Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties

Article abstract of DOI:10.1016/j.bmc.2006.01.042

A variety of bis[3-aryl-4,5-dihydro-1H-pyrazol-1-carboxaldehydes] 4a-h were obtained via reaction of bis[1-aryl-2-propen-1-ones] 3a-h with hydrazine hydrate in refluxing formic acid. In addition, the corresponding bis[1-acetyl-3-aryl-4,5-dihydro-1H-pyrazo

Full text of DOI:10.1016/j.bmc.2006.01.042

Bioorganic & Medicinal Chemistry 14 (2006) 3929–3937
Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory
and molluscicidal properties
Flora F. Barsoum,a Hanaa M. Hosnib and Adel S. Girgisb,*
aPharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
bPesticide Chemistry Department, National Research Centre, Dokki, 12622 Cairo, Egypt
Received 30 October 2005; revised 19 January 2006; accepted 20 January 2006
Available online 7 February 2006
Abstract—A variety of bis[3-aryl-4,5-dihydro-1H-pyrazol-1-carboxaldehydes] 4a–h were obtained via reaction of bis[1-aryl-2-pro-
pen-1-ones] 3a–h with hydrazine hydrate in refluxing formic acid. In addition, the corresponding bis[1-acetyl-3-aryl-4,5-dihydro-
1H-pyrazoles] 4i–m were formed through conducting the reaction of 3 with hydrazine hydrate in refluxing acetic acid. The starting
bis(2-propen-1-ones) 3a–h were prepared stereoselectively as E,E0-geometric isomer via condensation of bisbenzaldehydes 1a,b with
(un)substituted acetophenones 2 in ethanolic KOH solution. Anti-inflammatory as well as ulcerogenic activities of the prepared
pyrazolines were evaluated in vivo and compared with that of a standard drug (indomethacin). Many of the tested compounds
show remarkable anti-inflammatory properties with an ulcerogenic liability (especially 4f, g, j, and k) lower than that of the standard
used drug. Compound 4f was established to be the best effectively prepared anti-inflammatory active pyrazoline derivative and safer
than indomethacin with respect to its ulcerogenic liability. Molluscicidal activity of the prepared compounds against Biomphalaria
alexandrina snails (the intermediate host of Schistosoma mansoni) was screened. Where, some of the prepared compounds show
considerable activities.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Chalcones, one class of the anthochlor pigments, usually
give yellow to orange colours to the tissues in which they
are located. Although these compounds are not respon-
sible for pigmentation in the most yellow-coloured flow-
ers, they are still attractive to insects and in such a way
they contribute to the flowers’ pollination.14 The impor-
tance of these compounds is due not only to their
colours but also to their chemical in addition to biolog-
ical activities and the fact that they are good accessible
starting materials used for construction of various het-
erocyclic derivatives.1–3,15,16 One of these important het-
erocyclic systems which attracts progressive interest of
many researchers is pyrazoline. The interest of scientists
in such compounds has been stimulated by their biolog-
ical, pharmacological and industrial importance. For
example, 1-unsubstituted-3,5-diaryl-2-pyrazolines were
reported to exhibit human acyl CoA cholesterol acyl-
transferase17 as well as low-density lipoprotein oxida-
tion inhibitors.18 Moreover, 1,3,5-triaryl-2-pyrazolines
were reported to possess antidepressant properties19,20
in addition to monoamine oxidase inhibitory
activities.21,22
Chalconoids constitute an important class of naturally
occurring compounds1–3 exhibiting a wide spectrum of
biological activities. The term chalconoid has been
used to designate the whole family of compounds pos-
sessing a 1,3-diarylpropane skeleton, which can be
functionalized in the propane chain by the presence
of olefinic, keto and/or hydroxyl groups. The most
common and widespread compounds of the chalco-
noid group are the chalcones, which possess a 1,3-dia-
ryl-2-propen-1-one carbon framework.1,2 Several
potential properties of chalcones were exhibited as
antimalarial,4–7 and anti-tuberculosis,8 activities.
Moreover, many recent publications were reported
dealing with the cytotoxic9–12 as well as anti-HIV13
properties of hydroxychalcone derivatives.
Keywords: Bis(2-propen-1-ones); Bis(2-pyrazolines); Anti-inflammatory;
Ulcerogenic liability; Molluscicides.
*
Recent progressive interest was directed towards
1,3,5-triaryl-2-pyrazoline
Corresponding author. Tel.: +202 2352405; fax: +202 3370931;
e-mail: girgisas10@yahoo.com
derivatives’
nanocrystal
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.01.042

3930
F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
investigation23–28 due to their well-known fluorescence
properties with high quantum yield useful as whitening
or brightening agents for textile fibre, plastic and paper
industries.29–32 Many efforts have been also directed
towards utilization of this behaviour for construction
of organic electroluminescence devices with a multi-
layer structure and as fluorescence probes in some elab-
orated chemosensors.33–39
In the present work, it is intended to synthesize a novel
variety of bis(1-acyl-2-pyrazoline) containing com-
pounds. This investigation is prompted mainly by the
aforementioned biological and/or pharmacological
activities of that ring system in addition to the recog-
nized anti-inflammatory, analgesic as well as antipyretic
properties of 1-acetyl-2-pyrazoline analogues.40,41
Moreover, many bispyrazole derivatives are involved
in a wide variety of medicinally and pharmacologically
active materials.42,43 Construction of new heterocyclic
derivatives containing two biologically active moieties
(1-formyl- or 1-acetyl-2-pyrazolines) could enhance the
total observed biological activities and may be a hint
for determination of highly pronouncing effective new
materials. Ulcerogenic properties of the most anti-in-
flammatory active synthesized compounds will be also
considered.
