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 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.

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.

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.

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 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.

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.

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.

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.

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).

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.

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).

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.

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.

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.

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 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 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.

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.

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.