Rational design, synthesis and 2D-QSAR study of novel vasorelaxant active benzofuran-pyridine hybrids

Article abstract of DOI:10.1016/j.bmcl.2016.03.054

Reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a-c with malononitrile in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol proceeds in a regioselective manner to afford 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-pyridin

Full text of DOI:10.1016/j.bmcl.2016.03.054

Accepted Manuscript
Rational design, synthesis and 2D-QSAR study of novel vasorelaxant active
benzofuran-pyridine hybrids
Aladdin M. Srour, Somaia S. Abd El-Karim, Dalia O. Saleh, Wafaa I. El-Eraky,
Zeinab M. Nofal
PII:
S0960-894X(16)30274-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.054
BMCL 23697
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
4 February 2016
12 March 2016
14 March 2016
Please cite this article as: Srour, A.M., Abd El-Karim, S.S., Saleh, D.O., El-Eraky, W.I., Nofal, Z.M., Rational
design, synthesis and 2D-QSAR study of novel vasorelaxant active benzofuran-pyridine hybrids, Bioorganic &
Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.054
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Rational design, synthesis and 2D-QSAR study of novel vasorelaxant
active benzofuran-pyridine hybrids
a,
a
b
b
Aladdin M. Srour *, Somaia S. Abd El-Karim , Dalia O. Saleh , Wafaa I. El-Eraky ,
a
Zeinab M. Nofal
a
Therapeutical Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt.
Pharmacology Department, National Research Centre, Dokki, Cairo 12622, Egypt.
b
Keywords:
Benzofuran
Pyridinecarbonitrile
Vasodilator
Amiodarone
QSAR
Abstract
Reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a–c with malononitrile in the
presence of sufficient amount of sodium alkoxide in the corresponding alcohol proceeds in
a
regioselective
manner
to
afford
2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-
pyridinecarbonitriles 4–37, which also obtained by treating ylidenemalononitriles 6a–q
with 2-acetylbenzofuran 1 in the presence of sufficient amount of sodium alkoxide in the
corresponding alcohol. The new chemical entities showed significant vasodilation
properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine
hydrochloride standard technique. Compounds 11, 16, 21, 24 and 30 exhibited remarkable
activity compared with amiodarone hydrochloride the reference standard used in the
present study. CODESSA-Pro software was employing to obtain a statistically significant
2
QSAR model describing the bioactivity of the newly synthesized analogs (N = 31, n = 5, R
2
2
2
=
0.846, R cvOO=0.765, R cvMO = 0.778, F = 27.540. s = 0.002).
*
Corresponding author, Tel:+20 2 01229749596, E-mail address: aladdinsrour@gmail.com,
1

