Synthesis and vasodilation activity of some novel bis(3- pyridinecarbonitrile) derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.08.032

A variety of bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles) 4a-m were prepared via reaction of bis(2-propen-1-ones) 3a-g with malononitrile in the appropriate alcohol in the presence of KOH. The reaction was assumed to take place via Michael addition followed by cyclization due to the alkoxide nucleophilic attack at one of the nitrile groups. This assumption was substantiated by the reaction of ylidenemalononitrile 5 with the corresponding acetophenone 2 in the appropriate alcohol in the presence of KOH. The starting bis(2-propen-1-ones) 3e and f were prepared stereoselectively as E,E′-geometric isomer via condensation of bisbenzaldehyde 1 with substituted acetophenones 2e and f in ethanolic KOH solution. Vasodilating activity screening of the synthesized compounds 4a-g and 4i-m utilizing isolated rat's thoracic aorta pre-contracted by norepinephrine hydrochloride exhibited that many of the tested compounds reveal considerable vasodilating properties, especially 4e and f which reveal remarkable activities.

Full text of DOI:10.1016/j.ejmech.2010.08.032

European Journal of Medicinal Chemistry 45 (2010) 5176e5182
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and vasodilation activity of some novel bis(3-pyridinecarbonitrile)
derivatives
Flora F. Barsoum
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles) 4aem were prepared via reaction of bis
(2-propen-1-ones) 3aeg with malononitrile in the appropriate alcohol in the presence of KOH. The
reaction was assumed to take place via Michael addition followed by cyclization due to the alkoxide
nucleophilic attack at one of the nitrile groups. This assumption was substantiated by the reaction
of ylidenemalononitrile 5 with the corresponding acetophenone 2 in the appropriate alcohol in the
presence of KOH. The starting bis(2-propen-1-ones) 3e and f were prepared stereoselectively as
E,E0-geometric isomer via condensation of bisbenzaldehyde 1 with substituted acetophenones 2e and f in
ethanolic KOH solution. Vasodilating activity screening of the synthesized compounds 4aeg and 4iem
utilizing isolated rat’s thoracic aorta pre-contracted by norepinephrine hydrochloride exhibited that
many of the tested compounds reveal considerable vasodilating properties, especially 4e and f which
reveal remarkable activities.
Received 9 April 2010
Received in revised form
3 August 2010
Accepted 10 August 2010
Available online 18 August 2010
Keywords:
Bis(2-propen-1-ones)
Bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles)
Michael reaction
Vasodilation activity
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
Several nicotinate esters (3-pyridinecarboxylate esters) have been
shown to possess cardiovascular properties, for example, micini-
Research in the field of hypertension has continued to grow in
recent years because hypertension is a major cardiovascular disease
resulting in high mortality and morbidity in today’s world [1,2].
Hypertension is a rise in blood pressure of unknown cause that
increases risk for cerebral, cardiac and renal events [3e5]. Consis-
tent control of blood pressure is of crucial importance and should
be achieved throughout the 24 h dosing interval where, uncon-
trolled hypertension is associated with acute end-organ damage [6]
as congestive heart failure [7] or renal failure as in type 2 diabetes
patients [8]. Drugs currently used for hypertension include
diuretics [9]; drugs that prevent the action of peripheral sympa-
thetic activity as beta-adrenergic [10, 11] and alpha-adrenergic [12]
blocking agents; centrally sympathetic alpha 2-adrenoceptors [13];
angiotensin-converting enzyme inhibitors [14,15]; angiotensin II
receptor blockers [15,16] and calcium channel blockers [17]; in
addition to drugs directly dilating the blood vessels (arterial dila-
tors) [18].
cate, hepronicate, inositol nicotinate that are well known phar-
macologically active drugs as vasodilators [20e22]. With the aim of
obtaining new vasodilator drugs with greater activity and fewer
side effects, in the work described herein, replacing the acid and
ester moieties of 3-pyridinecarboxylate esters by their bioisosteric
cyano moiety, resulted in the design of 3-pyridinecarbonitrile
derivatives and they were investigated in vascular smooth muscle
in an effort to identify new drug candidates with vasodilatory
properties and fewer side effects and a structureeactivity rela-
tionship analysis was also done in order to understand the struc-
tural requirements for optimum activity.
