6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone -An important chemical moiety for development of cardioactive agents: A review

Abstract

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone moiety is a vital structural part of many cardio-active pyridazinone derivatives which are either in clinical use or have been tested in clinical trials. These include imazodan, CI-930, pimobendan, indolidan, levosimendan, SK&F-93741, Y-590, meribendan, NSP-804, NSP-805, bemoradan, senazodan, amipizone, prinoxodan, SKF 95654, siguazodan and KF 15232. This article briefly reviews relevant literature on various reports on the synthesis and use of this moiety for development of cardio-active agents.

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Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1579
Tropical Journal of Pharmaceutical Research July 2016; 15 (7): 1579-1590
ISSN: 1596-5996 (print); 1596-9827 (electronic)
© Pharmacotherapy Group, Faculty of Pharmacy, Uni versity of Benin, Benin City, 300001 Nigeria.
All rights reserved.
Available online at http://www.tjpr.org
http://dx.doi.org/10.4314/tjpr.v15i7.30
Review Article
6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone - An
important chemical moiety for development of cardioactive
agents: A review
Mohd Imran* and Abida
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha 91911, PO Box 840,
Kingdom of Saudi Arabia
*For correspondence: Email: imran_inderlok@yahoo.co.in; Tel: +966535129629
Received: 4 July 2015 Revised accepted: 16 April 2016
Abstract
6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone moiety is a vital structural part of many cardio-active
pyridazinone derivatives which are either in clinical use or have been tested in clinical trials. These
include imazodan, CI-930, pimobendan, indolidan, levosimendan, SK&F-93741, Y-590, meribendan,
NSP-804, NSP-805, bemoradan, senazodan, amipizone, prinoxodan, SKF 95654, siguazodan and KF
15232. This article briefly reviews relevant literature on various reports on the synthesis and use of this
moiety for development of cardio-active agents.
Keywords: 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, Cardio-active agents, Imazodan,
Pimobendan, Indolidan, Levosimendan
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INTRODUCTION
Cardiovascular disease is a major public health
problem worldwide, even in the United States of
America, and it accounts for approximately 30 %
of all deaths [1]. Cardiovascular disease has also
been considered to be the major cause of death
in the Kingdom of Saudi Arabia [2]. Due to
increasing prevalence of cardiovascular disease
in children, researchers have recommended the
establishment of well-equipped hospitals to for
the care of children with cardiovascular disease
in developing countries as well as in Kingdom of
Saudi Arabia [3]. Studies have also revealed that
there is a need for more research in the field of
cardiovascular disease in developing countries
because of the likelihood of prevalence of
cardiovascular disease in all age groups in these
countries [4,5].
There are many cardio-active derivatives of 6-(4-
aminophenyl)-4,5-dihydro-3(2H)-pyridazinone
containing 6-(4-aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone moiety (1) as their vital structural
component. These derivatives are either in
clinical use or have been tested in clinical trials.
They include imazodan [6,7]; CI-930 [7,8];
pimobendan [7,9]; indolidan [7,10]; levosimendan
[7,11]; SK&F-93741 [7,12]; Y-590 [7,13];
meribendan [14]; NSP-804 [15]; NSP-805 [15];
bemoradan [16,17]; senazodan [18]; amipizone
[7,17]; prinoxodan [19]; SKF 95654 [20];
siguazodan [21] and KF 15232 [21].
Some reviews on pyridazinone derivatives have
been published [22-25]. However, these reviews
are directed towards the general chemistry and
general biological activities of diverse pyridazine

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1580
derivatives. None of these articles focused on the
use of any specific chemical moiety for the
development of cardio-active agents.
The current review gives an insight on the
potential of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone moiety for the development of
cardio-active agents, and briefly discusses
relevant literature related to the synthesis and
use of this chemical for the preparation of cardio-
active agents. Accordingly, literature references
wherein 6-(4-aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone moiety was not synthesized and/or
not used for the preparation of cardio-active
agents were excluded.
N
N
H
ONH2
1
NN
H
O N
N
Imazodan
NN
H
O N
N
CH3
CI-930
NN
H
O
CH3
NH
N
OCH3
Pimobendan
NN
H
ONH
O
CH3
CH3
Indolidan
NN
H
NH
N
CH3
O
N
N
Levosimendan
NN
H
O NH
CH3
OCH3
SK&F-93741
NN
H
O
CH3
N
CH3
O
Y 590
N
N
H
O
HCH3N
H
N
NH
N
Meribendan
N
H
N
NH
O
CH3
O
NSP 804

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1581
N
H
N
O
NH
O
CH3
CH3
NSP 805
NN
HO
N
H
O
O
CH3
Bemoradan
N
NH
N
H
N
O
Senazodan
NN
H
O NH
OCH3Cl
CH3
Amipizone
N
H
N
NN
H
O
CH3
O
Prinoxodan
N
H
N
NO
CH3
O
SKF 95654
N
NH
OCH3
NNCHN
NH
CH3
Siguazodan
N
N
NHCH2C6H5
N
NH
OCH3
KF 15232
Figure 1: Some pyridazinone derivatives
6-(4-AMINOPHENYL)-4,5-DIHYDRO-3(2H)-
PYRIDAZINONE DERIVATIVES AS
CARDIOACTIVE AGENTS
6-(4-Aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone (1) was first reported in 1967 by
Gerhard and August [26]. Gerhard and August
also reported that this compound is associated
with anti-inflammatory and sustained blood
pressure reducing activities [27].