Benzofuran scaffold attracted considerable attention due to the profound
1
chemotherapeutic properties as well as its wide spread in nature. Bezofuran-containing
2
3,4
3,4
compounds are reported to possess antihyperglycemic, analgesic, anti-inflammatory,
5
6
7
8
antiparasitic, antimicrobial, antitumor and kinase inhibitory effects. Vasodilation, anti-
arrhythmic and hypotensive effects are the most interesting bioactive properties associated
9
,10
with benzofuran skelton. Amiodarone and its analog KB130015 (Figure 1) are powerful
antiarrhythmic agents used for various types of cardiac dysrhythmias, possesses coronary
and peripheral vasodilator properties. This effect appears to be mainly due to the release of
nitric oxide (NO). Amiodarone dilates preconstricted human hand veins in vivo and acts as
a venodilator through the cyclooxygenase pathway, activation of NO synthase, and
1
1–14
blockade of α adrenergic mechanisms.
A new noniodinated benzofuran derivative
dronedarone (Fig. 1) was approved by food and drug administration (FDA) for treatment of
atrial fibrillation and atrial flutter. Dronedarone differs from amiodarone by a remaining
2
+
relaxant effect refractory to the inhibition of NO synthase pathway probably due to its Ca
antagonist property. Consequently, dronedarone may induce a coronary dilation involving a
2
+
dual mechanism, stimulation of NO synthase pathway and putative Ca channels
1
5,16
inhibition.
Amiodarone and dronedarone are known to induce a variety of side effects
including neurotoxicity, characterized by a set of symptoms such as headache, dizziness,
fatigue, tremor, peripheral sensorimotor neuropathy, proximal muscle weakness and ataxia
1
7– 20
in addition to gastrointestinal side effects such as nausea, vomiting, and diarrhea.
Moreover, It is well documented that, nicotinate esters are one of the most known
2
1,22
vasodilatory active heterocycles.
Many nicotinate analogs are well known as
2
3
vasodilating active agents such as, micinicate, hepronicate and inositol nicotinate. Interest
in developing these scaffolds could be attributed to the fact that, 3-pyridinecarbonitrile is
recognized as bioisosteric forms of nicotinate analog (pyridine-3-carboxylate) where only
2
3
the cyano group replaces the acid/ester function.
Based on the afore-mentioned findings and in an attempt to design new potent vasorelaxant
agents, hybrids of 3-pyridinecarbonitriles and benzofuran function have been synthesized
for their vasodilation properties.
Cardiovascular diseases (CVDs) remain the biggest cause of deaths worldwide.
More than 17.5 million people died from CVDs in 2012 representing 31% of all global
deaths. More than 3 million of these deaths occurred before the age of 60 and could have
2
4,25
26
largely been prevented.
CVDs caused by disorders of the heart and blood vessels.
2

Notably, hypertension is the most common cardiovascular disorders that represent
2
7
the major risk factor for endothelial dysfunctions, vasodilators are smooth muscle
2
8–29
relaxant which causes blood vessels to dilate.
They are prominently used to treat
cerebrovascular disease, peripheral arter y disease, rheumatic heart disease, congenital heart
3
0,31
disease, heart failure and hypertension.
Uncontrolled hypertension is associated with
3
2
33
acute end-organ damage as congestive heart failure or renal failure as in type-2 diabetes
3
4
patients. Several direct vasodilators have been synthesized but none of them has
3
5,36
presented a specific action while being free of side effects,
reinforcing the importance
of identifying new clinically safe useful vasodilator agents with higher potency and fewer
side effects. Exploring the controlling factors governing the observed pharmacological
properties of the synthesized hyprids and validation the observed activity will be studied by
quantitative structure activity relationships (QSAR).
N
N
OH
O
I
I
O
O
O
O
O
O
H
I
O
N
I
S
O
O
O
O
Amiodarone
KB130015
Dronedarone
Figure 1 Benzofuran based Vasorelaxant agents.
In this paper, 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a–c were treated with
malononitrile in the presence of sufficient amount of sodium alkoxide in the corresponding
alcohol afforded only one product which structure was assigned to be either 2-alkoxy-4-
aryl-6-(benzofuran-2-yl)-3-pyridinecarbonitriles 4–37 or their isomeric form 2-alkoxy-6-
aryl-4-(benzofuran-2-yl)-3-pyridinecarbonitriles 5, based on the observed spectroscopic
1
13
(
IR, H NMR, C NMR, Mass) and elemental analysis data, 4–37 were formed. On the other
hand, the treatment of ylidenemalononitriles 6a–q with 2-acetylbenzofuran 1 in the
presence of sufficient amount of sodium alkoxide in the corresponding alcohol not only
adds good support for the assumed structures but also confirms that the reaction of 2-
propen-1-ones 3 with malononitrile proceeds in a regioselective manner via Michael
addition (due to active methylene malononitrile attack at the β-carbon of 3 with subsequent
cyclization via nucleophilic attack of the alkoxide at one of the nitrile groups followed by
3