2. Results and discussion
2.1. Chemistry
Reaction of 2,20-[1,2-ethanediylbis(oxy)]bisbenzaldehyde 1 with
substituted acetophenones 2e and 2f in 4% ethanolic potassium
hydroxide solution afforded directly 3,30-[1,2-ethanediylbis(oxy-
2,1-phenylene)]bis[1-aryl-2-propen-1-ones] 3e and 3f in good
yield and their structures were confirmed on the basis of their
elemental and spectral data (Scheme 1). The IR spectra of 3e and 3f
Relaxation of vascular smooth muscle is the basis for the
treatment of hypertension [19]. Several pharmacological drugs
have been synthesized but none of them has had a specific action,
free of side effects. It is important to find new vasodilators with
a potential for clinical use and not associated with adverse effects.
reveal a strong band at
n
¼ 1652e1645 cmꢀ1 region assignable for
the a,b
-unsaturated ketonic residue and the 1H NMR spectra
E-mail address: ffbarsoum@yahoo.com.
confirm that, the isolated products are E,E0-isomeric form structure
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.032

F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
5177
(2)
RCOCH3
R
OHC
EtOH, KOH
O
O
R
O
R
O
CHO
O
(1)
O
(3)
CH2(CN)2, R`OH, KOH
NC
NC
(2)
RCOCH3
CN
CN
R
N
O
O
O
CN
R`OH, KOH
O
N
OR`
OR`
NC
(4)
(5)
2a, 3a; R = Ph
2b, 3b; R = 4-ClC6H4
2c, 3c; R = 4-FC6H4
4a; R = Ph, R` = CH3
4b; R = Ph, R` = CH2CH3
4c; R = 4-ClC6H4, R` = CH3
4d; R = 4-ClC6H4, R` = CH2CH3
4e; R = 4-FC6H4, R` = CH3
4f; R = 4-FC6H4, R` = CH2CH3
4g; R = 4-H3CC6H4, R` = CH3
4h; R = 4-H3CC6H4, R` = CH2CH3
4i; R = 4-H3COC6H4, R` = CH3
4j; R = 4-H3COC6H4, R` = CH2CH3
4k; R = 4-OHC6H4, R` = CH2CH3
4l; R = 2-thienyl, R` = CH3
2d, 3d; R = 4-H3CC6H4
2e, 3e; R = 4-H3COC6H4
2f, 3f; R = 4-OHC6H4
2g, 3g; R = 2-thienyl
4m; R = 2-thienyl, R` = CH2CH3
Scheme 1.
depending on the mutual coupling constant values between the
aortic rings pre-contracted with norepinephrine hydrochloride
[24,25]. From the obtained results (Table 1, Figs.1 and 2), it has been
noticed that several newly prepared compounds exhibit consider-
able vasodilating activity especially 4e and 4f which reveal
remarkable activities with IC50 0.517 and 0.470.
a,
b
-unsaturated olefinic protons “J ¼ 15.6 Hz” [23].
Meanwhile, reaction of 3,30-[1,2-ethanediylbis(oxy-2,1-phe-
nylene)]bis[1-aryl-2-propen-1-ones] 3aeg with malononitrile in
the presence of potassium alkoxide in the corresponding alcohol
afforded directly the bis(3-pyridinecarbonitrile) derivatives
4aem and their structures were deduced by spectroscopic and
elemental analyses data. The IR spectra reveal a band attributed
to the nitrile group and the absence of a band assignable for the
carbonyl group confirming the cyclized form structure. In addi-
tion, 1H NMR spectra display the alkoxide protons confirming
the involvement of either methoxide or ethoxide function that
derives from the corresponding solvent used in the reaction
(Scheme 1).