N
N
H
ONH2
1
Curran and Ross [28] prepared and tested a
series of 6-phenyl-4,5-dihydro-3(2H)-
pyridazinones. They concluded that the potent
and most active hypotensive agents (2) in
normotensive rats were derivatives with
acetamido and cyano groups in the para or meta
position of the benzene ring, combined with 5-
methyl substituent in the hetero ring.
NN
H
O
R3
R2
R1
R1 = NHCOCH3 or CN; R2 = CH3R3 = H
2
Thyes et al [29] prepared 6-Aryl-4,5-dihydro-
3(2H)-pyridazinones which exhibited
aggregation-inhibiting activity on human platelets
in vitro and on rat platelets ex vivo, as well as a
hypotensive action on rats. The strongest
pharmacological effects were found with
dihydropyridazinones that have R =
chloroalkanoyl substituent, together with a methyl
group in the 5-position (3). The hypotensive

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1582
actions of these compounds were 40 times
higher than that of dihydralazine.
NN
H
O
CH3
NH
R
R = chloroalkanoyl substituent
3
These authors further demonstrated that the
para-substituted compounds had a strong
inhibiting effect on collagen-induced and ADP-
induced aggregation of human platelets. It is
known that platelet aggregation plays an
important role in the pathogenesis of
cardiovascular disease [30].
The in vitro human platelet aggregation and the
ex vivo rat platelet aggregation-inhibiting
activities of 6-aryl-4,5-dihydropyridazinones (4)
with R1 = R2 = R4 = Me or H; and R3 = amine
containing, groups were correlated with the van
der Waals volume (Vw) of R3 by Gupta et al [31].
Their results suggested that the size of the
substituent on the aryl group plays an important
role in the inhibition of platelet aggregation in this
series of compounds. Based on the correlating
equations obtained, it was further suggested that
the inhibition of platelet aggregation most likely
involved hydrophobic interaction. A moderate
correlation existed between the hypotensive
activity of these drugs in rats and Vw, indicating
that hypotensive activity also was partly affected
by the size of the substituent on the aryl group.
Although it was assumed that hydrophobic
interactions also played some role in the
hypotensive action, it was argued, based on the
results, that platelet aggregation inhibition and
hypotensive activity involved two different
receptor sites.
NN
O
R2
R4
R1
R3
R1 = R2 = R4 = Me or H; R 3 = amine containing groups
4
A series of 4,5-dihydro-6-[4-(1H-imidazol-1-
yl)phenyl]-3(2H)-pyridazinones and related
compounds were synthesized and evaluated for
positive inotropic activity by Sircar et al [32]. Most
members of this series produced dose-related
increases in myocardial contractility that were
associated with relative minor increase in heart
rate and decrease in systemic arterial blood
pressure. Among the synthesized compounds
(5), the one with R = H (CI-914) and R = Methyl
(CI-930) were more potent than amrinone and
milrinone, respectively. It was also postulated
that the positive inotropic effect of these
compounds was due to the inhibition of cardiac
phosphodiesterase fraction III, rather than the
stimulation of β-adrenergic receptors.
N
N
H
O
NH2
Amrinone
N
N
H
O
CH3
N
Milrinone
NN
H
O
R
N
N
R = H (CI-914); Methyl (CI-930)
5
Okushima et al [33] reported pyridazinone
derivatives with cardiac activity. These
pyridazinones, with R = H and Me; R1 = 4-pyridyl,
2-pyridyl, 2-pyrimidyl and 4-quinolyl, were
evaluated for inotropic activities in vitro and for
cardio-hemodynamic effects in vivo. The
hydrochloride salts of compound (6) with R = H
(MCI-154) or Me and R1 = 4-pyridyl showed
extremely potent positive inotropic and
vasodilating activities, and good ED50 relative to
amrinone.
NN
H
O
R
NH
R1
R = H (MCI-154) or Me; R 1= 4-pyridyl
6
Sircar et al investigated the structure-activity
relationships of a series of 4,5-dihydro-6-[4-(1H-
imidazol-1-yl)phenyl]-3-(2H)-pyridazinones (7)
with R = H, Me, CH2Ph, CH2CH2OH,

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1583
CH2CH2OAc; R1 = H, Me, NH2, CONH2; and R2 =
H, Me, Et; R3 = H, Me, SH, SMe, SOMe, Et, for
their in vivo inhibition of different forms of cyclic
nucleotide phosphodiesterase (PDE) isolated
from guinea pig ventricular muscle [34]. With few
exceptions, these 4,5-dihydropyridazinones were
potent inhibitors of cardiac type III
phosphodiesterase. The most selective PDE III
inhibitor was CI-930 (R = R1 = R3 = H, R2 = Me)
with an ED50 of 0.6 µM.