Figure 1. Single crystal X-ray diffraction of 3a. Selected intramolecular
˚
bond lengths (A) and bond angles (ꢁ) of 3a. O(1)–C(8) = 1.439(3),
O(1)–C(11) = 1.369(3), O(2)–C(16) = 1.359(3), O(2)–C(17) = 1.432(3),
O(3)–C(7) = 1.231(2), O(4)–C(19) = 1.233(3), C(5)–C(7) = 1.484(3),
C(5)–C(18) = 1.382(3), C(5)–C(20) = 1.385(3), C(6)–C(7) = 1.471(3),
C(6)– C(13) = 1.319(3), C(8)–C(17) = 1.486(3), C(9)–C(15) = 1.326(3),
C(9)–C(19) = 1.471(3),
C(10)–C(11) = 1.412(3),
C(10)–C(13) =
1.461(3), C(10)–C(22) = 1.396(3), C(11)–C(23) = 1.380(3), C(12)–
C(19) = 1.490(3), C(12)–C(27) = 1.371(4), C(12)–C(30) = 1.386(4),
C(14)–C(15) = 1.463(4),
C(14)–C(16) = 1.399(3),
C(14)–C(24) =
1.406(4), C(16)–C(21) = 1.385(3), C(18)–C(26) = 1.357(4), C(20)–
C(31) = 1.379(3), C(21)–C(36) = 1.382(5), C(22)–C(32) = 1.376(4),
C(23)–C(34) = 1.389(4),
C(24)–C(33) = 1.395(4),
C(25)–C(26) =
The molluscicidal activity of the newly prepared com-
pounds against Biomphalaria alexandrina snails (the
intermediate host of Schistosoma mansoni) will be
also screened. Schistosomiasis is the most important
endemic trematode disease in human in many tropi-
cal and subtropical regions. It is considered a nation-
al problem in many countries (including Egypt).
Searching for an effective, easily available and low-
cost molluscicidal active material could be a promis-
ing tool for controlling the disease from spreading
widely.
1.363(4), C(25)–C(31) = 1.363(4), C(27)–C(29) = 1.376(3), C(28)–
C(29) = 1.360(4), C(28)–C(35) = 1.361(4), C(30)–C(35) = 1.366(4),
C(32)–C(34) = 1.375(4),
C(33)–C(36) = 1.349(4),
C(6)–H(6) =
0.960(2), C(9)–H(9) = 1.00(2), C(13)–H(13) = 0.86(2), C(15)–H(15) =
0.94(2), C(8)–O(1)–C(11) = 119.4(2), C(16)–O(2)–C(17) = 118.9(2),
C(7)–C(5)–C(18) = 119.6(2), C(7)–C(5)–C(20) = 123.5(2), C(18)–C(5)–
C(20) = 116.9(2), C(7)–C(6)–C(13) = 122.3(2),
119,2(2), O(3)–C(7)–C(6) = 121.0(2),
O(3)–C(7)–C(5) =
C(5)–C(7)–C(6) = 119.8(2),
O(1)–C(8)–C(17) = 107.2(2), C(15)–C(9)–C(19) = 121.7(3), C(11)–
C(10)–C(13) = 125.2(2), C(11)–C(10)–C(22) = 116.9(2), C(13)–C(10)–
C(22) = 117.9(2), O(1)–C(11)–C(10) = 115.3(2), O(1)–C(11)–C(23) =
123.2(3),
123.2(3),
C(10)–C(11)–C(23) = 121.4(3),
C(19)–C(12)–C(30) = 119.5(3),
C(19)–C(12)–C(27) =
C(27)–C(12)–
C(30) = 117.3(3), C(6)–C(13)–C(10) = 131.2(2), C(15)–C(14)–C(16) =
125.1(3), C(15)–C(14)–C(24) = 116.6(3), C(16)–C(14)–C(24) =
2. Results and discussion
2.1. Chemistry
118.3(3), C(9)–C(15)–C(14) = 128.8(3), O(2)–C(16)–C(14) = 116.8(2),
O(2)–C(16)–C(21) = 123.6(3), C(14)–C(16)–C(21) = 119.5(3), O(2)–
C(17)–C(8) = 107.9(2), C(5)–C(18)–C(26) = 122.1(3), O(4)–C(19)–
C(9) = 121.4(3), O(4)–C(19)–C(12) = 119.2(3), C(9)–C(19)–C(12) =
119.4(3), C(5)–C(20)–C(31) = 121.3(2), C(16)–C(21)–C(36) = 120.3(3),
C(10)–C(22)–C(32) = 122.2(3), C(11)–C(23)–C(34) = 119.2(3), C(14)–
C(24)–C(33) = 121.3(3), C(26)–C(25)–C(31) = 120.3(3), C(18)–C(26)–
Reaction of 2,20-[1,2-ethanediylbis(oxy)]bisbenzalde-
hyde (1a) with (un)substituted acetophenones 2 in
4% ethanolic KOH solution afforded the correspond-
ing 3,30-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[1-ar-
yl-2-propen-1-ones] 3a–e. The structure of 3 was
established through spectroscopic (IR, 1H NMR)
and elemental analyses data. The IR spectra of 3a–e
reveal the presence of a strong band at m = 1658–
1643 cmꢀ1 region assignable for the a,b-unsaturated
C(25) = 119.9(3),
C(12)–C(27)–C(29) = 121.7(3),
C(29)–C(28)–
C(35) = 119.8(3), C(27)–C(29)–C(28) = 119.7(3), C(12)–C(30)–C(35) =
121.0(3), C(20)–C(31)–C(25) = 119.5(3), C(22)–C(32)–C(34) = 119.4(3),
C(24)–C(33)–C(36) = 118.6(3), C(23)–C(34)–C(32) = 120.9(3), C(28)–
C(35)–C(30) = 120.5(3), C(21)–C(36)–C(33) = 122.0(3), C(7)–C(6)–H(6) =
119.4(3), C(13)–C(6)–H(6) = 118.3(3), C(15)–C(9)–H(9) = 118.3(11), C(19)–
C(9)–H(9) = 119.8(11), C(6)–C(13)–H(13) = 114.5(14), C(10)–C(13)–H(13) =
114.3(14), C(9)–C(15)–H(15) = 116.7(14), C(14)–C(15)–H(15) = 114.4(13).
