73 (s, 3H, OCH3), 4.94 (s, 2H, CH2), 6.89-8.29 (m, 8H,
arom. H), 10.10 (br.s, 1H, D2O exchangeable NH), 10.43 (br.s, 1H, D2O exchangeable NH); MS: m/z
(%) = 342 (M+, 54), 220 (6), 162 (90), 123 (100); Anal. Calcd. For C18H18N2O5 (342.34): C, 63.15; H,
5.30; N, 8.18%. Found: C, 63.23; H, 5.39; N, 8.03%.
2-Acetylaminobenzoic acid (4-chlorophenylcarbamoyl)methyl ester (7c): m.p.191-192 °C (from
1
ethanol); yield 85%; IR νmax/cm-1: 3424 (NH), 1658, 1618 (C=O), 1596 (C=C); H-NMR δ/ppm
(DMSO-d6): 2.13 (s, 3H, CH3), 4.96 (s, 2H, CH2), 7.20-8.27 (m, 8H, arom. H), 10.39 (br.s, 1H, D2O
exchangeable NH), 10.41 (br.s, 1H, D2O exchangeable NH); MS: m/z (%) = 348 (M+2, 6), 346 (M+,
14), 220 (21), 162 (83), 120 (100); Anal. Calcd. For C17H15 Cl N2O4 (346.76): C, 58.88; H, 4.36; N,
8.08%. Found: C, 58.63; H, 4.53; N, 8.29%.
2-Acetylaminobenzoic acid (4-sulfamoylphenylcarbamoyl)methyl ester (7d): m.p. 230-231 °C (from
Crystallization 5:1 v/v N,N-dimethylformamide-water); yield 89%; IR νmax/cm-1: 3383, 3341, 3277
1
(NH, NH2), 1709, 1687 (C=O), 1596 (C=C); H-NMR δ/ppm (DMSO-d6): 2.13 (s, 3H, CH3), 5.00 (s,
2H, CH2), 7.23-8.27 (m, 10H, arom. H + NH2), 10.41 (br.s, 1H, D2O exchangeable NH), 10.59 (br.s,
1H, D2O exchangeable NH); Anal. Calcd. For C17H17N3O6S (391.39): C, 52.17; H, 4.38; N, 10.74%.
Found: C, 52.24; H, 4.53; N, 10.83%.
Synthesis of 4-(2,5-Dioxopyrrolidin-1-yl)benzoic acid (4-(un)substitutedphenylcarbamoyl)methyl
esters 10a-d
Method A: The same method adopted in the general procedure starting with 4-(2-
carboxyethylcarboxamido)benzoic acid 8 (5 mmol), potassium hydroxide (10 mmol) and the
appropriate chloroacetanildes 2a-d (10 mmol).
Method B: A mixture of equimolar amounts of 4-(2,5-dioxopyrrolidin-1-yl)benzoic acid (9) and
potassium hydroxide (5 mmol) in dry N,N-dimethylformamide (5 mL) was stirred in a boiling water
bath for 15 minutes. The reaction mixture was then treated with a solution of the appropriate
chloroacetanilides 2a-d (5 mmol) in N,N-dimethylformamide (3 mL) in a boiling water bath for one
hour. The reaction mixture was then cooled, poured onto ice-cooled water and the separated solid was
collected, dried and crystallized from a suitable solvent affording 10a-d as colourless crystals.
4-(2,5-Dioxopyrrolidin-1-yl)benzoic acid phenylcarbamoylmethyl ester (10a): m.p. 171-173 °C (from
ethanol); yield 73% (method A); IR νmax/cm-1: 3359 (NH), 1782 (C=O cyclic), 1707 (C=O ester), 1605
1
(C=O amide), 1551, 1514 (C=C); H-NMR δ/ppm (DMSO-d6): 2.81 (s, 4H, OC-CH2-CH2-CO), 4.95
(s, 2H, COOCH2), 7.08 (t, 1H, arom. H, J = 7.5 Hz), 7.32 (t, 2H, arom. H, J = 7.8 Hz), 7.50 (d, 2H,
arom. H, J = 8.7 Hz), 7.59 (d, 2H, arom. H, J = 7.5 Hz), 8.14 (d, 2H, arom. H, J = 8.7 Hz), 10.20 (br.s,
1H, D2O exchangeable NH); MS: m/z (%) = 352 (M+, 12), 260 (33), 202 (100), 93 (22); Anal. Calcd.