NN
O
R2
N
R
R1
N
R3
7
Slater et al [35] reported the design and
synthesis of a series of combined vasodilator-β-
adrenoceptor antagonists based on 6-
arylpyridazinones, and evaluated them as
vasodilator-β-adrenoceptor antagonists and
potential antihypertensive agents. Many of the
synthesized compounds showed high level of
intrinsic sympathomimetic activities (ISA) and
relatively short durations of action. Di-substitution
in the 2,3-positions or in the 4-position of the
aryloxy ring produced compounds with low ISA
levels and, in some cases, improved duration of
action. The 5-methylpyridazinone derivatives
displayed more antihypertensive activity than
their 5-H homologs. The compound, SK&F
95018, was selected for further development.
O
O NH
OH
NH
O
N
N
H
CH3
O
SK&F 95018
Benzodioxane pyridazinones (8) and
benzodioxane dihydropyridazinone (9) have
been reported as antihypertensive agents by
Stefano et al [36]. Derivatives with Z = 1,4-di-
substituted piperazine showed good hypotensive
activities, which were related to anti-adrenergic
effects.
O
O
Z
N
N
H
O
8
N
H
N
O
NH
O
O
9
Alfred et al [37] have reported 4,5-dihydro-6-(1H-
indol-5-yl)-pyridazin-3(2H)-ones and related
compounds with positive inotropic activities. Most
of these compounds produced increases in
myocardial contractility with little effects on heart
rate and blood pressure. The cardiotonic effect of
compound (10) was at least 2-fold higher than
that of pimobendan following oral administration.
It has been suggested that, for optimal
cardiotonic activity within this class of indole
derivatives, a heterocyclic aromatic ring in
position 2, a hydrogen or a Me group in position
3 and a dihydropyridazinone ring system in
position 5 of the indole are necessary.
N
NH
N
H
OCH3
N
10
7-substituted-4,4a-dihydro-4a-methyl-5H-
indeno[1,2-c]pyridazin-3[2H]-ones and 8-
substituted-4a-methylbenzo[h]cinnolin-3[2H]-
ones have been synthesized and their PDE III
inhibitory, inotropic and vasodilator potencies
compared with those of their normethyl and their
bicyclic 4,5-dihydro-6-phenylpyridazinone
analogues by Bakewell et al [38]. The study
revealed that the structure-activity relationships
of the tricyclic pyridazinones differ from those of
bicyclic pyridazinones mainly in respect of the
effect produced by introducing a methyl group in
the pyridazinone ring. Introduction of a 5-methyl
group has been widely reported to lead to
compounds of significantly greater potencies in

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1584
the 4,5-dihydro-6-phenylpyridazin-3(2H)-ones.
On the other hand, the tricyclic 4a-
methylpyridazinones showed similar levels of
inotropic, vasodilator and PDE III inhibitory
potencies to their normethyl analogues. In this
series of compounds, the tricyclic 4a-
methylpyridazinones (11) with R = cyano,
CONH2, NH2, NHAc, or OMe, and n = 1,2, ….,
showed good inotropic, vasodilator and PDE III
inhibitory potencies.
(CH2)n
NN
H
R
CH3
O
11
R = cyano, CONH2, NH2
, NHAc, OMe, n = 1,2, ….
Jiang and Sun [39] synthesized 6-(4-substituted
phenyl)-4,5-dihydro-3(2H)-pyridazinones and
demonstrated that compound (12) was a good
inhibitor of platelet aggregation in rats.
Preliminary pharmacological tests of the other
compounds revealed that they inhibited ADP-
induced platelet aggregation.
N
NH
NN
H
O
12
Lee et al [40] have reported potential
antihypertensive properties of 8-methyl
derivatives of 6-(1,4,5,6-tetrahydro-6-
oxopyridazin-3-yl)-1,2,3,4-tetrahydro-1-oxo-β-
carboline. In vitro studies revealed that
compound (13) exhibited particularly potent and
long lasting hypotensive activity. Molecular
modeling also revealed that this compound (13)
met all the stipulations of 5-point model required
for inhibition of cAMP phosphodiesterase activity.
N
H
NH
O
N
NH
O
13
A series of 6-[4-(amino)phenyl]-4,5-
dihydropyridazin-3(2H)-ones (14) derivatives with
R = H, Me; R1
= R2
= alkyl; R1R2
= piperazinyl,
piperidinyl, and related compounds have been
evaluated as inhibitors of cardiac cAMP
phosphodiesterase (cAMP PDE) by Abou-Zeid et
al [41]. However, none of the tested compounds
exhibited considerable inhibitory activity on
cAMP PDE.
N
NH
ONH
O
N
R
R2
R1
14
Abou-Zeid et al [42] have also reported synthesis
of positive inotropic 6-substituted 4,5-
dihydropyridazin-3(2H)-ones, for example
compound (15) with Z = O, S; R = H, OH, Me;
R1 = H, Me; R2 = R3 = H, and alkyl; and a ring
between R2 and R3. An example of these
compounds is compound (16).