1
ketonic residue. H NMR spectra of 3a–e exhibit each
of the olefinic protons as a doublet signal at d = 7.79–
7.84, 7.89–7.97 regions with a mutual coupling con-
stant value J = 15.6–15.9 Hz. These observed coupling
constant values indicate the presence of E,E0-configu-
rational form structure.
angles ‘H(6)–C(6)–C(7)–O(3) = ꢀ169.8(6), H(6)–C(6)–
C(13)–H(13) = ꢀ178.(3),
H(9)–C(9)–C(19)–O(4) =
177.(2), and H(9)–C(9)–C(15)–H(15) = 176.(3)’ confirm
this assumption.
Single crystal X-ray diffraction of 3a (Fig. 1) adds a
sharp evidence for the presence of E,E0-configurational
stereochemical structure. Where, the observed torsion

F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
3931
Similarly, reaction of 4,40-[1,2-ethanediylbis(oxy)]bis-
benzaldehyde (1b) with acetophenones 2 under the pre-
viously described reaction conditions gave the
corresponding bis-2-propen-1-ones 3f–h in good yield
4i–m reveal each of the methylene protons as a doublet
signal at d = 2.98–3.14 and 3.51–3.75 region beside the
vicinal methine proton at d = 5.49–5.76. Moreover, the
methyl protons of acetyl group appear as a singlet signal
at d = 2.21–2.41 region.
1
(Scheme 1). H NMR spectra of 3f–h confirm that, the
isolated products are 2E,20E-isomeric form structure
depending on the mutual coupling constant values be-
tween the a,b-unsaturated olefinic protons ‘J = 15.3–
15.6 Hz’.
2.2. Anti-inflammatory activity
The anti-inflammatory activity of the prepared pyrazo-
lines 4 was determined by the carrageenin-induced paw
oedema standard method in rats.40,41,47,48 From the
obtained results (Table 1, Figs. 2 and 3), it has been
noticed that all the tested pyrazoline derivatives show
considerable anti-inflammatory activities. In addition,
Reaction of 3a–h with hydrazine hydrate in refluxing
formic acid yielded exclusively, bis[3-aryl-4,5-dihydro-
1H-pyrazole-1-carboxaldehydes] 4a–h. The structure of
4a–h was inferred from spectroscopic as well as elemen-
tal analyses data. The IR spectra exhibit the presence of
only one carbonyl band at m = 1680–1658 cmꢀ1 assign-
able for the carbonyl formyl function. 1H NMR spectra
of 4a–h reveal the presence of two unequivalent protons
of a methylene group ‘at d = 3.03–3.23, 3.54–3.88’ cou-
pled with each other and in turn with the vicinal methine
proton (H-5) ‘at d = 5.49–5.67.’ It has also been noticed
that, the upfield shifted proton of methylene residue
coupled with the vicinal methine one (H-5) with a cou-
pling constant value ‘J = 4.8–5.4 Hz,’ indicating the
presence of trans-configuration. In other words, this
mentioned proton is located cis to the aryl group at-
tached to the pyrazole C-5. Also, the coupling constant
value between the downfield shifted proton of methylene
function and the vicinal methine proton (H-5) ‘J = 11.7–
12 Hz’ supports this assumption.44–46 Moreover, the
formyl proton appear as a sharp singlet signal at
d = 8.80–8.96.
Table 1. Anti-inflammatory activity of the tested compounds using
carrageenin-induced paw oedema in rats
Compound
Oedema weight (g)
% inhibition
of oedema
Control
Indomethacin
(reference standard)
0.74 0.02
0.20 0.00*
0.00
72.97
4a
4c
4d
4e
4f
0.34 0.04*
0.43 0.10*
0.44 0.05*
0.42 0.03*
0.12 0.02*
0.24 0.02*
0.32 0.08*
0.34 0.06*
0.28 0.03*
0.28 0.03*
0.40 0.03*
0.46 0.04*
54.05
42.57
40.54
43.24
83.78
67.57
56.76
54.05
62.16
62.16
45.95
37.84
4g
4h
4i
4j
4k
4l
4m
Similarly, reaction of 3 with hydrazine hydrate in reflux-
ing acetic acid afforded the corresponding bis[1-acetyl-3-
aryl-4,5-dihydro-1H-pyrazoles] 4i–m (Scheme 1). IR
spectra of 4i–m exhibit the presence of a strong carbonyl
band at m = 1666–1658 cmꢀ1 region. 1H NMR spectra of
All values are represented as means SE ‘standard error’.