dehydration and dehydrogenation to give eventually 4–37) rather than Knoevenagel
pathway (condensation of malononitrile's active methylene with the ketonic residue of 3
with subsequent cyclization due to alkoxide attack at one of the nitrile groups followed by
2
3
dehydrogenation to give 5). IR spectrum of 4a (as a representative example of the
synthesized analogs) reveals the presence of a strong stretching nitrile vibration band at ν =
−
1
1
2
215 cm while, no assignable band due to carbonyl stretching vibration was detected. H
NMR spectrum of 4 exhibits the characteristic pyridinyl H-5 at δ = 7.64 in addition to the
1
3
methoxide signal at δ = 4.18. C NMR spectrum of 4 reveals the methoxide carbon at δ =
4.79, pyridinyl C-3 and C-5 at δ = 93.77 and 108.23 respectively in addition to nitrile
carbon at δ = 115.59. Mass spectrum (EI) of 4 reveals the molecular ion peak 326.3 with
5
1
13
relative intensity value 100%. The spectral data (IR, H NMR, C NMR, Mass) of all the
other new chemical entities showed similar observations to that of compounds 4–37
confirming their established structures (c.f. Experimental section, Figures 3–136 of
Supplementary data).
O
O
RCHO (2)
KOH, EtOH
O
O
CH3
R
3a-c
1
CH CN)
2
2(
Na, R'OH
R
O
R
N
O
N
O
N
O
R'
R'
4
-37
N
5
Na, R'OH
O
+
RCH=C(CN)2
O
CH3
6a-q
1
2
2
a, 3a; R = Ph
b, 3b; R = 4-ClC
4; R = Ph, R' = Me
5; R = Ph, R' = Et
6
H
4
4

2
c, 3c, R = 4-H
3
COC
6
H
4
6; R = 1-Naphthyl, R' = Me
7
8
; R = 1-Naphthyl, R' = Et
; R = 2-Naphthyl, R' = Me
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a; R = Ph
b; R = 1-Naphthyl
c; R = 2-Naphthyl
9; R = 2-Naphthyl, R' = Et
10; R = 4-ClC
11; R = 4-ClC
6
H
H
4
, R' = Me
, R' = Et
6
4
d; R = 4-ClC
e; R = 2,4-Cl
f; R = 4-BrC
g; R = 4-FC
h; R = 4-H CC
i; R = 4-H COC
j; R = 2,4-(H CO)
k; R = 2,5-(CH O)
l; R = 3,4,5-(CH
m; R= 4-(CH
n; R = 2-Thienyl
6
H
4
12; R = 2,4-Cl
13; R = 2,4-Cl
2
C
C
6
H
H
3
, R' = Me
, R' = Et
2
C
6
H
3
2
6
3
6
H
4
14; R = 4-BrC
51; R = 4-BrC
6
H
H
4
, R' = Me
, R' = Et
6
H
4
6
4
3
6
H
6
4
56; R= 4-FC
5ꢀ; R = 4-FC
6
H
4
, R' = Me
, R' = Et
3
H
4
6
H
4
3
2
C
C
6
H
3
5ꢁ; R = 4- H
5ꢂ; R = 4- H
2ꢃ; R = 4- H
25; R = 4- H
3
CC
CC
COC
COC
6
H
H
4
, R' = Me
, R' = Et
3
2
6
H
3
3
3
3
6
4
3
O)
3
C
6
H
2
6
H
H
4
, R' = Me
, R' = Et
3
)
2
NC
6
H
4
6
4
22; R = 2,4-(H
2ꢄ; R = 2,4-(H
2ꢅ; R = 2,5-(H
21; R = 2,5-(H
3
CO)
CO)
2
C
6
H , R' = Me
3
o; R = 5-Methyl-2-furanyl
p; R = N-Metyl-3-indolyl
q; R = N-Ethyl-3-indolyl
3
2
C
6
H
3
, R' = Et
, R' = Me
, R' = Et
3
CO)
CO)
2
C
C
6
H
H
3
3
2
6
3
2
2
2
2
6; R= 3,4,5-(H
ꢀ; R= 3,4,5-(H
3
CO)
CO)
3
C
C
6
H
H
2
, R' = Me
, R' = Et
3
3
6
2
ꢁ; R = 4-(CH
ꢂ; R = 4-(CH
3
)
)
2
NC
NC
6
H
4
, R' = Me
, R' = Et
3
2
6
H
4
ꢄꢃ; R = 2-Thienyl, R' = Me
ꢄ5; R = 2-Thienyl, R' = Et
3
3
3
3
3
3
2; R = 5-Methyl-2-furanyl, R' = Me
3; R = 5-Methyl-2-furanyl, R' = Et
4; R = N-Methyl-3-indolyl, R' = Me
5; R = N-Methyl-3-indolyl, R' = Et
6; R = N-Ethyl-3-indoly, R' = Me
7; R = N-Ethyl-3-indoly, R' = Et
Scheme 1. Synthetic routes of compounds 4–37.
Vasodilation properties of the synthesized 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-
pyridinecarbonitriles 4–37 were investigated using isolated thoracic aortic rings of rats pre-
contracted with norepinephrine hydrochloride according to the standard reported
3
7
procedure
adrenoceptor antagonist), which was used as a reference standard. The observed data
Table 1), (Figures 1 and 2 of Supplementary data) reveal that, all the synthesized
compounds show significant vasodilation properties. Whilst, compounds 4, 5, 10, 11, 14,
5, 18–21, 24, 26, 28, 30, 31, 32, 34 and 36 exhibit remarkable activity (IC50, concentration
necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture
and compared with amiodarone hydrochloride (highly selective α -
1
(
1
=
0.163–310 mM) compared with amiodarone hydrochloride (IC50 = 0.312 mM). Through
5