N
NH
Z
R1
R
N
O
O
R2
R3
Z = O, S; R = H, OH, Me; R 1 = H, Me; R 2, R 3 = H, alkyl; R 2R3 form a ring
15
N
NH
ON
O
O
16
The synthesis and platelet aggregation-inhibitory
activities of 6-(4-substituted acylamidophenyl)-
4,5-dihydro-3(2H)-pyridazinones and 6-(4-
substituted acylaminophenyl)-4,5-dihydro-3(2H)-
pyridazonones have been described by Liu et al
[43,44]. Preliminary pharmacological tests
revealed that all the synthesized compounds
inhibited appreciable ADP-induced platelet
aggregation activities in rabbits. Liu et al [45]
have further reported synthesis of 6-(4-
substituted acylaminophenyl)-4,5-dihydro-3(2H)-
pyridazinones and their inhibitory actions on
platelet aggregation. These compounds were
synthesized based on structure-activity
relationships of anti-platelet aggregation of
dihydropyridazinones. The synthesized
compounds showed different levels of inhibitory
activities on ADP induced-platelet aggregation.
Synthesis of 6-(4-(substituted amino) phenyl)-
4,5-dihydropyridazin-3(2H)-ones as potential
positive inotropic agents has been described by
Abou-Zeid et al [46]. Some of the synthesized
compounds exhibited good positive inotropic
effects.

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1585
The synthesis and anti-platelet aggregation
activities of 6-(4-substituted acylaminophenyl)-
4,5-dihydro-3(2H)-pyridazinones have been
reported by Liu et al [47]. These compounds
appreciably inhibited ADP-induced platelet
aggregation, with some having more potencies
than the standard compound, CI-930. Zhao et al
[48] have reported synthesis of analogues of
pyridazinones and their inhibition of platelet
aggregation, with evidence of their ADP-induced
platelet-inhibitory activities.
Zhao and Liu [49] have reported synthesis of 6-
substituted acylpiperazinyl phenyl dihydro
pyridazinones and their inhibition of platelet
aggregation. Preliminary in vitro tests showed
that all the compounds were effective against
platelet aggregation induced by ADP.
Synthesis and vasodilator activities of some [(4-
arylidene-2-phenyl-5-oxoimidazolin-1-yl) phenyl]-
4,5-dihydro-3(2H)-pyridazinones and 4-[(4-
arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-
1(2H)-phthalazinones have been reported by
Demirayak et al [50]. The most significant
decrease in blood pressure in vivo occurred with
compound (17).
N
H
N
O
N
N
O
CH3
17
Demirayak et al [51] have also reported some
pyrrole-substituted aryl pyridazinones, for
example compound (18), and demonstrated that
some of them had antihypertensive activities.
N
N
O
CH3
N
OMe
CH3
O
O
CH3
18
6-(4-substituted phenyl)-4,5-dihydro-3(2H)-
pyridazinones have been synthesized prepared
as anti-thrombotic agents by Ren et al [52].
Preliminary in vitro tests revealed that all the
synthesized compounds were active against
platelet aggregation induced by ADP.
Synthesis and cardiovascular activities of 6-(4-
aminophenyl)-2,3,4,5-tetrahydropyridazine-3-one
derivatives have been studied by Dong et al [53].
Although these compounds possessed strong
inotropic activities, they had little effect on the
right atria of the rat in vitro. Wang et al. [54]
synthesized series of 6-phenyl-4,5-dihydro-
3(2H)-pyridazinones and studied their cardiotonic
activities on isolated perfused toad heart, relative
to levosimendan. From the series, compound
(19) exhibited very potent cardiotonic activity.
N
NH
O
CH3
NH
O NO2
Cl
19
Three series of pyridazinones were designed as
vasorelaxant agents using three dimensional
pharmacophore developed with catalyst software
by Khaled et al [55]. Several compounds with
higher fit scores to the developed
pharmacophore were synthesized, for example,
6-(3-ethoxycarbonyl-4-oxo-1,4-dihydroquinolin-6-
yl)-5-substituted-4,5-dihydro-3(2H)-pyridazinones
(20) and 6-[4-(2,6-disubstituted quinolin-4-
ylamino)-2-substituted phenyl]-5-substituted-4,5-
dihydropyridazin-3(2H)-ones (21). The
vasodilator activities of the newly synthesized
compounds were examined on isolated main
pulmonary rabbit arteries. Some of the tested
compounds showed moderate vasorelaxant
activities relative to the standard drug, Milrinone.
N
H
O
EtOOC
N
NH
OR1
20
The anti-platelet aggregation activities of 6-(4-
substituted acetamido phenyl)-4,5-dihydro-3(2H)-
pyridazinones derived from different piperazine
groups have been studied by Xu et al [56]. All the
synthesized compounds had potent anti-platelet
aggregation activities. It was also found that anti-
aggregation activity was influenced by the carbon
chain length of the 4-substituted piperazine

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1586
N
R4
R3
NH
N
NH
OR1
R2
21
group. Sun et al [57] synthesized and
demonstrated anti-platelet aggregative activities
of 6-(4-substituted acetamidophenyl)-4,5-
dihydro-3(2H)-pyridazinones bearing different
heterocyclic groups. However stereospecific
blockage and hydrophilicity of different
heterocylic groups had impacts on the anti-
platelet aggregative activities of these
compounds.