Statistical analysis was carried out by using one-way ANOVA (F test)
followed by Dunnett’s t test at p < 0.05.
* Significantly different from the control value at p < 0.05.
A
A
RCOCH3
(2)
R
R
EtOH, KOH
CHO
OHC
O
(3)
N2H4.H2O, R'CO2H
O
(1)
A
R
R
N
N
N
N
O
O
R'
R'
(4)
Scheme 1. 1a, A = 2-O(CH2)2O-20; 1b, A = 4-O(CH2)2O-40; 3a, A = 2-O(CH2)2O-20, R = Ph; 3b, A = 2-O(CH2)2O-20, R = 4-ClC6H4; 3c, A = 2-
O(CH2)2O-20, R = 4-FC6H4; 3d, A = 2-O(CH2)2O-20, R = 4-H3CC6H4; 3e, A = 2-O(CH2)2O-20, R = 2-thienyl; 3f, A = 4-O(CH2)2O-40, R = Ph; 3g,
A = 4-O(CH2)2O-40, R = 4-ClC6H4; 3h, A = 4-O(CH2)2O-40, R = 4-H3CC6H4; 4a, A = 2-O(CH2)2O-20, R = Ph, R0 = H; 4b, A = 2-O(CH2)2O-20,
R = 4-ClC6H4, R0 = H; 4c, A = 2-O(CH2)2O-20, R = 4-FC6H4, R0 = H; 4d, A = 2-O(CH2)2O-20, R = 4-H3CC6H4, R0 = H; 4e, A = 2-O(CH2)2O-20,
R = 2-thienyl, R0 = H; 4f, A = 4-O(CH2)2O-40, R = Ph, R0 = H; 4g, A = 4-O(CH2)2O-40, R = 4-ClC6H4, R0 = H; 4h, A = 4-O(CH2)2O-40, R = 4-
H3CC6H4, R0 = H; 4i, A = 2-O(CH2)2O-20, R = 4-ClC6H4, R0 = CH3; 4j, A = 2-O(CH2)2O-20, R = 4-FC6H4, R0 = CH3; 4k, A = 2-O(CH2)2O-20,
R = 4-H3CC6H4, R0 = CH3; 4l, A = 2-O(CH2)2O-20, R = 2-thienyl, R0 = CH3; 4m, A = 4-O(CH2)2O-40, R = 4-H3CC6H4, R0 = CH3.

3932
F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
*
*
*
*
*
*
*
*
*
*
*
*
*
Tested compounds
Figure 2. Mean oedema weight (g) of the tested compounds.
Table 2. Ulcerogenic liability of the most observed anti-inflammatory
actively prepared compounds
90
80
70
60
50
40
30
20
10
0
Compound
Number
% incidence Average Average Ulcer
of ulcer severity index
number
of animals divided
with ulcer by 10
Control 0
Indomethacin 5/5
0
10
4
0
0
0
8.25
0.6
2.6
2.25
5.8
3.5
0.4
1.8
1.25
2.6
21.75
5
4f
4g
4j
2/5
5/5
4/5
5/5
10
8
14.4
11.5
18.4
4k
10
Tested compounds
25
20
15
10
5
Figure 3. % inhibition of oedema of the tested compounds.
it has been found that, the 1-acetyl-2-pyrazoline ana-
logues ‘4j–l’ reveal slightly enhanced anti-inflammatory
properties than those of the corresponding 1-formyl
derivatives ‘4c–e.’ Moreover, it has been also observed
that, the bis(2-pyrazoline-1-carboxaldehyde) analogues
linked by para-phenylene moiety ‘4f, h’ exhibit better
activities than those linked by the ortho-phenylene resi-
due ‘4a, d.’
0
Tested compounds
Figure 4. Ulcer index of the tested compounds.
Generally, it has been observed that, several newly pre-
pared compounds (such as 4g, j and k) reveal remarkable
anti-inflammatory properties (67.57–62.16% inhibition of
oedema) comparable to those of indomethacin which
used as a reference standard (72.97% inhibition of oede-
ma). Moreover, 4f exhibits better anti-inflammatory
activity (83.78% inhibition of oedema) than that of the
used reference standard (indomethacin) itself.
indexes of 4f and indomethacin are 5, 21.75,
respectively).
2.4. Molluscicidal activity
Schistosomiasis (also called Bilharziasis) is the most
important trematode disease in human. It is an endemic
disease in many tropical and subtropical regions. The
intermediate host of Schistosoma mansoni, which affects
the intestinal system, is Biomphalaria alexandrina snails.