Structureeactivity relationships based on the observed results
indicated that, the type of aryl group substitution attached to the 6-
position of the pyridine nucleus plays a controlling role in devel-
oping the exhibited pharmacological properties. It has been noticed
that, substitution with an electron-withdrawing group such as
a chlorine or a fluorine atom (4c-f: IC50: 0.470e0.665), seems more
favourable for constructing a vasodilating active agent than the case
of substitution with an electron-donating group such as a methyl,
methoxy or a hydroxyl residue (4g-k: IC50: 0.696e0.970). In addi-
tion, comparing the activity of the compounds bearing the elec-
tron-withdrawing groups 4c-f, it was observed that, the
vasodilating activity increases by increasing the electron-with-
drawing substitution as exhibited in pairs 4e, 4c: IC50 0.517, 0.665
and 4f, 4d: IC50 0.470, 0.622.
On the other hand, it was also observed that the length of
carbon chain attached to the 2-position of the pyridine nucleus is
an effective factor governing the observed pharmacological
properties. The ethyl (2 carbon chain length) function seems the
more enhancing element for developing a vasodilating active
agent than the methyl (1 carbon chain length) residue as
exhibited in pairs 4b vs. 4a; 4d vs. 4c; 4f vs. 4e; 4j vs. 4i and 4m
vs. 4l, respectively. Meanwhile, it was found that adopting
a thienyl function (a bio-isostere of phenyl group) at the 6-posi-
tion of the pyridine heterocycle shows a slight decrease in the
activity as exhibited in pairs 4a, l (IC50 1.053, 1.267) and 4b, m
(IC50 0.862, 0.865).
The reaction was assumed to take place via addition of the active
methylene malononitrile to the
becarbon of 3 with subsequent
cyclization due to nucleophilic attack of the alkoxide at one of the
nitrile groups followed by dehydration and dehydrogenation to
give eventually 4 (Michael addition). On the other hand, the reac-
tion was also assumed to take place via condensation of the active
methylene malononilrile with the ketonic residue of 3 with
subsequent cyclization due to alkoxide attack at one of the nitrile
groups followed by dehydrogenation to give 6 (Knoevenagel
addition). However, both Michael and Knoevenagel addition were
also assumed to take place to give eventually 7 (Scheme 2).
As a conclusion, reaction of 3 with malononitrile in the presence
of potassium alkoxide in the corresponding alcohol afforded 4
rather than the isomeric forms 6 and 7. This phenomenon was
substantiated via independent synthesis of 4 through the reaction
of ylidenemalononitrile 5 with the appropriate acetophenone 2
under the same experimental reaction conditions. In other words,
the reaction obeys Michael addition pathway rather than Knoeve-
nagel condensation route (Scheme 1).
As
a conclusion, it was found that in the bis(3-pyr-
idinecarbonitrile) derivatives 4aem, increasing the electron-with-
drawing substitution of the aryl group attached to the 6-position of
the pyridine nucleus and increasing the number of carbon atoms
from 1 to 2 of the alkyl side chain at position 2 of the pyridine
heterocycle led to an increase in potency, accordingly, compound 4f
has the highest vasodilating activity (IC50: 0.470).
2.2. Vasodilation activity
The vasodilating activity of the 12 representative compounds
4aeg; 4iem, was determined in vitro using isolated thoracic rat

5178
F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
R
O
O
R
O
(3)
O
CH2(CN)2, R`OH, KOH
R
R
R
O
O
R
O
O
NC
CN
O
O
R
CN
R
NC
CN
O
NC
CN
O
O
NC
CN
NC
NC
CN
OR`
OR`
OR`
OH
R
R
OH
R
R
N
O
R
N
O
OH
NC
O
O
CN
N
O
R
O
OR`
N
CN
OR`
N
CN
CN
OR`
N
NC
OR`
OR`
OR`
-H2O
-2H
-H2O
-2H
-2H
R
R
R
R
CN
N
O
R
N
O
R
N
O
O
CN
O
NC
O
CN
OR`
N
OR`
N
OR`
OR`
N
NC
CN
OR`
(7)
OR`
(4)
(6)
Scheme 2.