Wang et al [21] has designed, synthesized and
studied the structure-activity relationships of 6-
phenyl-4,5-dihydro-3(2H)-pyridazinone deriva-
tives with respect to their cardiotonic properties.
Among these compounds, 2,3-dichloro-N-(4-(4-
methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-
yl)phenyl) benzamide (22), 4-amino-3-methyl-N-
(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-
yl)phenyl) benzamide (23), 3-methyl-4-nitro-N-(4-
(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)
benzamide (24) and 4-amino-3-methyl-N-(4-(6-
oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl)
benzamide (25) exhibited cardiotonic activities
which were comparable to that of levosimendan.
Cai et al [58] reported anti-platelet aggregation
activities of N-[4-(1, 4, 5, 6-tetrahydro-6-oxo-3-
pyridazinyl) phenyl] acetamides. The in vitro
activities of several of the derivatives were higher
than that of MCI-154 [4,5-dihydro-6-[4-(4-
pyridinylamino) phenyl]-3(2H)-pyridazinone
hydrochloride]. It was also found that
stereospecific blocking and hydrophilicity of
different secondary amino groups in the target
compounds affected their anti-platelet
aggregation activities.
Chai et al [59] have reported synthesis and
potent anti-platelet aggregation activities of 6-[4-
(substituted aminoacetamidophenyl)]-4,5-
dihydro-3(2H)-pyridazinones. It was also
observed that the anti-platelet aggregation
activities of the compounds were enhanced by
introduction of different substituted amino groups
enhanced. Thota et al [60] synthesized and
reported significant anti-platelet aggregation
N
N H
O
CH 3
NH
O C l
C l
22
N
N H
O
CH 3
NH
O
C H 3
N H 2
23
N
N H
O
NH
O
C H 3
NO 2
24
N
N H
O
NH
O
C H 3
N H 2
25

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1587
activities of a series of 6-(4-(substituted amino)
phenyl)-4,5-dihydro-3(2H)-pyridazinones. The
compounds (26) and (27) displayed two times
more platelet aggregation-inhibitory effects than
the standard drug aspirin.
N
NH
NH
O
OH
26
N
NH
NH
O
N
H
27
Amin et al [61] successfully synthesized new 4,5-
3(2H)-pyridazinone derivatives with the general
formula (28), where R = alkyl, alkylamine,
alkanoylamine or alkoxy group; R1 = alkyl, acetyl,
COOEt, CN; and RR1 = five membered
heterocycle. The cardiotonic, hypotensive, and
platelet-aggregation inhibition activities were also
investigated. Results from in vitro studies of their
positive inotropic effects on isolated rabbit heart
revealed that twelve of the compounds exhibited
higher effective responses than digoxin, while
nine compounds were comparable to digoxin in
their responses. However eight of the
compounds were less active than digoxin.
NN
H
ONH
N
COR
R1
28
CONCLUSION
Cardiovascular disease has become the leading
cause of death worldwide and remains the
foremost cause of preventable death globally.
The need for more research in the field of
cardiovascular disease in developing countries is
underscored by the prevalence of cardiovascular
disease in all age group of patients in these
countries. 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone is an important chemical moiety
that is useful for the development of cardio-active
agents. The potential of its derivatives as
cardioactive agents is evident from the literature
as reviewed in this article. It is our belief that the
exploitation of 6-(4-aminophenyl)-4,5-dihydro-
3(2H)-pyridazinone derivatives can produce
more potent cardio-active agents for clinical use
in the treatment of cardiovascular disease.
DECLARATIONS
Acknowledgement
The authors express their deepest appreciation
to the Library Deanship, Northern Border
University, for providing access to its databases
used to carry out literature search for the
preparation of this article.
Conflict of Interest
No conflict of interest associated with this work.
Contribution of Authors
The authors declare that this work was done by
the authors named in this article and all liabilities
pertaining to claims relating to the content of this
article will be borne by them.
REFERENCES
1. Gaetano S. Epidemiology of cardiovascular disease in
the 21st century: Updated numbers and updated facts. J
Cardiovasc Dis 2013; 1(1): 1-2.
2. Al-Sieni AI, Baghdadi MA, Al-Abbasi FA. Country wide
statistical assessment of smoking induced
atherosclerotic and metabolic risk factors in Saudi
population. Asian J Pharm Health Sci 2014; 4(1): 916-
920.
3. Al-Mendalawi MD. Pediatric heart diseases in Madina,
Saudi Arabia. Saudi Med J 2010; 31(8): 943-944.
4. Temilolu OA, Miller M. Cardiovascular disease: A global
problem extending into the developing world. World J
Cardiol 2009; 1(1): 3-10.

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1588
5. Reddy KS. Cardiovascular diseases in the developing
countries: Dimensions, determinants, dynamics and
directions for public health action. Public Health Nutr
2002; 5(1A): 231-237.
6. Steffen RP, Weishaar RE, Evans DB, Kaplan HR.
Imazodan (CI-914). Cardiovasc Drug Rev 1986; 4(1):
81-105.
