INTRODUCTION:

Pyridazinones are heteroaromatic organic compound which have two nitrogen atoms along with carbonyl group. Pyridazinones have been reported to possess variety of biological activities. Various derivatives incorporating a 3(2H)-pyridazinone ring have been described and their cardiotonic,^1,2antisecretory and antiulcer, ³ as well as analgesic and anti-inflammatory,^4,5activities have been investigated.⁶ after the studies on pyridazinone derivatives it founds that pyridazinone have diverse chemical reactivity and broad spectrum of biological activity.

Although they have been known from long ago to be biologically active, their varied biological features are still of great scientific interest. In recent years, the 6-phenyl-3(2H)-pyridazinone system has aroused a great deal of attention due to its structural relationship to the 5-aryl-2(1H)-pyridones and, in particular, to milrinone and amrinone, the prototypes of a series of non-glycoside, non-catecholamine-based drugs that have mixed ionotropic/vasodilator activity.⁷ 3(2H)-pyridazinone, 2(1H)-pyridones and related compounds also show antiplatelet activity,⁸the inhibition of the cyclic adenosine monophosphate (c-AMP) phosphodiesterase (PDE III in cardiac muscle and platelets) being assumed to be the primary source of these activities. Given below is a brief account of various alterations conducted on pyridazinone ring and their associated biological activities.

Anti-inflammatory activity:

Various derivatives incorporating a 3-(2H)-pyridazinone ring have been described for their anti-inflammatory activity.

Among the various pyridazinone derivatives, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (emorfazone) is currently being marketed in Japan as an analgesic and anti-inflammatory drug.⁹In recent years a number of pyridazinone derivatives have been synthesized and found to display anti-inflammatory activity.

The anti-inflammatory profile of [6-(3,5-dimethyl-4-dhloropyrazole-1-yl)-3(2H)-pyridazinon-2-yl]acetamides (1) were investigated by sukuroglu et al.¹⁰ by using the carrageenan-induced hind paw edema method, the method of kasahara¹¹ was followed. The amide derivatives 1a, 1b, and 1c exhibited (at 100mg/kg) potent anti-inflammatory activity as indometacin. The N-octyl derivative 1c especially showed the highest anti-inflammatory activity comparable to indometacin. The tests of these compounds are indicating that these are exerting their anti-inflammatory activities through the mechanisms that involve the inhibition of chemical mediators such as histamine and serotonin and also presumably the COX isoforms.

Chintakunta et al.¹² prepared some new 3-O-substituted benzyl pyridazinone (2) and (3) derivatives and were found to display significant anti-inflammatory activity. Among the compounds synthesized, three compounds (3a-3b) have shown in vitro Cox-2 selectivity. These compounds have been evaluated for their in vivo potential using carrageenan-induced rat paw edema assay.

N-substituted 4, 6-diaryl-3-pyridazinones (4) were synthesized by Rubat et al.¹³ through a Mannich reaction involving formaldehyde and N-arylpiperazine and alkyl halides. It was investigated that the introduction of arylpiperazinomethyl moiety in the 2-position of the pyridazinone ring resulted in the most potent anti-inflammatory activities. From 19 derivatives 4a and 4b two derivatives which produced a good level of anti-inflammatory activity at 200 mg/kg.

Siddique et al.¹⁴ has synthesized a series of 6-(substituted aryl)-2,3,4,5-tetrahydro-3-thiopyridazinones (5) by using Friedel-Craft’s acylation of appropriate hydrocarbons. the substituents in the phenyl group at 6-position of the thiopyridazinone ring have been found to exert variable effect on the anti-inflammatory activity. Presence of p-isobutyl (5a), p-phenyl (5b), p-phenoxy (5c), p-methoxy (5d) and p-ethoxy (5e) group was found to enhance the said activity.

Matsuda et al.¹⁵ synthesized some novel 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one derivatives (6) as anti-inflammatory agents. These derivatives evaluated for their inhibitory activity against interleukin-1 beta (IL-1β). The observations suggested that a planar substituent at the 2-position of the pyridazinone ring seems to be favorable activity.