For C19H16N2O5 (352.34): C, 64.76; H, 4.58; N, 7.95%. Found: C, 65.02; H, 4.81; N, 7.74%.
4-(2,5-Dioxopyrrolidin-1-yl)benzoic acid (4-methoxyphenylcarbamoyl)methyl ester (10b): m.p. 205-
207 °C (from methanol); yield 65 and 87% (method A and B respectively); IR νmax/cm-1: 3356 (NH),
1779 (C=O cyclic), 1707 (C=O ester), 1608 (C=O amide), 1554, 1514 (C=C); 1H-NMR δ/ppm

Molecules 2009, 14
677
(DMSO-d6): 2.81 (s, 4H, OC-CH2-CH2-CO), 3.72 (s, 3H, OCH3), 4.91 (s, 2H, COOCH2), 6.90 (d, 2H,
arom. H, J = 9.3 Hz), 7.49 (d, 4H, arom. H, J = 8.4 Hz), 8.15 (d, 2H, arom. H, J = 8.7 Hz), 10.05 (br.s,
13
1H, D2O exchangeable NH); MS: m/z (%) = 382 (M+, 32), 260 (11), 202 (100), 123 (45); C-NMR
δ/ppm (APT) (DMS-d6): 29.24 (pyrrolidinyl H2C-3, H2C-4), 55.87 (OCH3), 64.01 (COOCH2), 114.63
(arom. CH-2`, CH-6`), 121.60 (arom. CH-3, CH-5), 121.80 (arom. CH-3`, CH-5`), 129.37 (arom. C-1),
130.66 (arom. CH-2, CH-6), 132 (arom. C-4`), 137.83 (arom. C-4), 156.23 (arom. C-1`), 165.46
(COO), 165.54 (CONH), 177.19 (pyrrolidinyl CO-2, CO-5); Anal. Calcd. For C20H18N2O6 (382.36): C,
62.82; H, 4.74; N%, 7.33. Found: C, 62.53; H, 4.65; N, 7.70%.
4-(2,5-Dioxopyrrolidin-1-yl)benzoic acid (4-chlorophenylcarbamoyl)methyl ester (10c): m.p. 200-202
°C (from ethanol); yield 57% (method A); IR νmax/cm-1: 3353 (NH), 1780 (C=O cyclic), 1706 (C=O
ester), 1605 (C=O amide), 1547, 1513 (C=C). 1H-NMR δ/ppm (DMSO-d6): 2.81 (s, 4H, OC-CH2-CH2-
CO), 4.95 (s, 2H, COOCH2), 7.38 (d, 2H, arom. H, J = 9.0 Hz), 7.50 (d, 2H, arom. H, J = 8.4 Hz), 7.62
(d, 2H, arom. H, J = 9.3 Hz), 8.15 (d, 2H, arom. H, J = 8.4 Hz), 10.35 (br.s, 1H, D2O exchangeable
NH); MS: m/z (%) = 388 (M+2, 10), 386 (M+, 27), 260 (58), 202 (100), 126 (13); Anal. Calcd. For
C19H15ClN2O5 (386.78): C, 59.00; H, 3.91; N, 7.24%. Found: C, 59.03; H, 4.16; N, 7.46%.