the observed vasodilation properties of the synthesized hyprids a general SAR (structure
activity relationship) rule could be attained, the vasodilation activity was enhanced when
the 2-position of 3-pyridinecarbonitriles is occupied by methoxy group rather than the case
when an ethoxy group was adopted, as shown in all of the tested analogs. In order to
understand the observed pharmacological properties and determining the main controlling
factors governing these activities, 2D-QSAR study was initiated.
Table 1
Concentration of compounds necessary to reduce maximal norepinephrine hydrochloride induced contracture
by 50% (IC50) in rat thoracic aortic rings.
Entry Compound
R
Ph
Ph
R'
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Potency (IC50), mM
0.232
0.310
0.359
0.344
0.320
0.423
0.286
0.221
0.322
0.442
0.298
0.227
0.321
0.396
0.266
0.290
0.262
0.204
0.425
0.488
0.246
0.327
0.310
0.365
0.278
0.338
0.163
0.308
0.285
0.417
0.262
0.327
0.299
0.358
0.312
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
1-Naphthyl
1-Naphthyl
2-Naphthyl
2-Naphthyl
4-ClC
4-ClC
2,4-Cl
2,4-Cl
4-BrC
4-BrC
4-FC
4-FC
4-H
4-H
4-H
4-H
2,4-(H
2,4-(H
2,5-(H
2,5-(H
3,4,5-(H
3,4,5-(H
4-(H
4-(H
2-Thienyl
2-Thienyl
5-Methyl-2-furanyl
5-Methyl-2-furanyl
N-Methyl-3-indolyl
N-Methyl-3-indolyl
N-Ethyl-3-indolyl
N-Ethyl-3-indolyl
−
6
H
H
4
6
4
2
C
C
6
H
H
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
2
6
3
6
H
H
4
6
4
6
H
H
4
6
4
3
3
3
3
CC
CC
6
H
H
4
6
4
COC
COC
6
H
H
4
6
4
3
3
3
3
CO)
2
2
2
2
C
C
C
C
6
6
6
6
H
H
H
H
3
3
3
3
CO)
CO)
CO)
3
CO)
CO)
NC
NC
3
C
C
6
H
H
2
3
3
6
2
3
C)
C)
2
6
H
H
4
3
2
6
4
Me
Et
Me
Et
Me
Et
Me
Et
36
37
Amiodarone.HCl
−
6