Antinociceptive activity:

Arylpyridazinone have been the subjected of intensive synthetic investigations, because they possess a wide spectrum of pharmacological potencies¹⁶. Some 3-(2H)-pyridazinone derivatives endowed with analgesic properties have been reported recently¹⁷. A series of 4-phenyl-6-aryl-2-[3-(arylpiperazin-1-yl)propyl] pyridazin-3-ones (7) related to trazodone (8) have been synthesized and evaluated for analgesic activity. In the phenylquinone-induced writhing test, most compounds have been found several times more potent than acetaminophen and noramidopyridine¹⁸.

Giovannoni et al.¹⁹ prepared a number of [(3-chlorophenyl)piperazinylpropyl] pyridazinones (9) and the corresponding isoxazolopyridazinones (10). They were tested for their analgesic activity. The investigated compounds showed Antinociceptive properties in the mouse hot-plate test (thermal nociceptive stimulus).

Piaz et al.²⁰ synthesized a series of 2-substituted 4,5-functionalized 6-phenyl-3(2H)-pyridazinones (11). The Antinociceptive activities were evaluated in the mouse abdominal constriction model. Single dose studies showed that compound 12a, 12b, 12c were most active. Compounds 11a, 11c caused a reduction in the number of abdominal constrictions of 60 and 79%, respectively and thus both compounds appeared to be more active than Emorfazone at this dose level using this method of assessing Antinociceptive protection.

The compound 4-amino-5-heteocyclic-pyridazinones (12) were synthesized by giovannoni et al.²¹ and tested for their analgesic activity. All the derivatives of 11 were evaluated in the experimental model of the abdominal constriction test in mice in which a painful chemical stimulus was applied. Compounds 12a, 12b, 12c, and 12d were the most potent of the series because they were able to induce a potent antinociceptive effect at a dose of 3 mg/kg po.

Antiplatelet activity:

The need to prevent thrombus formation without impairing haemostasis has spurred extensive research aimed at the development of non-thrombotic haemostatic agents and platelet aggregation inhibitors. The cyclic adenosine monophosphate (c-AMP) phosphodiesterase III (PDE III) has been one of the most studied targets in the search for new Antiplatelet agents. Among the extensive family of PDE III inhibitors, compounds containing the 3(2H)-pyridazinone ring have been widely studied^22-24 and several pyridazinones, such as Zardaverine (13) and Pimobendan (14), have been selected for further clinical assays²⁴.

Sotelo et al.²⁵ prepared a series of 4,5-disubstituted -6-phenyl-3(2H)-pyridazinones (15) which examined for platelet aggregation inhibitory activities on washed human platelets using the turbidimetric method of born and thrombin as inducer of platelet aggregation. Comparison of these results with the Antiplatelet activity of the 5-substituted-6-phenyl-3(2H)-pyridazinones (16a, 16b) shows that the introduction of a substituent at position 4 of these compounds produces an increase in the platelet inhibitory activity; this effect is particularly significant in compounds (15a, 15b, 15c and 15d). A slight increase in activity was observed within the series due to the modification of the alkoxy group in the ester function; the isopropyl derivative 15c is the most active.

Coelho et al.²⁶ have been synthesized some 5-alkylidenepyridazine-3-ones (17) derivatives with four point diversity and all the derivatives were evaluated as platelet aggregation inhibitors. Several derivatives eliciting Antiplatelet activity in the low micromolar range (17a, 17b, 17c, 17d, IC₅₀≡ 1µM) were identified. Structure – activity relationships studies on these compounds revealed the key molecular determinants of this new family of antiplatelet agents: (a) two ester groups in the alkoxy moieties; (b) lipophilic substituents at the N2 position of the pyridazin-3-one. The preliminary results of a pharmacological study aimed at determining the mechanism of action of a set of representative compounds revealed that, unlike other pyridazinones, the documented antiplatelet effect is not a consequence of a PDE-III inhibitory activity.

Cardiotonic activity:

Several noncatecholamine, nonglycoside cardiotonics including milrinone,^27,28 piroximone,²⁹ and isomazole,^30-32are being studied clinically for the chronic management of congestive heart failure. This new class of cardiotonics, which simultaneously displays inotropic and vasodilator activities, incontrovertibly produces salutary hemodynamic effects in patients with severe congestive heart failure following either intravenous or short-term oral administration.³³

Okushima et al.³⁴synthesized a series of [4-(substituted-amino)phenyl]pyridazinones (18) and [4-[(substituted methyl)amino]phenyl]pyridazinones (19) and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Compounds were evaluated in the isolated dog papillary muscle for positive inotropic activities indicated by their ED₁₅’s (doses that increased developed tension by 15%). The compound 18b is particularly potent, the increase in myocardial contractility being detected even at a dose of 1 µg/kg. It could be the most potent among the novel cardiotonics. Oral effectiveness is essential to cardiotonic drugs compound 18a produced a dose-dependent increase in dose-response (dp/dt_max) after oral administration in conscious dogs.