3. Experimental
3.1. Synthesis of bis-2-propen-1-ones (3e and 3f)
Melting points are uncorrected and recorded on an Electro-
thermal 9100 digital melting point apparatus. IR spectra (KBr) were
recorded on a Bruker Vector 22 and Jasco FT/IR plus 460 spectro-
photometers. 1H NMR spectra were recorded on a Varian MERCURY
300 (300 MHz) spectrometer. The starting compounds 1 [26],
3aed, g [23] and 5 [27] were prepared according to the previously
reported procedures.
A mixture of 1 (5 mmol) and the corresponding acetophenone
2e and f (10 mmol) in ethanolic KOH solution (25 ml, 4%) was
stirred at room temperature (25e30 ꢁC) for the suitable time. The
solid separated was collected, washed with water and crystallized
from a suitable solvent affording the corresponding 3e and 3f.
3.1.1. 3,30-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis[1-(4-
methoxyphenyl)-2-propen-1-one] (3e)
Table 1
Reaction time 48 h, pale yellow crystals from acetic acid, mp
The concentration of compounds necessary to
reduce maximal norepinephrine hydrochloride-
induced contracture by 50% (IC50) in thoracic rat
aorta rings.
168e170 ꢁC, yield 88%. IR: nmax/cmꢀ1 1652 (C]O), 1600, 1568
(C]C). 1H NMR (DMSO-d6):
d 3.71 (s, 6H, 2 OCH3), 4.63 (s, 4H, 2
OCH2), 6.52e7.76 (m, 16H, arom. H), 7.77 (d, 2H, 2 ArCOCH,
J ¼ 15.6 Hz), 8.09 (d, 2H, 2 ArCH]CH, J ¼ 15.6 Hz). 13C NMR
Compound
IC50
(DMSO-d6):
d 55.2 (OCH3), 66.9 (CH2), 111.2, 112.3, 113.6, 120.6,
4a
4b
4c
4d
4e
4f
4g
4i
4j
1.053
0.862
0.665
0.622
0.517
0.470
0.795
0.890
0.696
0.970
1.267
0.865
121.0, 122.9, 130.0, 130.3, 131.6, 138.5 (arom. CH þ 2 olefinic CH),
123.1, 129.5, 157.7, 162.5 (arom. quaternary C), 187.2 (C]O). Anal.
Calcd. for C34H30O6 (534.58): C, 76.39; H, 5.66. Found: C, 76.60;
H, 5.75.
3.1.2. 3,30-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis[1-(4-
hydroxyphenyl)-2-propen-1-one] (3f)
Reaction time 96 h, yellow crystals from N,N-dimethylforma-
mide e water as 4:1 v/v, mp 273e275 ꢁC, yield 85%. IR: nmax/cmꢀ1
3303 (OH), 1645 (C]O), 1601, 1570 (C]C). 1H NMR (DMSO-d6):
4k
4l
4m

F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
5179
Compound 4a
Compound 4b
100
90
80
70
60
50
40
30
20
100
90
80
70
60
50
40
30
20
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
1.1 1.2
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
Concentration (mM)
Concentration (mM)
Compound 4d
Compound 4c
100
90
80
70
60
50
40
30
20
10
100
90
80
70
60
50
40
30
20
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Concentration (mM)
Concentration (mM)
Compound 4e
Compound 4f
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
-10
-20
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Concentration (mM)
Concentration (mM)
Fig. 1. Effect of tested compounds on contracture induced by norepinephrine hydrochloride (NE.HCl) in thoracic rat aortic rings.
d
4.61 (s, 4H, 2 OCH2), 6.52e7.80 (m, 16H, arom. H), 7.82 (d, 2H, 2
at room temperature (25e30 ꢁC) for the appropriate time. The
separated solid was collected, washed with water and crystallized
from a suitable solvent affording 4aej, l and m. In case of 4k, the
clear reaction mixture was neutralized by HCl, the separated solid
was collected, washed with water and crystallized from a suitable
solvent affording 4k.