Molecular descriptors of the 2D-QSAR are the physic-chemical parameters used to
correlate chemical structure and property value expressed as log(IC50) (Figure 2). The
descriptors were obtained based on BMLR (Best Multiple Linear Regression) method. The
descriptors controlling the bio-activity (property) by the established multi-linear QSAR
model are presented in Table 2 and are arranged, based on their level of significance (t-
criterion). The first descriptor controlling the BMLR-QSAR model based on its t-criterion
value (t = 6.578) is minimum e-e repulsion for bond H-C which is a semi-empirical
descriptor. Electron-electron repulsion between two given atoms can be determined by
3
8
equation (1).
E (AB) 
P P  
……………… (1)
ee
   

, A ,B
Where, A stands for a given atomic species, B is another atomic species P, P,isdensity
matrix elements over atomic basis {},   is the electron repulsion integrals on
atomic basis {}. The second descriptor controlling the BMLR-QSAR model (t =
5
.289) is charged surface area (MOPAC PC) for atom C, which is a charge-related
descriptor. The partial positively/negatively charged surface areais determined by equation
3
8
(
2).
PPSA1  S
A

A  0 ………………….. (2)

A
A
Where, S
A
stands for positively/negatively charged solvent-accessible atomic surface area.
The third descriptor controlling BMLR-QSAR model (t = -4.374) is WNSA1 weighted
PNSA (PNSA1*TMSA/1000) (Zefirov PC). Surface weighted charged partial negative
3
8
charged surface area (WNSA1) is determined by equation (3).
PNSA1TMSA
WNSA1 
…
………………… (3)
1000
Where, PNSA1 stands for partial negatively charged molecular surface area, TMSA for total
molecular surface area. The fourth descriptor controlling BMLR-QSAR model (t = -8.078)
ismaximum e-n attraction for bond C-O which is a semi-empirical descriptor. Thenuclear-
38
electron attraction energy between two given atoms is determined by equation (4).
ZB
Ene

AB


P 

 …………………. (4)
 
RiB
B
 , A
Where, A stands for given atomic species, B for another atomic species, P fordensity
matrix elements over atomic basis {}, Z
B
forcharge of atomic nucleus B, RiB fordistance
7

ZB
between the electron and atomic nucleus B,


for electron-nuclear attraction
RiB
integrals on atomic basis {}. The fifth descriptor controlling BMLR-QSAR model (t = -
0.863) is total molecular 1-center E-N attraction which is also a semi-empirical descriptor.
The total molecular one-center electron-nuclear attraction energy is determined by equation
1
3
8
(
5).
…
…………………….. (5)
Where, A stands for given atomic species, Ene(A)for electron-nuclear attraction energy for
atom A
Figure 2. BMLR-QSAR model plot of correlations representing the observed vs. predicted
vasodilatory active agents (compound 19 is an outlier).
Table 2
Descriptor of the BMLR-QSAR model for the vasodilatory active agents.
2
2
2
2
Entry N=31, n=5, R =0.846, R cvOO=0.765, R cvMO=0.778, F=27.540, s =0.002
ID
0
coefficient s
t
Descriptor
1
2
3
16.850
0.166
0.115
2.657
6.341
6.578
5.289
Intercept
D
1
2
0.025
0.022
Min. e-e repulsion for bond H-C
Charged surface area (MOPAC PC)
D
8