The toxicities of the prepared products towards these
snails were carried out using the previously reported stan-
dard procedure.51–54 From the molluscicidal activity
screening data (Table 3), it is obvious that most of the pre-
pared chalcone as well as pyrazoline derivatives show
moderate properties. It has also been noticed that, the
bispyrazolines 4 exhibit better molluscicidal properties
than those of their starting bispropenones 3. Moreover,
the substituents attached to the phenyl group have been
2.3. Ulcerogenic liability
The ulcerogenic liability of the most observed anti-in-
flammatory actively prepared compounds (4f, g, j and
k) was determined in albino rats following the previous-
ly reported standard method.49,50 From the obtained
data (Table 2, Fig. 4), it has been noticed that all the
tested prepared pyrazoline derivatives possess less
ulcerogenic potentialities comparable with that of indo-
methacin (used as a reference standard). Considering
oral administration of the tested compounds and the ref-
erence drug, compound 4f (the most effectively prepared
anti-inflammatory agent) was found to be safer than
indomethacin with respect to ulcerogenic liability (ulcer

F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
Table 3. Molluscicidal activity of the prepared compounds
3933
ic acid (25 ml) ‘in case of 4e–h, l, m, 5 ml of N,N-dimeth-
ylformamide was added to the reaction mixture to assist
solubility of the reactant’ and was boiled under reflux
for the appropriate time. The solid separated upon
pouring the reaction mixture into ice-cold water
(200 ml) was collected, washed with water and crystal-
lized from a suitable solvent affording 4a–m (for physi-
cal and spectroscopic data of compounds 4a–m, cf.
Tables 4 and 5).
Compound
% of snails killed at a
concentration of
20 ppm
10 ppm
5 ppm
3a
3b
20
30
10
0
10
20
0
0
0
3c
3d
0
0
0
3e
10
20
0
0
0
3f
3g
10
0
0
3.3. Single crystal X-ray crystallographic data of 3a57
0
3h
4a
0
0
0
30
20
50
10
20
40
30
0
20
10
30
0
10
10
30
0
The crystallographic data were collected at T = 298 K on
a Kappa CCD Enraf Nonius FR 590 diffractometer using
a graphite monochromator with Mo-Ka radiation
4b
4c
4d
4e
˚
(k = 0.71073 A). The crystal structure was determined
0
0
by SIR9258 and refined by maXus59 (Bruker Nonius,
Delft and MacScience, Japan). Chemical formula
C32H26O4, Mr = 474.556, monoclinic, crystallizes in space
group P21/c, Cell lengths ‘a = 11.8232(5), b = 13.0964(6)
4f
4g
30
10
0
20
0
4h
4i
0
30
50
10
20
30
100
0
10
30
0
0
˚
and c = 17.4029(11) A,’ cell angles ‘a = 90.00,
4j
4k
20
0
3
˚
b = 109.363(2), c = 90.00ꢁ,’ V = 2542.3(2) A , Z = 4,
Dc = 1.240 mg/m3, h values 2.910–22.986ꢁ, absorption
coefficient l(Mo-Ka) = 0.08 mmꢀ1 and F(000) = 1000.
The unique reflections measured 4232 of which 1442
reflections with threshold expression I > 3r(I) were used
in the structural analysis. Convergence for 379 variable
parameters by least-squares refinement on F2 with
w ¼ 1=½r2ðF o2 þ 0:10000F 2oꢁ. The final agreement factors
were R = 0.040 and wR = 0.072 with a goodness-of-fit of
1.549.
4l
4m
10
20
100
0
10
10
100
0
Baylucide (reference standard)a
Control
a Baylucide
nitrosalicylanilide’.
‘2-aminoethanol
salt
of
20,5-dichloro-40-
found to be of great importance, enhancing the observed
biological activity. The best results obtained of com-
pounds 4, where the phenyl residue is either unsubstituted
(4a, f) or substituted with a halogen moiety (chloro ‘as in
case of 4b, g, i’ or fluoro ‘as in case of 4c, j’ substitutions).
3.4. Anti-inflammatory activity
Adult albino rats of either sex (pregnant female animals
were excluded) weighing 160–190 g were divided into 14
groups of five animals each. Indomethacin (reference
standard) and the tested compounds (100 mg/kg) were
suspended in saline solution by the aid of few drops of
Tween 80 (to improve wettability of particles) and given
intraperitoneally 1h before induction of inflammation.
The control group was given saline solution containing
few drops of Tween 80.
3. Experimental
Melting points are uncorrected and recorded on an Elec-
trothermal digital 9100 melting point apparatus. IR
spectra were recorded (KBr) on a Mattson Genesis II
FT-IR spectrophotometer. 1H NMR spectra were
recorded on a Varian MERCURY 300 (300 MHz) spec-
trometer. The starting compounds 1a, b55,56 were pre-
pared according to the previously reported procedures.
Carrageenin paw oedema was induced according to a
modified method of Winter et al.47 by subcutaneous injec-
tion of 0.05 ml of 1% carrageenin sodium gel into the sub-
plantar region of the right hind paw of rats. All rats were
sacrificed by cervical dislocation 3 h after the injection of
carrageenin. The hind feet were cut off at the tibio-talar
joint and weighed. The weight of oedema was determined
from the difference between the injected and non-injected
foot. Data were collected, checked and revised. Quantita-
tive variables from normal distribution were expressed as
means SE ‘standard error’. The significant difference
between groups was tested by using one-way ANOVA
(F test) followed by Dunnett’s t test at p < 0.05.60 The
anti-inflammatory activity was expressed as a percentage
inhibition of oedema weight in treated animals in compar-
ison with the control group40,41,48 (Table 1, Figs. 2 and 3)
3.1. Preparation of bis-2-propen-1-ones 3 (general
procedure)
A mixture of the appropriate 1a, b (5 mmol) and the cor-
responding acetophenone 2 (10 mmol) in ethanolic
KOH solution (25 ml, 4%) was stirred at room temper-
ature (25–30 ꢁC) for the suitable time. The solid separat-
ed was collected, washed with water and crystallized
from a suitable solvent affording the corresponding
3a–h (for physical and spectroscopic data of compounds
3a–h, cf. Tables 4 and 5).