ArCOCH, J ¼ 15.6 Hz), 8.01 (d, 2H, 2 ArCH]CH, J ¼ 15.6 Hz), 10.25
(s, 2H, 2 OH). 13C NMR (DMSO-d6) “APT”:
d
66.9 (CH2), 109.2, 112.3,
115.1, 120.4, 121.1, 122.8, 130.5, 131.4, 131.6, 138.6 (arom. CH þ 2
olefinic CH), 123.2, 129.1, 157.7, 161.7 (arom. quaternary C), 187.1
(C]O). Anal. Calcd. for C32H26O6 (506.53): C, 75.87; H, 5.17. Found:
C, 75.96; H, 5.23.
3.2.2. Method B
3.2. Synthesis of bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles)
(4aem)
A mixture of 5 (2.5 mmol) and the corresponding acetophenone
2 (5 mmol) in the appropriate alcohol (10 ml) containing KOH
(6 mmol) was stirred at room temperature (25e30 ꢁC) for the
appropriate time. The solid separated was collected, washed with
water and crystallized from a suitable solvent affording the corre-
sponding 4.
3.2.1. Method A
A mixture of 3aeg (2.5 mmol) and malononitrile (5 mmol) was
stirred in the appropriate alcohol (25 ml) containing KOH (6 mmol)

5180
F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
Compound 4i
Compound 4g
100
100
90
80
70
60
50
40
30
20
10
0
90
80
70
60
50
40
30
20
10
0
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0
0
0
0.1
0.1
0.1
0.2
0.2
0.2
0.3
0.3
0.3
0.4
0.5
0.6
0.7
0.7
0.7
0.8
0.8
0.8
0.9
0.9
0.9
1
1
1
Concentration (mM)
Concentration (mM)
Compound 4j
Compound 4k
100
90
80
70
60
50
40
100
90
80
70
60
50
40
30
20
0.4
0.5
0.6
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Concentration (mM)
Concentration (mM)
Compound 4l
Compound 4m
100
90
80
70
60
50
40
100
90
80
70
60
50
40
30
0.4
0.5
0.6
0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
1
1.1 1.2 1.3 1.4 1.5
Concentration (mM)
Concentration (mM)
Fig. 1. (continued)
3.2.3. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-6-
phenyl-3-pyridinecarbonitrile) (4a)
OCH2CH3, J ¼ 6.9 Hz), 7.04e7.96 (m, 20H, 18 arom. H þ 2 pyridine
H-5). 13C NMR (CDCl3):
14.5 (CH3), 63.1 (OCH2CH3), 67.2
d
Reaction time 72 h, yellow crystals from n-butanol, mp
(OCH2CH2), 94.9 (pyridinyl C-3), 112.8 (pyridinyl C-5), 115.6 (C^N),
114.5, 121.2, 127.1, 128.6, 130.0, 130.3, 131.1 (arom. CH), 125.7, 137.4,
154.1, 155.3, 157.4 (arom. quaternary C), 163.9 (pyridinyl C-2). Anal.
Calcd. for C42H34N4O4 (658.72): C, 76.58; H, 5.20; N, 8.51. Found: C,
76.42; H, 5.09; N, 8.43.
227e229 ꢁC, yield 56, 71% (method A and B respectively). IR: nmax
/
cmꢀ1 2224 (C^N), 1602, 1583 (C]N, C]C). 1H NMR (CDCl3):
d 4.14
(s, 6H, 2 OCH3), 4.44 (s, 4H, 2 ArOCH2), 7.01e7.98 (m, 20H, 18 arom.
H þ 2 pyridine H-5). Anal. Calcd. for C40H30N4O4 (630.67): C, 76.17;
H, 4.79; N, 8.88. Found: C, 76.20; H, 4.83; N, 8.83.