for atom C
4
D
3
-0.002
0.0005
0.008
-4.374
-8.078
WNSA1 Weighted PNSA
(
PNSA1*TMSA/1000) (Zefirov PC)
5
6
D
4
5
-0.062
Max. e-n attraction for bond C-O
D
-0.0003
2.64318E-005 -10.863 Tot. molecular 1-center E-N attraction
) + (0.115 x D ) – (0.002 x D ) – (0.062 x D ) – (0.0003 x D
logIC50 = 16.850 + (0.166 x D
1
2
3
4
5
)
The reliability and statistical relevance of the attained BMLR-QSAR model is examined by
internal and external validation procedures. Internal validation is applied by the
CODESSA-Pro (Comprehensive Descriptors for Structural and Statistical Analysis)
technique employing both Leave One Out (LOO), which involves developing a number of
models with one example omitted at a time, and Leave Many Out (LMO), which involves
developing a number of models with many data points omitted at a time (up to 20% of the
total data points). The observed correlations due to the internal validation techniques are
2
2
R
cvOO = 0.765, R cvMO = 0.778. Both of them are significantly correlated with the
2
squared correlation coefficient of the attained QSAR model (R = 0.846). Standard
2
deviation of the regressions (s = 0.002) is also a measurable value for the attained model
together with the Fisher test value (F = 27.540) that reflects the ratio of the variance
explained by the model and the variance due to their errors. A high value of F-test
2
compared with the s is a validation of the model. The predicted/estimated IC50 values of all
the training set compounds according to the attained BMLR-QSAR model are presented in
table 3. From the results obtained it is obvious that, the most potent analogue 30 among all
the synthesized compounds, reveals observed bio-activity comparable to its experimentally
predicted one (IC50 = 0.163, 0.187 mM, respectively, error “difference between observed
and predicted values” = -0.024). The BMLR-QSAR model has controlled the other potent
training set analogues (compounds 4, 11, 15, 21 and 24) relative to amiodarone
hydrochloride (standard reference clinically used as antihypertensive, IC50 = 0.312 mM),
exhibited estimated bio-properties matched with their observed potencies (IC50 = 0.204–
0
.246, 0.217–0.282 mM, corresponding to the observed and predicted values respectively,
error = 0.013–0.036). Compounds 5 and 26 that showed bio-potency similar to the standard
reference (IC50 = 0.310 mM), revealed predicted vasodilatory properties close to their
experimentally observed ones (IC50 = 0.263, 0.306 mM respectively). The other
synthesized compounds (6–9, 12–14, 16–20, 22, 23, 25, 27, 28, 31, 32 and 34–37) with
vasodilatory activities better than the standard reference used (experimentally observed
9

IC50 = 0.262–0.488 mM) showed compatible bio-data (estimated IC50 = 0.238–0.435 mM,
error = 0.003–0.069).
Table 3
Observed and predicated values of the training set compounds 4–9, 11–28, 30–32 and 34–37 according to the
multi-linear QSAR model.
Entry Compd. R
R'
Observed
IC50, mM
0.232
0.31
Predicted
IC50, mM
0.217
0.263
0.404
0.398
0.316
0.381
0.247
0.331
0.390
0.259
0.240
0.335
0.403
0.242
0.359
0.238
0.217
0.403
0.435
0.282
0.322
0.306
0.370
0.286
0.187
0.287
Error
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
4
Ph
Me
Et
0.015
0.047
-0.045
-0.054
0.004
0.042
-0.026
-0.009
0.052
0.039
-0.013
-0.014
-0.007
0.024
-0.069
0.024
-0.013
0.022
0.053
-0.036
0.005
0.004
-0.005
-0.008
-0.024
0.021
5
Ph
6
1-Naphthyl
1-Naphthyl
2-Naphthyl
2-Naphthyl
Me
Et
0.359
0.344
0.32
7
8
Me
Et
9
0.423
0.221
0.322
0.442
0.298
0.227
0.321
0.396
0.266
0.29
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
30
31
4-ClC
6
H
4
Et
2,4-ClC
6
H
3
3
Me
Et
2,4-ClC
6
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
4-BrC
6
6
H
4
4
Me
Et
4-BrC
H
4-FC
6
6
H
4
4
Me
Et
4-FC
H
4-H
4-H
4-H
4-H
3
3
3
3
CC
6
6
H
4
Me
Et
CC
H
4
COC
6
6
H
4
4
Me
Et
0.262
0.204
0.425
0.488
0.246
0.327
0.31
COC
H
2,4-(H
2,4-(H
2,5-(H
2,5-(H
3
3
3
3
CO)
2
2
2
2
C
C
C
C
6
6
6
6
H
H
H
H
3
3
3
3
Me
Et
CO)
CO)
CO)
Me
Et
3,4,5-(H
3
3
CO)
CO)
3
C
6
6
H
2
2
Me
Et
3,4,5-(H
3
C
H
0.365
0.278
0.163
0.308
4-Me
2
NC
6
H
4
Me
Me
Et
2-Thienyl
2-Thienyl
10