7. Asif M, Anita S. Synthesis of new derivative of 2-[2-(1H-
indol-1-yl)ethyl]-6-pheny l-4,5-dihydropyridaz in-3(2H)-
one. Ovidius Univ Ann Chem 2011; 22(2): 98-101.
8. Xin-Sheng C, Hua-Wu Z, Yuang-Ying J, Wei-Qin W, Kun
L. Effect of CI-930, a novel phosphodiestrase III
inhibitor, on platelet aggregation and arachidonic acid
metabolism. Acta Pharmacol Sin 1990; 11(4): 338-343.
9. Dobariya TD, Multani PJ. Development and validation of
methods for estimation of pimobendan in
pharmaceutical dosage form. Int J ChemTech Res
2013; 5(5): 2154-2164.
10. Kauffman RF, Utterback BG, Robertson DW. Specific
binding of [3H]LY186126, an analogue of indolidan
(LY195115), to cardiac membranes enriched in
sarcoplasmic reticulum vesicles. Circ Res 1989; 64(5):
1037-1040.
11. Nieminen MS, Fruhwald S, Heunks LMA, Suominen PK,
Gordon AC, Kivikko M, Pollesello P. Levosimendan:
Current data, clinical use and future development. Heart
Lung Vessel 2013; 5(4): 227-245.
12. Kumar D, Carron R, De La Calle D, J indal DP, Bansal R.
Synthesis and evaluation of 2-substituted-6-phenyl-4,5-
dihydropyridazin-3(2H)-ones as potent inodilators. Acta
Pharm 2008; 58: 393-405.
13. Hiroshi M, Tohru N, Kazuhiro G. Y-590 (A new
pyridazinone derivative), a potent anti-thrombotic agent-
I. Effect on platelet function. Thromb Res 1983; 31(4):
599-609.
14. Jonas R, Klockow M, Lues I, Prucher H, Schliep HJ,
Wurziger H. Synthesis and biological activities of
meribendan and related heterocyc lic benzimidazolo-
pyridazinones. Eur J Med Chem 1993; 28(2): 129-140.
15. Mochizuki N, Uchida S, Miyata H. Cardiovascular effects
of NSP-804 and NSP-805, novel cardiotonic agents with
vasodilator properties. J Cardiovasc Pharmacol 1993;
21(6): 983-995.
16. Moore JBJ, Combs DW, Tobia AJ. Bemoradan - a novel
inhibitor of the rolipram insensitive cyclic AMP
phosphodiesterase from canine heart tissue. Biochem
Pharmacol 1991; 42(3): 679-683.
17. Bansal R, Thota S. Pyridazin-3(2H)-ones: The versatile
pharmacophore of medicinal significance. Med Chem
Res 2013; 22: 2539-2552.
18. Warren SE, Kihara Y, Pesaturo J, Gwathmey JK, Phillips
P, Morgan JP. Inotropic and lusitropic effects of MCI-
154 (6-[4-(4-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-
pyridazinone) on human myocardium. J Mol Cell Cardiol
1989; 21(10): 1037-1045.
19. Johan AB, Richard FW, Robert SS, Charles K, William
CF, Henry FC, Mark HP. Pharmacology of RG W-2938:
A cardiotonic agent with vasodilator activity. J
Cardiovasc Pharmacol 1990; 16(4): 537-545.
20. Kenneth JM, Roger JE, John SD, Dav id CG, Catherine
AS, Bella P, Aileen K, Angela W, James AL, William JC.
The effect of SK&F 95654, a novel phosphodiesterase
inhibitor, on cardiovascular, respiratory and platelet
function. Br J Pharmacol 1992; 107: 463-470.
21. Wang T, Dong Y, Wang L, Xiang B, Chen Z, Qu L.
Design, synthesis and structure activity relationship
studies of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone
derivatives as cardiotonic agents. Arzneim Forsch 2008;
58(11): 569-573.
22. Pooja BS. Various biological activities of pyridazinone
ring derivatives. Asian J Chem 2011; 23(5): 1905-1910.
23. Singh TA, Verma P, Anish C . A rev iew on biological
profile of pyridazinone containing drugs. Asian J Res
Chem 2010; 3(2): 265-271.
24. Asif M, Singh A, Siddiqui AA. The effect of pyridazine
compounds on the cardiovascular system. Med Chem
Res 2012; 21: 3336-3346.
25. Khaidem S, Sarveswari S, Gupta R, Vijayakumar V.
Synthesis and biological evaluation of some
pyridazinone derivatives. Int J Res Pharm Chem 2012;
2(2): 258-266.
26. Gerhard B, August A. 6-Aminophenyl- and 6-
acylaminophenyl-4,5-dihydropyridazones-(3). French
Patent Number 1,507,475 1967: 1-2.
27. Gerhard B, August A. 6-Aminophenyl- and 6-
acylaminophenyl-4,5-dihydropyridazones-(3). United
States Patent Number 3,475,431 1969: 1.
28. Curran WV, Ross A. 6-Phenyl-4,5-dihydro-3(2H)-
pyridazinones. A series of hypotensive agents. J Med
Chem 1974; 17(3): 273-281.