3.2.5. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-6-
(4-chlorophenyl)-3-pyridinecarbonitrile) (4c)
3.2.4. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
phenyl-3-pyridinecarbonitrile) (4b)
Reaction time 72 h, pale yellow crystals from ethanol-chloro-
Reaction time 72 h, yellow crystals from n-butanol, mp
form as 1:1 v/v, mp 224e226 ꢁC, yield 40% (method A). IR: nmax
/
198e200 ꢁC, yield 33, 42% (method A and B respectively). IR: nmax
/
cmꢀ1 2225 (C^N), 1585, 1550 (C]N, C]C). 1H NMR (CDCl3):
d 3.98
cmꢀ1 2223 (C^N), 1583, 1549 (C]N, C]C). 1H NMR (CDCl3):
(t, 6H, 2 CH2CH3, J ¼ 7.2 Hz), 4.44 (s, 4H, 2 ArOCH2), 4.62 (q, 4H, 2
d
1.50
(s, 6H, 2 OCH3), 4.44 (s, 4H, 2 ArOCH2), 6.96e7.72 (m, 18H, 16 arom.
H þ 2 pyridine H-5). 13C NMR (CDCl3) “APT”:
d 54.1 (OCH3), 67.1

F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
5181
1.4
1.2
1
0.8
0.6
0.4
0.2
0
4a
4b
4c
4d
4e
4f
4g
4i
4j
4k
4l
4m
Tested compounds
Fig. 2. Potency (IC50, mM) of the tested compounds on contracture induced by norepinephrine hydrochloride in thoracic rat aortic rings.
(OCH2), 95.1 (pyridinyl C-3), 112.4 (pyridinyl C-5), 115.4 (C^N),
114.2, 121.1, 128.0, 128.6, 130.1, 131.4 (arom. CH), 125.0, 135.1, 136.2,
153.9, 155.0, 155.7 (arom. quaternary C), 163.7 (pyridinyl C-2). Anal.
Calcd. for C40H28Cl2N4O4 (699.56): C, 68.67; H, 4.03; N, 8.01. Found:
C, 68.83; H, 4.14; N, 7.87.
1584, 1548 (C]N, C]C). 1H NMR (CDCl3):
d 2.40 (s, 6H, 2 CH3), 4.14
(s, 6H, 2 OCH3), 4.43 (s, 4H, 2 ArOCH2), 7.00e7.88 (m, 18H, 16 arom.
H þ 2 pyridine H-5). 13C NMR (CDCl3) “APT”:
d 21.4 (CH3), 54.2
(OCH3), 67.2 (OCH2), 94.5 (pyridinyl C-3),112.9 (pyridinyl C-5),115.7
(C^N),114.3,121.2,127.1,129.4,130.3,131.1 (arom. CH),125.8, 134.6,
140.4, 154.0, 155.3, 157.5 (arom. quaternary C), 164.2 (pyridinyl C-2).
Anal. Calcd. for C42H34N4O4 (658.72): C, 76.58; H, 5.20; N, 8.51.
Found: C, 76.73; H, 5.37; N, 8.39.
3.2.6. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
(4-chlorophenyl)-3-pyridinecarbonitrile) (4d)
Reaction time 72 h, colourless crystals from benzene, mp
138e140 ꢁC, yield 53% (method A). IR: nmax/cmꢀ1 2224 (C^N), 1586,
3.2.10. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
(4-methylphenyl)-3-pyridinecarbonitrile) (4h)
1546(C]N,C]C).1HNMR(CDCl3):
d
1.48(t,6H,2CH2CH3, J ¼ 7.2 Hz),
4.43 (s, 4H, 2 ArOCH2), 4.52 (q, 4H, 2 OCH2CH3, J ¼ 6.9 Hz), 6.98e7.83
Reaction time 96 h, yellow crystals from n-butanol, mp
(m, 18H, 16 arom. H þ 2 pyridine H-5). 13C NMR (CDCl3):
d 14.4 (CH3),
205e207 ꢁC, yield 44% (method A). IR: nmax/cmꢀ1 2222 (C^N),
63.2 (OCH2CH3), 67.2 (OCH2CH2), 95.2 (pyridinyl C-3),112.8 (pyridinyl
C-5), 115.5 (C^N), 114.2, 121.3, 128.3, 128.8, 130.3, 131.3 (arom. CH),
125.5, 135.7, 136.2, 154.1, 155.2, 156.0 (arom. quaternary C), 163.8
(pyridinyl C-2). Anal. Calcd. for C42H32Cl2N4O4 (727.62): C, 69.32; H,
4.43; N, 7.70. Found: C, 69.54; H, 4.63; N, 7.62.