2
2
2
3
3
7
8
9
0
1
32
34
35
36
37
5-Methyl-2-furanyl
1-Methyl-3-indolyl
1-Methyl-3-indolyl
1-Ethyl-3-indolyl
1-Ethyl-3-indolyl
Me
Me
Et
0.285
0.262
0.327
0.299
0.358
0.276
0.267
0.324
0.288
0.367
0.009
-0.005
0.003
0.011
-0.009
Me
Et
Compounds 10, 29, and 33 were used as an external test set not only for validating the
attained QSAR model but also for examining its predicative ability. The test set analogues
experimentally exhibited high and low vasodilatory potencies relative to the standard
reference used. The variation in potency can indicate the predication capabilities of the
attained QSAR model. Table 4 summarizes the observed and predicted IC50 values of the
test set compounds. From the observed data, it has been noticed that, compound 10 which
is considered a high potent vasodilatory active agent (experimentally observed IC50 = 0.286
mM), relative to amiodarone hydrochloride, standard reference used, reveals a predicted
IC50 = 0.210 mM with minimum error value = 0.076. Compounds 29, and 33 which
considered low potent analogues relative to the standard reference used (experimentally
observed IC50 = 0.338, 0.417 mM, respectively), reveal predicted IC50 = 0.443, 0.305 mM,
respectively (error values = -0.105, 0.112, respectively). These observations give good sign
for the predictive capability of the attained BMLR-QSAR model and support the previous
statement concerning its predictive power due to the statistical values.
Table 4
Observed and predicated values of the external test set compounds 10, 29 and 33 according to the multi-linear
QSAR model.
Entry Compd. R
R'
Observed
IC50, mM
0.286
Predicted Error
IC50, mM
1
2
3
10
29
33
4-ClC
6
H
4
Me
Et
0.210
0.443
0.305
0.076
-0.105
0.112
4-Me
2
NC
6
H
4
0.338
5-Methyl-2-furanyl Et
0.417
In conclusion, 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-pyridinecarbonitriles 4–37 were
successfully prepared via a regioselective reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-
1
-ones 3a–c with malononitrile which also attained by a facile synthesis of
ylidenemalononitriles 6a–q with 2-acetylbezofuran 1 in the presence of sodium alkoxide in
11

the corresponding alcohol. All the newly synthesized compounds showed significant
vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with
norepinephrine hydrochloride standard technique. Compounds 30, 21, 11, 15 and 24 (IC50
=
0
.163, 0.204, 0.221, 0.227 and 0.246 mM respectively) exhibited remarkable activity
compared with amiodarone hydrochloride (standard reference used IC50 = 0.312 mM).
CODESSA-Pro software was employed to obtain a statistically significant QSAR model
describing the bioactivity of the newly synthesized analogues 4–37, revealed a good
2
2
predictive and statistically significant 5 descriptor model (R = 0.846, R observed = 0.765,
2
R
prediction = 0.778). External validation supported the attained model. From all the above it
could be concluded that, designing new hybrids of benzofuran scaffold incorporating 3-
pyridinecarbonitrile analogs, seems highly promising approach toward developing
vasodilting active hits.
Acknowledgment
This work was supported financially by National research centre, Dokki, Cairo
1
2622, Egypt, (project No. 100-10-116).
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15

Graphical abstract
Some novel bezofuran-pyridinecarbonitrile hyprids as vasorelaxant active agents
R
O
N
O
N
R'
16