3.2. Reaction of 3a–h with hydrazine hydrate (general
procedure)
W c ꢀ W t
A solution of 3a–h (2.5 mmol) and hydrazine hydrate
(10 mmol, 80%) in the corresponding aliphatic carboxyl-
%Inhibition of oedema ¼
ꢂ 100;
W c

3934
F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
Table 4. Physical data of the prepared compounds
Compound
Mp (ꢁC) (solvent)
Yield (%), reaction time (h), (colour)
Mol. formula (Mol. wt.)
Analysis (%) Calcd/Found
C
H
N
3a
3b
3c
3d
3e
3f
146–147
(benzene)
156–157
84, 48
(pale yellow)
81, 48
C
32H26O4
(474.53)
32H24Cl2O4
80.99
81.20
70.72
70.87
75.28
75.22
81.25
81.39
69.11
69.42
80.99
80.83
70.72
70.59
81.25
80.97
73.10
73.21
65.07
65.32
68.68
68.77
73.70
73.49
63.14
63.09
73.10
72.93
65.07
65.29
73.70
73.66
65.95
65.71
69.44
69.50
74.24
74.50
64.19
64.32
74.24
74.33
5.52
5.61
4.45
4.68
4.74
4.70
6.02
6.28
4.56
4.78
5.52
5.39
4.45
4.41
6.02
5.70
5.41
5.53
4.50
4.69
4.75
4.86
5.84
5.69
4.59
4.50
5.41
5.23
4.50
4.63
5.84
5.79
4.92
4.74
5.18
5.27
6.23
6.42
5.05
5.27
6.23
6.29
—
—
C
—
—
(benzene)
186–187
(almost colourless)
86, 48
(543.42)
C32H24F2O4
(510.51)
—
—
(benzene)
185–187
(almost colourless)
88, 48
(yellow)
C34H30O4
(502.58)
—
—
(acetic acid)
203–205a
74, 48
(colourless)
88, 24
C28H22O4S2
(486.58)
—
—
188–190
(benzene)
C32H26O4
(474.53)
—
—
(colourless)
85, 72
a
3g
3h
4a
4b
4c
4d
4e
4f
228–230
C32H24Cl2O4
(543.42)
—
—
(almost colourless)
84, 24
237–239
(1,4-dioxane)
242–244
C34H30O4
(502.58)
—
—
(colourless)
72, 9
C34H30N4O4
(558.61)
10.03
10.19
8.93
9.19
9.42
9.48
9.55
9.47
9.82
9.94
10.03
9.88
8.93
8.85
9.55
9.66
8.55
8.33
9.00
9.16
9.11
9.24
9.36
9.52
9.11
8.96
(benzene)
243–244
(colourless)
57, 9
C34H28Cl2N4O4
(627.50)
(benzene)
169–171
(colourless)
60, 9
C34H28F2N4O4
(594.59)
(methanol)
225–227b
(pale yellow)
82, 9
C36H34N4O4
(586.66)
(pale yellow)
56, 9
245–247c
C30H26N4O4S2
(570.66)
(very pale yellow)
57, 9
214–216
(benzene)
214–216a
C34H30N4O4
(558.61)
(colourless)
81,9
4g
4h
4i
C34H28Cl2N4O4
(627.50)
(colourless)
75, 9
206–207
(benzene)
179–181
(benzene)
193–195
(benzene)
205–207b
C36H34N4O4
(586.66)
(colourless)
64, 6
C36H32Cl2N4O4
(655.56)
(colourless)
58, 6
4j
C36H32F2N4O4
(622.65)
(colourless)
67, 6
4k
4l
C38H38N4O4
(614.71)
(colourless)
60, 6
231–233c
152–154b
C32H30N4O4S2
(598.71)
(pale yellow)
59, 6
(very pale yellow)
4m
C38H38N4O4
(614.71)
a N,N-Dimethylformamide.
b Chloroform–ethanol mixture as 1:3 v/v.
c N,N-Dimethylformamide (50%).
where Wc and Wt are the weights of oedema for the con-
trol and drug-treated animal groups, respectively.
ine with few drops of Tween 80. One hour following the
last dose, the animals were sacrificed by cervical disloca-
tion and the stomach was removed, opened along the
greater curvature and rinsed with saline. The gastric
mucosa was examined with a magnifying lens (10·) for
the presence of lesions and erosions. The ulcer index
was calculated (Table 2, Fig. 4) and the degree of ulcero-
genic effect was expressed in terms of
3.5. Ulcerogenic liability
The ulcerogenic liability was determined in albino rats
following the previously reported standard method.49,50
Rats of either sex weighing 120–140 g were divided into
six groups of five animals each. Pregnant female rats
were excluded. The animals were fasted 18 h before drug
administration. Indomethacin (reference standard) and
the tested compounds (100 mg/kg) 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 sal-
1. Average number of ulcers per stomach.
2. Average severity of ulcers.
3. Percentage incidence of ulcer divided by 10.
The ulcer index is the value that resulted from the sum
of the above three values.