1584, 1545 (C]N, C]C). 1H NMR (CDCl3):
d 1.50 (t, 6H, 2
CH2CH3, J ¼ 7.2 Hz), 2.40 (s, 6H, 2 ArCH3), 4.43 (s, 4H, 2 ArOCH2),
4.61 (q, 4H, 2 OCH2CH3, J ¼ 6.9 Hz), 7.00e7.87 (m, 18H, 16 arom.
H þ 2 pyridine H-5). 13C NMR (CDCl3) “APT”:
d 14.5 (OCH2CH3), 21.3
(ArCH3), 63.0 (OCH2CH3), 67.2 (OCH2CH2), 94.5 (pyridinyl C-3),112.8
(pyridinyl C-5), 115.7 (C^N), 114.1, 121.2, 127.0, 129.3, 130.3, 131.0
(arom. CH), 125.8, 134.6, 140.3, 153.9, 155.3, 157.4 (arom. quaternary
C), 163.9 (pyridinyl C-2). Anal. Calcd. for C44H38N4O4 (686.77): C,
76.95; H, 5.58; N, 8.16. Found: C, 76.74; H, 5.45; N, 8.33.
3.2.7. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-6-
(4-fluorophenyl)-3-pyridinecarbonitrile) (4e)
Reaction time 72 h, colourless crystals from N,N-dime-
thylformamide, mp 246e249 ꢁC, yield 27% (method A). IR: nmax
/
cmꢀ1 2225 (C^N), 1603, 1583 (C]N, C]C). 1H NMR (DMSO-d6):
4.00 (s, 6H, 2 OCH3), 4.38 (s, 4H, 2 ArOCH2), 7.05e8.05 (m, 18H, 16
3.2.11. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-
6-(4-methoxyphenyl)-3-pyridinecarbonitrile) (4i)
d
arom. H þ 2 pyridine H-5). Anal. Calcd. for C40H28F2N4O4 (666.65):
Reaction time 48 h, yellow crystals from benzene, mp
C, 72.06; H, 4.23; N, 8.40. Found: C, 72.23; H, 4.36; N, 8.61.
234e236 ꢁC, yield 38% (method A). IR: nmax/cmꢀ1 2220 (C^N),
1582, 1549 (C]N, C]C). 1H NMR (CDCl3):
d 3.85 (s, 6H, 2 ArOCH3),
3.2.8. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
(4-fluorophenyl)-3-pyridinecarbonitrile) (4f)
4.08 (s, 6H, 2 pyridine OCH3), 4.43 (s, 4H, 2 ArOCH2), 6.85e7.89 (m,
18H, 16 arom. H þ 2 pyridine H-5). 13C NMR (CDCl3) “APT”:
d 54.1
Reaction time 72 h, colourless crystals from ethanol, mp
(OCH3), 55.3 (OCH3), 67.2 (OCH2), 93.8 (pyridinyl C-3), 112.7 (pyr-
idinyl C-5), 115.9 (C^N), 113.7, 113.9, 121.2, 128.6, 130.3, 131.1 (arom.
CH), 125.8, 129.8, 153.7, 155.3, 157.1, 161.3 (arom. quaternary C),
164.0 (pyridinyl C-2). Anal. Calcd. for C42H34N4O6 (690.72): C,
73.03; H, 4.96; N, 8.11. Found: C, 72.78; H, 4.88; N, 8.23.
183e185 ꢁC, yield 59% (method A). IR: nmax/cmꢀ1 2224 (C^N),
1603, 1583 (C]N, C]C). 1H NMR (CDCl3):
d
1.46 (t, 6H, 2 CH2CH3,
J ¼ 7.2 Hz), 4.44 (s, 4H,
2
ArOCH2), 4.47 (q, 4H, 2
OCH2CH3, J ¼ 7.2 Hz), 6.97e7.85 (m, 18H, 16 arom. H þ 2 pyridine H-
5). Anal. Calcd. for C42H32F2N4O4 (694.71): C, 72.61; H, 4.64; N, 8.07.