4-(2,5-Dioxopyrrolidin-1-yl)benzoic acid (4-sulfamoylphenylcarbamoyl)methyl ester (10d): m.p. 233-
235 °C (from glacial acetic acid); yield 78% (method A); IR νmax/cm-1: 3325, 3227 (NH, NH2), 1778
(C=O cyclic), 1719 (C=O ester), 1690 (C=O amide), 1596, 1541 (C=C). 1H-NMR δ/ppm (DMSO-d6):
2.82 (s, 4H, OC-CH2-CH2-CO), 4.99 (s, 2H, COOCH2), 7.25 (br.s, 2H, D2O exchangeable NH2),
7.51(dd, 2H, arom. H, J = 1.8, 6.6 Hz), 7.77 (d, 4H, arom. H, J = 9.3 Hz), 8.15 (dd, 2H, arom. H, J =
1.8, 6.6 Hz), 10.56 (br.s, 1H, D2O exchangeable NH); MS: m/z (%) = 431 (M+, 16), 260 (24), 202
(100), 172 (18); Anal. Calcd. For C19H17N3O7S (431.41): C, 52.89; H, 3.97; N, 9.74%. Found: C,
52.56; H, 4.24; N, 9.63%.
Anti-inflammatory Activity Screening
Anti-inflammatory activity screening for the prepared compounds was determined in vivo by the
standard acute carrageenan-induced paw oedema method in rats [21-23]. Wister albino rats of either
sex (pregnant female animals were excluded) weighing 160-190 g were divided into 19 groups of six
animals each. Ibuprofen and naproxen (reference standards) and the tested compounds (3a-d, 5a-d, 7a-
d and 10a-d) dissolved in DMSO, at a dose of 50 mg/kg body weight, were administered
intraperitoneally, while the control group received DMSO, 1 hour before induction of inflammation.
Carrageenan paw oedema was induced by subcutaneous injection of 1% solution of carrageenan in
saline (0.1 mL/rat) into the right hind paw of rats. Paw volumes were measured volumetrically after 4
hours with a 7140 plethysmometer (Ugo Basile, Italy) and compared with the initial hind paw volume
of each rat for determining the oedema volume. Data were collected, checked and revised.
Quantitative variables from normal distribution were expressed as means ± SE "standard error". The
significant difference between groups was tested by using one-way ANOVA followed by Tukey HSD
test at p < 0.05. The anti-inflammatory activity was expressed as percentage inhibition of oedema
volume in treated animals in comparison with the control group (Table 1):

Molecules 2009, 14
678
Vc −Vt
% Inhibition of oedema =
x100
Vc
where, Vc and Vt are the volumes of oedema for the control and drug-treated animal groups.
Ulcerogenic liability
The ulcerogenic liability was determined in albino rats following the previously reported standard
method [23,24]. Rats of either sex (pregnant female rats were excluded) weighing 120-140 g were
divided into nine groups of five animals each. The animals were fasted 18 hours before drug
administration. Ibuprofen and naproxen (reference standards) and the tested compounds at a dose 50
mg/kg body weight, were suspended in saline solution by the aid of few drops of Tween® 80 and were
administered orally for three successive days to fasted rats. The control group animals were given
saline with few drops of Tween® 80. One hour after the last dose, the animals were sacrificed by
cervical dislocation and the stomach was removed, opened along the greater curvature and rinsed with
saline. The gastric mucosa was examined with a magnifying lens (10 x) for the presence of lesions
and erosions. The ulcer index was calculated (Table 2) and the degree of ulcerogenic effect was
expressed in terms of:
1. Percentage incidence of ulcer divided by 10.
2. Average number of ulcers per stomach.
3. Average severity of ulcers.
The ulcer index is the value that resulted from the sum of the above three values.