Sircar et al.³⁵ synthesized a novel series of analogues of (E)-4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3(2H)-pyridazinone (20) as a variation on the imazodan (21) series. The hemodynamic responses to compounds were evaluated following intravenous administration in acutely instrumented anesthetized dogs and following oral administration in the conscious dog. The compound 20a produced a substantial increase in myocardial contractility and was twice as potent as imazodan. Addition of methyl group at the 5-position of the 4,5-dihydro-3-(2H)-pyridazinone ring (20b) enhanced the inotropic potency, but the effect was less significant than that in the imazodan and amrinone series. As it suggested earlier,³⁰ hydrophobic and topological effects of the methyl substituent seem to play a major role in altering inotropic potency. Compound 20b was reported to be most potent in this series, demonstrated in vivo antithrombotic activity.

Robertson et al.³⁶ described the synthesis and inotropic activity of a series of 5’-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)spiro [cycloalkane-1,3’-[3H]indol]-2’(1’H)-ones (22). The inotropic activity of these compounds was examines after intravenous administration to open-chested, pentobarbital-anesthetized dogs; a Walton- Brodie strain-gage arch was used to monitor right ventricular contractility. The most potent compound of this series was 22a which had an iv ED₅₀1.5 µg/kg. In the activity it was observed that the spirocyclopentane analogue 22b increased contractility in a dose-dependent fashion, with an ED₅₀ of 133 µg/kg.

Several benzothiazolyl, imidazobenzothiazolyl, benzothienyl, benzothienopyrimidinyl and quinazolinyl 4,5-dihydro-3(2H)-pyridazinones were synthesized and examined for cardiotonic activity in anesthetized dogs after i.v. administration. Nomoto et al.³⁷ were investigated that among them, 4-methylamino-7-(2,3,4,5-tetrahydro-5-methyl-3-oxo-6-pyridazinyl)quinazoline (23) showed potent and long-lasting inotropic activity (relative potency = 2.11, milrinone = 1). The activity of 23 was more potent than indolidan (24) (relative potency = 1.53) which is one of the most potent inotropic agents to date.

Alodose reductase inhibitors:

Increased glucose flux through the sorbitol pathway,³⁸ which is mediated by the enzyme aldose reductase, has been implicated in the pathogenesis of diabetic complication such as neuropathy, nephropathy, retinopathy, and cataracts. The discovery and development of aldose reductase inhibitors as potential therapeutic agents for alleviating these complications. The X-ray structure of aldose reductase complexed with zopolrestat (25), a phthalazineacetic derivative, has been reported.³⁹ The observation that several potent aldose reductase inhibitors (e.g. ponalrestat, zopolrestat, and analogs)⁴¹ contain a pyridazine moiety.

Mylari et al.⁴⁰ described some new aldose reductase inhibitors such are oxopyridazineacetic (26), and oxopyridopyridazine acetic acid (27). Target compounds were tested against aldose reductase from human placenta with NADPH as a cofactor and DL-glyceraldehyde as a substrate. Inhibitors active in this test, at or below 10^‑6 M, were evaluated for their ability to prevent increased accumulation of sorbitol in the sciatic nerve of streptozotocin-induced diabetic rats (acute test). Compound 26a and 27a are the potent aldose reductase inhibitors with IC₅₀ of 2.1 and 5.2 nM respectively.

Castantino et al.⁴¹ have been synthesized and new series of tricyclic pyridazinones and tested in vitro in order to asses (i) their ability to inhibit aldose reductase enzyme and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The most active aldose reductase inhibitors derivatives (28a, b, c, d) (IC₅₀ values ranging from 6.44 to 12.6 µM), comparable to sorbinil (IC₅₀ = 3.04 µM) but less effective than inhibitors like ponalrestat and zopolrestat, which act in the nanomolar range, exhibit a significant selectivity for aldose reductase.