29. Thyes M, Lehmann HD, Gries J, Koenig H, Kretzschmar
R, Kunze J, Lebkuecher R, Lenke D. 6-Aryl-4,5-dihydro-
3(2H)-pyridazinones. A new class of compounds with
platelet aggregation inhibiting and hypotensive activities.
J Med Chem 1983; 26(6): 800-807.
30. Stein B, Fuster V, Israel DH, Cohen M, Badimon L,
Badimon JJ, Chesebro JH. Platelet inhibitor agents in
cardiovascular disease: An update. J Am Coll Cardiol
1989; 14(4): 813-836.
31. Gupta SP, S hewade DG, Garg C, Handa A, Prabhakar
YS. A quantitative analysis of dependence of platelet
aggregation inhibition and hypotensive activities of
dihydropyridazinone derivatives on molecular size.
Indian J Biochem Biophys 1985; 22(2): 122-125.
32. Sircar I, Duell BL, Bobowski G, Bristol JA, Evans DB.
Cardiotonic agents. 2. Synthesis and structure activity
relationships of 4,5-dihydro-6-[4-(1H-imidazol-1-
yl)phenyl]-3(2H)-pyridazinones: A new class of positive
inotropic agents. J Med Chem 1985; 28(10): 1405-1413.
33. Okushima H, Narimatsu A, Kobayashi M, Furuya R,
Tsuda K, Kitada Y. A novel class of cardiotonics.
Synthesis and pharmacological properties of [4-
(substituted-amino)phenyl]pyridazinones and related
derivatives. J Med Chem 1987; 30(7): 1157-1161.

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1589
34. Sircar I, Weishaar RE, K obylarz D, Moos WH, Bristol JA.
Cardiotonic agents. 7. Inhibition of separated forms of
cyclic nucleotide phosphodiesterase from guinea pig
cardiac muscle by 4,5-dihydro-6-[4-(1H-imidazol-1-
yl)phenyl]-3(2H)-pyridazinones and related compounds.
Structure activity relationships and correlation with in
vivo positive inotropic activity. J Med Chem 1987;
30(11): 1955-1962.
35. Slater RA, Howson W, Swayne GTG, Taylor EM, Reavill
DR. Design and synthesis of a series of combined
vasodilator-β-adrenoceptor antagonists based on 6-
arylpyridazinones. J Med Chem 1988; 31(2): 345-351.
36. Stefano C, Giovannella S, Codagnone A. Synthes is and
antihypertensive properties of benzodioxane-
pyridazinones and benzodioxane-dihydropyridazinones
synthese und antihypertensive eigenschaften von
benzodioxan-pyridazinonen und benzodioxan-
dihydropyridazinonen. Arch P harm 1989; 322(11): 833-
835.
37. Alfred M, Friebe WG, Mueller-Beckmann B, Kampe W,
Kling L, Wolfgang VS. Nonsteroidal cardiotonics. 3. New
4,5-dihydro-6-(1H-indol-5-yl)-pyridazin-3(2H)-ones and
related compounds with positive inotropic activities. J
Med Chem 1990; 33(10): 2870-2875.
38. Bakewell SJ, Coates WJ, Comer MB, Reeves ML,
Warrington BH. Inotropic, vasodilator and low Km,
cAMP-selective, cGMP-inhibited phosphodiesterase
(PDE III) inhibitory activities of 4a-methyl-4,4a-dihydro-
5H-indeno[1,2-c]pyridazin-3(2H)-ones and 4a-methyl-
4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-ones. Eur J
Med Chem 1990; 25(9): 765-774.
39. Jiang Q, Sun CS. Synthesis and platelet aggregation
inhibitory activity of 6-(4-substitutedphenyl)-4,5-dihydro-
3(2H)-pyridazinones. Yaoxue Xuebao 1990; 25(8): 598-
603.
40. Lee AR, Huang WH, Sun IC, Lee HF. Synthesis of 6-
(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1,2,3,4-
tetrahydro-1-oxo-β-carboline and its 8-methyl derivative
as potential antihypertensive agents. Zhonghua Yaoxue
Zazhi 1993; 45(6): 551-562.
41. Abou-Zeid KAM, Youssef KM, Shaaban MA, El-Telbany
FA, Al-Zanfaly SH. 6-[4-(Substitutedamino)phenyl]-4,5-
dihydropyridazin-3(2H)-ones as cardiotonic agents. Bull
Fac Pharm Cairo Univ 1995; 33: 9-12.
42. Abou-Zeid KAM, Youssef KM, Shaaban MA, El-Telbany
FA, Al-Zanfaly SH. Synthesis and phosphodiesterase
inhibiting activity of some 6-substituted-4,5-
dihydropyridazin-3(2H)-ones. Bull Fac Pharm Cairo Univ
1995; 33: 25-28.
43. Liu C, Zhang G, Zhu W, Miao H, Jin Y. Synthesis and
platelet aggregation inhibitory activity of 6-(4-
substitutedacylamidophenyl)-4,5-dihydro-3-(2H)-
pyridazinones. Zhongguo Yiyao Gongye Zazhi 1998;
29(8): 349-351.