Measurement of PGE2 Level
Measurement of PGE2 level was determined by the previously described six-day-old air pouch
standard method in rats [25,26]. Male albino rats weighing 200-250 g were divided into six groups of
six animals each. The air pouch was induced as follows: on the first day of the experiment, 20 mL of
air was injected subcutaneously in the back of each rat. Two days later, another 10 mL of air was
injected at the same site. On the fifth day after the first injection, a further 10 mL of air was injected
into the pouch. Then, 24 h later and before injecting the pouch with carrageenan (2 mL of 1% solution
in saline), four groups of animals were treated orally with the tested compounds (3c, 5a, 7a and 10b) at
a dose of 50 mg/kg body weight, one group with indomethacin (reference standard) at a dose of 10
mg/kg body weight suspended in saline solution by the aid of few drops of Tween® 80 and the last
group with sterile saline (control group). All injections were conducted under light ether anaesthesia.
Then 6 h after the carrageenan injection, animals were lightly anaesthetised with ether and the contents
of the pouch were aspirated using a Pasteur pipette and transferred into graduated plastic tubes kept in
ice. The bulk of the exudates was frozen and stored at -20 °C until required for PGE2 assay. PGE2 was
measured by an ELISA (Beckman BiomekTM 1000 Automated Laboratory Workstation apparatus)
technique using PGE2 assay kit supplied by R&D Systems (Minneapolis, USA & Canada) according to
the manufacturer’s specifications. Data were collected, checked and revised. Quantitative variables
from normal distribution were expressed as means ± SE "standard error". The significant difference
between groups was tested by using one-way ANOVA followed by Dunnett`s test at p < 0.05 (Table
3).

Molecules 2009, 14
679
Acknowledgments
Thanks are due to Professor Mohamed T. Khayyal (Department of Pharmacology, Faculty of
Pharmacy, Cairo University, Cairo, Egypt) for his kind interest, valuable discussions and financial
assistance during PGE2 screening. Also thanks are due to Dr. Ebtehal El-Demerdash (Assistant
professor of Pharmacology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt) for providing
laboratory facilities for the anti-inflammatory and ulcerogenic screenings.
References
1. Vane, J.R. Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-Like
Drugs. Nature New Biol. 1971, 231, 232-235.
2. Marnett, L.J.; Kalgutkar, A.S. Cyclooxygenase 2 Inhibitors: Discovery, Selectivity and the
Future. Trends Pharmacol. Sci. 1999, 20, 465-469.
3. Dannhardt, G.; Kiefer, W. Cyclooxygenase Inhibitors-Current Status and Future Prospects. Eur.
J. Med. Chem. 2001, 36, 109-126.
4. Almansa, C.; Alfon, J.; De Arriba, A.F.; Cavalcanti, F.L.; Escamilla, I.; Gomez, L.A.; Miralles,
A.; Soliva, R.; Bartroli, J.; Carceller, E.; Merlos, M.; Garcia-Rafanell, J. Synthesis and Structure-
Activity Relationship of a New Series of COX-2 Selective Inhibitors: 1,5-Diarylimidazoles. J.
Med. Chem. 2003, 46, 3463-3475.
5. Jackson, L.M.; Hawkey, C.J. Gastrointestinal Effects of COX-2 Inhibitors. Expert Opin. Invest.
Drugs 1999, 8, 963-971.
6. Allison, M.C.; Howatson, A.G.; Torrance, C.J.; Lee, F.D.; Russell, R.I.G. Gastrointestinal
Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugs. N. Engl. J. Med.
1992, 327, 749-754.
7. Galanakis, D.; Kourounakis, A.P.; Tsiakitzis, K.C.; Doulgkeris, C.; Rekka, E.A.; Gavalas, A.;
Kravaritou, C.; Charitos, C.; Kourounakis, P.N. Synthesis and Pharmacological Evaluation of
Amide Conjugates of NSAIDs with L-cysteine Ethyl Ester, Combining Potent Antiinflammatory
and Antioxidant Properties with significantly reduced Gastrointestinal Toxicity. Bioorg. Med.
Chem. Lett. 2004, 14, 3639-3643.