Anticonvulsant activity:

A large number of pyridazinone derivatives evaluated for anticonvulsant activity and found to possess significant activity against various types of seizures. In the search of new anticonvulsant agent having pyridazinone nucleus, Siddiqui et al.⁴² synthesized a lots of 6-(substituted aryl)-2,3,4,5-tetrahydro-3-pyridazinones (29). All this compound found possess significant activity.

Rubat et al.⁴³ synthesized a series of 5-substituted benzylidene-6-methyl-(4H)-pyridazinone (30) derivatives and evaluated for anticonvulsant activity against electrically and chemically induced seizures. In the maximal electroshock-induced seizures test, most of the derivatives showed an anticonvulsant effect better than that of sodium valproate, a commonly used anticonvulsant drug. At 100mg/kg orally, compounds 30a and 30b respectively protected 50 and 60% of the mice against pentylentetrazole-induced seizures.

Miscellaneous:

Betti et al.⁴⁴ have synthesized new alkoxy arylpiperazinyl alkylpyridazinone derivatives (31). The new compounds were tested for their affinity toward α₁- and α₂-AR and toward the 5-HT_1A receptor. α₁-AR affinity data are n the subnanomolar rang, with 31a showing an affinity of 0.052 nM, about 5-fold higher than reference prazosin.

Wermuth et al.⁴⁵ have synthesized 3-amino-6-phenylpyridazine derivatives (32) in their studies. In this study derivatives were evaluated in mice for possible antidepressant, serotoninominetic and dopominomimetic activities. The antagonism of reserpine-induced ptosis was used to screen for antidepressant activity.⁴⁶ the potentiation of 5-hydorxytryptophan (5-HTP) was taken as an index of serotonergic activity.⁴⁷ The decrease of the turning behavior induce by a unilateral striatal 6-hydorxydopamine lesion was considered as predictive of dopaminergic activity.⁴⁸the compound 32a, 32b and 32c exhibited fairly potent dopminomimetic activity as predictive by the turning behavior model. On the other hand the effects of various substituents on the phenyl ring in the 6-position were evaluated. The cyclohexyl 33a and the alpha and beta-thienyl derivatives (33b, 33c) were active as antidepressants and serotoninomimetics, whereas the alpha-naphthyl derivative (33d) was selectively dopaminergic. All these studies were based on the dissociation of the dual activity parent minaprine (34) which is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile.

Livermore et al.⁴⁹ have been prepared a series of substituted imidazo[1,5-b]pyridazines and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells, and the influence of substitution at the 2-, 5-, and 7-positions on biological activity has been investigated. One compound, the imidazole derivative 35, has been discovered to be an exceptionally potent inhibitor (IC₅₀ 0.65 nM). In comparison with other repoted non-nucleoside inhibitors, this compound appears to have the capability to achieve additional enzyme- inhibitor interactions through an imidazole nitrogen atom and the side-chain benzoyl group. Rapid onset of resistance to non-nucleoside RT inhibitors such as 36 and 37 has been demonstrated in vitro ^50,
51 and is associated with a tyrosine 181 to cysteine mutation. The clinical use of these agents has also been accompanied by the rapid emergence of strains of HIV-1 which are much less sensitive to members of this pharmacological class.

CONCLUSIONS:

The reviewed new class of 3(2H)-pyridazinone has shown a wide spectrum of biological activities. The substituted benzothiazolyl, imidazobenzothiazolyl, benzothienyl, benzothienopyrimidinyl and quinazolinyl 4,5-dihydro-3(2H)-pyridazinones are having significant cardiotonic activity. Significant anti-inflammatory is displayed by some new 6-(substituted aryl)-2,3,4,5-tetrahydro-3-thiopyridazinones and [6-(3,5-dimethyl-4-dhloropyrazole-1-yl)-3(2H)-pyridazinon-2-yl]acetamides.

In search of new antiplatelet, Pimobendan and 5-alkylidenepyridazine-3-ones are found have potent activity. Potent antidiabetic activity was shown by a number of oxopyridazineacetic and oxopyridopyridazineacetic, whereas the [(3-chlorophenyl)piperazinylpropyl] pyridazinones and the corresponding isoxazolopyridazinones are found to show the Antinociceptive activity. These new class of pyridazinones have great potential to represent future research for different biological activity.

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Received on 19.01.2010 Modified on 25.02.2010

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