Found: C, 72.69; H, 4.75; N, 8.26.
3.2.12. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
(4-methoxyphenyl)-3-pyridinecarbonitrile) (4j)
3.2.9. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-6-
(4-methylphenyl)-3-pyridinecarbonitrile) (4g)
Reaction time 96 h, yellow crystals from n-butanol, mp
210e212 ꢁC, yield 29% (method A). IR: nmax/cmꢀ1 2222 (C^N),1604,
Reaction time 96 h, yellow crystals from acetone, mp
1584 (C]N, C]C). 1H NMR (CDCl3):
d
1.48 (t, 6H, 2 CH2CH3,
228e230 ꢁC, yield 43% (method A). IR: nmax/cmꢀ1 2222 (C^N),
J ¼ 6.9 Hz), 3.85 (s, 6H, 2 ArOCH3), 4.43 (s, 4H, 2 ArOCH2), 4.57

5182
F.F. Barsoum / European Journal of Medicinal Chemistry 45 (2010) 5176e5182
(q, 4H, 2 OCH2CH3, J ¼ 6.9 Hz), 6.86e7.90 (m, 18H, 16 arom. H þ 2
pyridine H-5). 13C NMR (CDCl3) “APT”:
14.5 (CH3), 55.3 (OCH3),
After an equilibrium period of 1 h, the contractile response to
a single concentration of norepinephrine hydrochloride 10ꢀ6 M
was measured before and after exposure to successive addition
of 0.1 ml dimethyl sulfoxide (DMSO) containing the tested
compounds taken from a stock solution (0.01 M/5 ml DMSO).
Control experiments performed in the presence of DMSO alone, at
the same concentrations as those used with the derivatives tested,
demonstrated that the solvent did not affect the contractile
response of isolated aorta. The observed vasodilating activity
screening data are reported (Table 1, Figs. 1 and 2) and the IC50 was
calculated by the best fit line technique.
d
62.7 (OCH2CH3), 67.2 (OCH2CH2), 93.8 (pyridinyl C-3), 112.8 (pyr-
idinyl C-5),115.9 (C^N),113.5,113.9,121.2,128.6,130.4,131.0 (arom.
CH), 125.9, 129.9, 153.7, 155.3, 157.1, 161.3 (arom. quaternary C),
163.8 (pyridinyl C-2). Anal. Calcd. for C44H38N4O6 (718.77): C, 73.52;
H, 5.33; N, 7.80. Found: C, 73.41; H, 5.08; N, 7.97.
3.2.13. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-ethoxy-6-
(4-hydroxyphenyl)-3-pyridinecarbonitrile) (4k)
Reaction time 48 h, yellow crystals from N,N-dimethylforma-
mideewater as 1:1 v/v, mp 252e254 ꢁC, yield 86% (method A). IR:
nmax/cmꢀ1 3392 (OH), 2224 (C^N), 1584, 1546 (C]N, C]C). 1H
Acknowledgements
NMR (DMSO-d6):
d
1.38 (t, 6H, 2 CH2CH3, J ¼ 7.5 Hz), 4.36 (s, 4H, 2
ArOCH2), 4.52 (q, 4H, 2 OCH2CH3, J ¼ 7.5 Hz), 6.78e7.90 (m, 20H, 16
arom. H þ 2 pyridine H-5 þ 2 OH). Anal. Calcd. for C42H34N4O6
(690.72): C, 73.03; H, 4.96; N, 8.11. Found: C, 73.22; H, 4.82; N, 7.95.
Thanks are due to Department of Pharmacology, National
Research Centre, Dokki, Cairo, Egypt, for allowing the performance
of pharmacological screening and for their kind interest and valu-
able discussions.
3.2.14. 4,40-[1,2-Ethanediylbis(oxy-2,1-phenylene)]bis(2-methoxy-
6-(2-thienyl)-3-pyridinecarbonitrile) (4l)
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