8. Kalgutkar, A.S.; Marnett, A.B.; Crews, B.C.; Remmel, R.P.; Marnett, L.J. Ester and Amide
Derivatives of the Nonsteroidal Antiinflammatory Drug, Indomethacin, as Selective
Cyclooxygenase-2 Inhibitors. J. Med. Chem. 2000, 43, 2860-2870.
9. Duflos, M.; Nourrisson, M.R.; Brelet, J.; Courant, J.; LeBaut, G.; Grimaud, N., Petit, J.Y. N-
Pyridinyl-indole-3-(alkyl)carboxamides and Derivatives as Potential Systemic and Topical
Inflammation Inhibitors. Eur. J. Med. Chem. 2001, 36, 545-553.
10. Borne, R.F. In Foye`s Principles of Medicinal Chemistry, 5th Ed.; Williams, D.A., Lemke T.L.,
Eds.; Lippincott Williams & Wilkins: New York, USA, 2002; pp. 751-793.
11. Hull, M.A.; Ko, S.C.W.; Hawcroft, G. Prostaglandin EP Receptors: Targets for Treatment and
Prevention of Colorectal Cancer. Mol. Canc. Ther. 2004, 3, 1031-1039.
12. Brueggemeier, R.W.; Richards, J.A.; Petrel, T.A. Aromatase and Cyclooxygenases: Enzymes in
Breast Cancer. J. Steroid Biochem. Mol. Biol. 2003, 86, 501-507.

Molecules 2009, 14
680
13. Julian, L. Antidepressants, Prostaglandins and the Prevention and Treatment of Cancer. Med.
Hypotheses 2007, 69, 684-689.
14. Sharma, S.; Srivastava, V.K.; Kumar, A. Newer N-Substituted Anthranilic Acid Derivatives as
Potent Anti-inflammatory Agents. Eur. J. Med. Chem. 2002, 37, 689-697.
15. Thomas, A.; Bhavar, P.K.; Lingam, V.S.P.R.; Joshi, N.K. Preparation of Heterocyclic Amides,
in Particular Azolanes and Pyridines as Phosphodiesterase IV (PDE4) Inhibitors for the
Treatment of Inflammatory and Allergic Disorders. PCT Int. Appl. WO 2004 22, 536; [Chem.
Abstr. 2004, 140, 270743].
16. Weggen, S.; Eriksen, J.L.; Das, P.; Sagl, S.A.; Wang, R.; Pletrzik, C.U.; Findlay, K.A.; Smith,
T.E.; Murphy, MP; Bulter, T.; Kang, D.E.; Marquez-Steriling, N.; Golde, T.E.; Koo, E.H. A
Subset of NSAIDs Lower Amyloidogenic A 42 Independently of Cyclooxygenase Activity.
Nature 2001, 414, 212-216.
17. Siskou, I.C.; Rekka, E.A.; Kourounakis, A.P.; Chrysselis, M.C.; Tsiakitzis, K.; Kourounakis,
P.N. Design and Study of Some Novel Ibuprofen Derivatives with Potential Nootropic and
Neuroprotective Properties. Bioorg. Med. Chem. 2007, 15, 951-961.
18. Fawzy, N.M.; Swelam, S.A.; Farid, M.A. Synthesis and Antimicrobial Activities of Some 3,4-
Dihydroquinazolinone-4-one, Quinoxaline, Benzoxazine, Benzothiazine, Pyran and
Pyrrolidinedione Derivatives. Biotechnology 2008, 7, 43-50.
19. Obniska, J.; Zagorska, A. Synthesis and Anticonvulsant Properties of New N-[(4-Arylpiperazin-
1-yl)methyl] Derivatives of 3-Aryl pyrrolidine-2,5-dione and 2-Aza-spiro[4.4]nonane-1,3-dione.
Farmaco, 2003, 58, 1227-1234.
20. Naik, S.D.; Ambaye, R.Y.; Gokhale, S.V. Anticancer Activity of New 3-Amino-
pyrrolidinedione-Nitrogen Mustard Derivatives on Murine Sarcoma 180. Anticancer Res. 1987,
7, 87-90.