Table 5. Spectroscopic data of the prepared compounds
Compound
MIR (mmax/cmꢀ1
)
1H NMR (solvent), d
3a
1657 (C@O), 1601, 1568 (C@C)
1658 (C@O), 1599, 1572 (C@C)
1658 (C@O), 1601, 1570 (C@C)
1655 (C@O), 1606, 1593 (C@C)
1643 (C@O), 1593, 1572 (C@C)
1653 (C@O), 1599, 1570 (C@C)
1655 (C@O), 1593, 1574 (C@C)
(CDCl3) 4.60 (s, 4H, 2OCH2), 7.05–7.62 (m, 14H, arom H), 7.82 (d, 2H, 2PhCOCH, J = 15.9 Hz), 7.84 (dd, 4H, arom H, J = 1.2,
8.7 Hz), 7.97 (d, 2H, 2 ArCH@CH, J = 15.9 Hz)
(CDCl3) 4.59 (s, 4H, 2OCH2), 7.01–7.74 (m, 16H, arom H), 7.79 (d, 2H, 2 ArCOCH, J = 15.6 Hz), 7.89 (d, 2H, 2 ArCH@CH,
J = 15.9 Hz)
3b
3c
3d
3e
3f
(CDCl3) 4.59 (s, 4H, 2OCH2), 6.69–7.85 (m, 16H, arom H), 7.84 (d, 2H, 2 ArCOCH, J = 15.6 Hz), 7.91 (d, 2H, 2 ArCH@CH,
J = 15.9 Hz)
(CDCl3) 2.30 (s, 6H, 2CH3), 4.56 (s, 4H, 2OCH2), 6.91–7.76 (m, 16H, arom H), 7.81 (d, 2H, 2 ArCOCH, J = 15.9 Hz), 7.95 (d, 2H, 2
ArCH@CH, J = 15.9 Hz)
(DMSO-d6) 4.61 (s, 4H, 2OCH2), 6.80–7.86 (m, 14H, arom H), 7.83 (d, 2H, 2ArCOCH, J = 15.6 Hz), 7.90 (d, 2H, 2 ArCH@CH,
J = 15.9 Hz)
(CDCl3) 4.42 (s, 4H, 2OCH2), 7.00–7.59 (m, 10H, arom H), 7.59 (d, 2H, 2PhCOCH, J = 15.3 Hz), 7.63 (d, 4H, arom H, J = 8.7 Hz),
7.81 (d, 2H, 2 ArCH@CH, J = 15.6 Hz), 8.03 (dd, 4H, arom H, J = 1.5, 9.6 Hz)
3g
(DMSO-d6) 4.43 (s, 4H, 2OCH2), 7.09 (d, 4H, para-sub. arom H, J = 8.7 Hz), 7.63 (dd, 4H, para-sub. arom H, J = 1.8, 8.7 Hz), 7.73 (d,
2H, 2ArCOCH, J = 15.3 Hz), 7.82 (d, 2H, 2ArCH@CH, J = 15.6 Hz), 7.88 (d, 4H, para-sub. arom H, J = 9 Hz), 8.16 (dd, 4H, para-
sub. arom H, J = 1.8, 8.7 Hz)
3h
1651 (C@O), 1604, 1587 (C@C)
(DMSO-d6) 2.40 (s, 6H, 2CH3), 4.42 (s, 4H, 2OCH2), 7.08 (d, 4H, para-sub. arom H, J = 8.7 Hz), 7.37 (d, 4H, para-sub. arom H,
J = 8.1 Hz), 7.69 (d, 2H, 2ArCOCH, J = 15.6 Hz), 7.79 (d, 2H, 2ArCH@CH, J = 15.3 Hz), 7.85 (d, 4H, para-sub. arom H, J = 8.7 Hz),
8.04 (d, 4H, para-sub. arom H, J = 8.1 Hz)
4a
4b
4c
4d
4e
4f
1668 (C@O), 1599, 1493 (C@N, C@C)
1674 (C@O), 1597, 1493 (C@N, C@C)
1678 (C@O), 1604, 1514 (C@N, C@C)
1676 (C@O), 1599, 1493 (C@N, C@C)
1680 (C@O), 1599, 1491 (C@N, C@C)
1670 (C@O), 1610, 1510 (C@N, C@C)
1672 (C@O), 1603, 1512 (C@N, C@C)
(DMSO-d6) 3.08 (dd, 2H, 2pyr. H-4trans, J = 5.1, 18 Hz), 3.75 (dd, 2H, 2pyr. H-4cis, J = 11.7, 18 Hz), 4.24 (s, 4H, 2OCH2), 5.57 (dd,
2H, 2pyr. H-5, J = 5.1, 11.7 Hz), 6.84–7.69 (m, 18 H, arom H), 8.86 (s, 2H, 2CHO)
(CDCl3) 3.10 (dd, 2H, 2pyr. H-4trans, J = 5.4, 17.7 Hz), 3.58 (dd, 2H, 2pyr. H-4cis, J = 12, 17.7 Hz), 4.20 (s, 4H, 2OCH2), 5.65 (dd, 2H,
2pyr. H-5, J = 5.4, 12 Hz), 6.67–7.58 (m, 16 H, arom H), 8.93 (s, 2H, 2CHO)
(CDCl3) 3.08 (dd, 2H, 2pyr. H-4trans, J = 5.4, 17.7 Hz), 3.63 (dd, 2H, 2pyr. H-4cis, J = 12, 17.7 Hz), 4.25 (s, 4H, 2OCH2), 5.67 (dd, 2H,
2pyr. H-5, J = 6, 12 Hz), 6.70–7.68 (m, 16 H, arom H), 8.92 (s, 2H, 2CHO)