44. Liu C, Zhang Z, Wu Q, Wu Y, Zhang D. Synthesis and
platelet aggregation inhibitory activity of 6-(4-
substitutedacylaminophenyl)-4,5-dihydro-3(2H)-
pyridazonones. Zhongguo Yaowu Huaxue Zazhi 1998;
8(3): 163-168.
45. Liu C, Zhang Z, Lu B, Wu Q, Zhang D. Synthesis of
dihydropyridazinones and their inhibitory action to
platelet aggregation. Zhongguo Yaowu Huaxue Zazhi
1998; 8(4): 254-259.
46. Abou-Zeid KAM, Youssef KM, Shaaban MA, El-Telbany
FA, Al-Zanfaly SH. Synthesis of 6-(4-(substituted
amino)phenyl)-4,5-dihydropyridazin-3(2H)-ones as
potential positive inotropic agents. Egypt J Pharm Sci
1998; 38: 319-331.
47. Liu C, Xue K, Y ao J, Jiang Y, Lu B, Wu Y. Synthesis of 6-
(4'-substitutedacylaminophenyl)-4,5-dihydro-3-(2H)-
pyridazinones and inhibitory activity on platelet
aggregation. Yaoxue Xuebao 1999; 34(1): 23-28.
48. Zhao D, Liu C, Wu Q, Zhang D. Synthesis of analogues
of pyridazinones and their inhibition of platelet
aggregation. Dier Junyi Daxue Xuebao 2002; 23(2):
215-217.
49. Zhao D, Liu C. Synthes is of 6-substituted acylpiperazinyl
phenyl dihydro pyridazinones and their inhibition of
platelet aggregation. Dier Juny i Daxue Xuebao 2003;
24(5): 510-513.
50. Demirayak S, Karaburun AC, Kayagil I, Erol K, Sirmagul
B. Some pyridazinone and phthalazinone derivatives
and their vasodilator activities. Arch Pharm Res 2004;
27(1): 13-18.
51. Demirayak S, Karaburun AC, Beis R. Some pyrrole
substituted ary l pyridazinone and phthalazinone
derivatives and their antihypertens ive activities. Eur J
Med Chem 2004; 39(12): 1089-1095.
52. Ren H, Wu Q, Song B. Synthesis of 6-(4-
substitutedphenyl)-4,5-dihydro-3(2H)-pyridaz inone
analogs and study on their platelet aggregation
inhibitory activity. Huaxi Yaoxue Zazhi 2004; 19(1): 19-
21.
53. Dong Y, Wang L, Jiang Z, Jia X. Synthesis and bioactivity
of 6-(4-aminophenyl)-2,3,4,5-tetrahydropyridazine-3-one
derivatives. Zhongguo Yaowu Huaxue Zazhi 2005;
15(2): 80-84.
54. Wang T, Dong Y, Wang L, Chen Z. Synthes is and
bioactivity of 6-phenyl-4,5-dihydro-3(2H)-pyridazinone
derivatives. Arzneim Forsch 2007; 57(10): 641-646.
55. Khaled A, Maha AK, Omnya K, Yosria M. Pyridazinone
derivatives: Design, synthesis, and in vitro vasorelaxant
activity. Bioorg Med Chem 2008; 16(1): 382-389.
56. Xu Y, Huang X, Xu J, Cai L, Song Y, Zhao Q, Wu Q.
Synthesis and antiplatelet aggregation activity of 4,5-
dihydro-3(2H)-pyridaz inones. Yaoxue Shijian Zazhi
2008; 26(3): 175-177.
57. Sun L, Huang X, Fan S, Yu S, Wu Q. Synthesis and the
antiplatelet aggregative activity of 6-(4-
substitutedacetamidophenyl)-4,5-dihydro-3(2H)-
pyridazinones. Yaoxue Shijian Zazhi 2008; 26(4): 278-
281.
58. Cai L, Xu J, Hu H, Song Y, Sun L, Yu S, Wu Q. Synthesis
and antiplatelet aggregation activities of 6-(4-
substitutedacetamidophenyl)-4,5-dihydro-3(2H)-

Imran & Abida
Trop J Pharm Res, July 2016; 15(7): 1590
pyridazinones. Zhongguo Yaowu Huaxue Zazhi 2007;
17(4): 209-212.
59. Chai X, Zhang C, Hu H, Zhao Q, Dan Z, Zou Y, Yu S, Wu
Q. Synthesis and antiplatelet aggregation activity of 6-
[4-(substitutedaminoacetamidophenyl)]-4,5-dihydro-
3(2H)-pyridazinones. Yaoxue Shijian Zazhi 2008; 26(6):
444-446.
60. Thota S, Bansal R . Synthesis of new pyridazinone
derivatives as platelet Aaggregation inhibitors. Med
Chem Res 2010; 19(8): 808-816.
61. Amin EN, Abdel-Alim AM, Abdel-Moty SG, El-Shorbagi
AA, Abdel-Rahman MS. Synthesis of new 4,5-3(2H)-
pyridazinone derivatives and their cardiotonic,
hypotensive, and platelet aggregation inhibition
activities. Arch Pharm Res 2010; 33(1): 25-46.