21. Winter, C.A., Fisley, E.A.; Nuss, G.W. Carrageenin-Induced Edema in Hind Paw of the Rat as
an Assay for Antiinflammatory Drugs. Proc. Soc. Exp. Biol. Med. 1962, 111, 544-547.
22. Franklin, P.X.; Pillai, A.D.; Rathod, P.D.; Yerande, S.; Nivsarkar, M.; Padh, H.; Vasu, K.K.;
Sudarsanam, V. 2-Amino-5-thiazolyl Motif: A Novel Scaffold for Designing Anti-inflammatory
Agents of Diverse Structures. Eur. J. Med. Chem. 2008, 43, 129-134.
23. Barsoum, F.F.; Hosni, H.M.; Girgis, A.S. Novel Bis(1-acyl-2-pyrazolines) of Potential Anti-
inflammatory and Molluscicidal Properties. Bioorg. Med. Chem. 2006, 14, 3929-3937.
24. Hamza, Y.E.; Sammour, O.A.; Abdel-Latif, H.A. Enhancement of Dissolution of Indometacin
and Modulation of Its Pharmacodynamics and Ulcerogenicity via Solid Dispersions. Pharm. Ind.
1994, 56, 286-291.
25. Khayyal, M.T.; El-Ghazaly, M.A.; Abdallah, D.M.; Okpanyi, S.N.; Kelber, O.; Weiser, D.
Mechanisms Involved in the Anti-inflammatory Effect of a Standardized Willow Bark Extract.
Arzneim.-Forsch./Drug Res. 2005, 55, 677-687.
26. El-Ghazaly, M.A. J. The Effect of Aqueous Propolis Extract on Cellular Migration,
Prostaglandins and histamine Release in Irradiated Rats. Egypt. Soc. Toxicol. 1996, 16, 69-73.
27. El-Said, M.K.; Aly, S.M.E.; Romeih, F.A.; Barsoum, F.F.; Hassan, A.B. Synthesis and
Pharmacological Testing of Some New Phenothiazine Derivatives. Egypt. J. Pharm. Sci. 1991,
32, 251-261.

Molecules 2009, 14
681
28. Ebeid, M.Y.; Aly, S.M.E.; Hanna, M.M.; Romeih, F.A.; Barsoum, F.F. Synthesis and Anti-HIV
Activity of Some 6,7-Dihydro-5H-pyrrolizine-3-carboxamide, 5,6,7,8-Tetrahydroindolizine-3-
carboxamide,
1-Thioxo-1,2,3,5,6,7,8,9,10,11-decahydropyrimido[1,6-a]azonine-4-carbonitrile
and
6-Thioxo-1,2,5,6,8,9,10,11,12,13,14,14a-dodecahydropyrimido[4,,5,:4,5]pyrimido[1,6-a]-
azonin-1-one Derivatives. Bull. Fac. Pharm. Cairo Univ. 1997, 35, 171-183.
29. El-Feky, S.A.; Al-Ashmawi, M.I.; Hazzaa, A.A.B.; Abd El-Fattah, B. Synthesis of Certain New
Sulphur Containing Quinazolinone Derivatives Likely to Possess CNS Depressant Action.
Egypt. J. Pharm. Sci. 1983, 24, 39-47.
30. Hassan, H.M.; Kora, F.A.; El-Naggar, A.M.; Abdel-Magged, T.T. Synthesis of Some Amino
Acid and Dipeptide Derivatives with Expected Antimicrobial Activity. Az. J. Pharm. Sci. 1998,
21, 133-141.
31. Abdel-Hamid, H.A.; Fahmy, A.F.M.; Shiba, S.A.; Hemdan, M.M. Synthesis and Reactions of p-
N-Succinimido Benzoic Acid Azide. Egypt. J. Chem. 1993, 36, 149-158.
Sample Availability: Samples of the new compounds are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).