(CDCl3) 2.27 (s, 6H, 2CH3), 3.03 (dd, 2H, 2pyr. H-4trans, J = 5.4, 17.7 Hz), 3.54 (dd, 2H, 2pyr. H-4cis, J = 11.7, 17.7 Hz), 4.09–4.17 (m,
4H, 2OCH2), 5.56 (dd, 2H, 2pyr. H-5, J = 5.4, 11.7 Hz), 6.60–7.50 (m, 16 H, arom H), 8.86 (s, 2H, 2CHO)
(DMSO-d6) 3.11 (dd, 2H, 2pyr. H-4trans, J = 5.4, 17.7 Hz), 3.76 (dd, 2H, 2pyr. H-4cis, J = 12, 18 Hz), 4.27 (s, 4H, 2OCH2), 5.58 (dd,
2H, 2pyr. H-5, J = 5.4, 12 Hz), 6.88–7.71 (m, 14 H, arom H), 8.80 (s, 2H, 2CHO)
(CDCl3) 3.23 (dd, 2H, 2pyr. H-4trans, J = 4.8, 18 Hz), 3.80 (dd, 2H, 2pyr. H-4cis, J = 11.7, 17.7 Hz), 4.28 (s, 4H, 2OCH2), 5.51 (dd, 2H,
2pyr. H-5, J = 4.5, 11.7 Hz), 6.88–7.77 (m, 18 H, arom H), 8.96 (s, 2H, 2CHO)
4g
(DMSO-d6) 3.18 (dd, 2H, 2pyr. H-4trans, J = 5.1, 18 Hz), 3.88 (dd, 2H, 2pyr. H-4cis, J = 12, 18 Hz), 4.26 (s, 4H, 2OCH2), 5.49 (dd, 2H,
2pyr. H-5, J = 5.1, 12 Hz), 6.93 (d, 4H, para-sub. arom H, J = 8.7 Hz), 7.15 (d, 4H, para-sub. arom H, J = 8.7 Hz), 7.53 (dd, 4H, para-
sub. arom H, J = 2.1, 6.6 Hz), 7.79 (dd, 4H, para-sub. arom H, J = 2.1, 6.6 Hz), 8.86 (s, 2H, 2CHO)
(CDCl3) 2.42 (s, 6H, 2CH3), 3.20 (dd, 2H, 2pyr. H-4trans, J = 4.8, 17.7 Hz), 3.78 (dd, 2H, 2pyr. H-4cis, J = 11.7, 17.7 Hz), 4.28 (s, 4H,
2OCH2), 5.49 (dd, 2H, 2pyr. H-5, J = 4.8, 11.7 Hz), 6.89–7.66 (m, 16 H, arom H), 8.94 (s, 2H, 2CHO)
(CDCl3) 2.36 (s, 6H, 2CH3), 2.98 (dd, 2H, 2pyr. H-4trans, J = 5.1, 17.7 Hz), 3.51 (dd, 2H, 2pyr. H-4cis, J = 12, 17.7 Hz), 4.17–4.28 (m,
4H, 2OCH2), 5.72 (dd, 2H, 2pyr. H-5, J = 5.1, 12 Hz), 6.68–7.58 (m, 16 H, arom H)
4h
4i
1658 (C@O), 1610, 1512 (C@N, C@C)
1662 (C@O), 1597, 1493 (C@N, C@C)
1662 (C@O), 1606, 1493 (C@N, C@C)
1664 (C@O), 1601, 1493 (C@N, C@C)
1666 (C@O), 1601, 1496 (C@N, C@C)
1658 (C@O), 1610, 1512 (C@N, C@C)
4j
(CDCl3) 2.38 (s, 6H, 2CH3), 2.99 (dd, 2H, 2pyr. H-4trans, J = 5.1, 17.7 Hz), 3.54 (dd, 2H, 2pyr. H-4cis, J = 12, 17.7 Hz), 4.20–4.33 (m,
4H, 2OCH2), 5.76 (dd, 2H, 2pyr. H-5, J = 5.1, 12.3 Hz), 6.74–7.67 (m, 16 H, arom H)
4k
4l
(CDCl3) 2.35 (s, 6H, 2ArCH3), 2.40 (s, 6H, 2COCH3), 3.00 (dd, 2H, 2pyr. H-4trans, J = 4.5, 17.4 Hz), 3.55 (dd, 2H, 2pyr. H-4cis, J = 12,
17.4 Hz), 4.18–4.31 (m, 4H, 2OCH2), 5.74 (dd, 2H, 2pyr. H-5, J = 4.5, 11.4 Hz), 6.71-7.61 (m, 16 H, arom H)
(DMSO-d6) 2.21 (s, 6H, 2CH3), 3.01 (dd, 2H, 2pyr. H-4trans, J = 4.8, 17.7 Hz), 3.75 (dd, 2H, 2pyr. H-4cis, J = 12, 17.7 Hz), 4.30–4.35
(m, 4H, 2OCH2), 5.65 (dd, 2H, 2pyr. H-5, J = 4.8, 12 Hz), 6.88–7.71 (m, 14 H, arom H)
4m
(CDCl3) 2.41 (s, 12H, 2ArCH3 + 2COCH3), 3.14 (dd, 2H, 2pyr. H-4trans, J = 4.5, 17.4 Hz), 3.71 (dd, 2H, 2pyr. H-4cis, J = 11.7,
17.7 Hz), 4.27 (s, 4H, 2OCH2), 5.49 (dd, 2H, 2pyr. H-5, J = 4.5, 11.7 Hz), 6.86–7.66 (m, 16 H, arom H)

3936
F. F. Barsoum et al. / Bioorg. Med. Chem. 14 (2006) 3929–3937
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