A brief review on Triazin-pyridazinones : Synthesis and biological activities

A series of substituted triazin-pyridazine compounds were exhibited diverse types of biological activities and synthesized by different methods. These compounds were mainly tested for their anti-inflammatory, anticancer, antifungal and antibacterial activities. These substituted triazin-pyridazine compounds have mild to potent activities on compare with their appropriate reference standards.


INTRODUCTION
Heterocyclic annelated pyridazines attract considerable attention, which mainly arises from the large variety of interesting pharmacological activities observed with pyridazine derivatives [1][2][3][4][5][6].In recent years, synthesis of novel pyridazinone derivatives and investigation of their chemical and biological behavior have gained more importance due to their biological, medicinal, and agricultural reason.This privileged structure attracts the interest of medicinal chemists as a nucleus of potential therapeutic utility and exhibits several pharmacological activities such as analgesic, anti-inflammatory, antidepressant, antihypertensive, anticonvulsant, cardiotonic, diuretic, anticancer, and anti-HIV activities [7][8][9][10][11][12].In addition, pyridazinones act as core nucleus in various drugs e.g.Sul-mazole, Amipizone, Indolidan, Levosimendan,Imazodan, Pimobendan, Emorfazone, Zardaverine and Milrinone [13][14][15].Triazole and its derivatives are noteworthy for their physiological and biological importance.They paved the attention of medicinal chemist due to their wide range of biological activities like anti-inflammatory, antiviral, antifungal, antibacterial, anticonvulsant and anticancerousetc [16][17][18][19][20]. Triazolopyridazine derivatives are frequently used in biological research [21,22].Anti inflammatory and analgesic activity: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for the treatment and/or management of pain, fever, and inflammation.However, their long term use is linked with gastroenteropathy such as gastric irritation, ulceration, bleeding and renal toxicity that limit their therapeutic usefulness [23].Therefore, the synthesis of new compounds devoid of such side effects poses a challenging task for medicinal chemists.The currently used NSAIDs inhibit the synthesis of non *corresponding author: e-mail: aasif321@gmail.comDOI: http://dx.doi.org/10.5564/mjc.v17i43.743selective or selective cyclooxygenases (COX1 & COX2 or prostaglandin, histamine and bradykinin [24][25][26].It has been suggested that prostaglandins and bradykinins play a major role in the analgesia or pain.So it may be pre dicted that the title compounds may act by inhibiting the synthesis of these chemical mediators involved in causing pain as well as inflammation [27].The pyridazinones having characteristic pharmacological features, relative stability and ease of preparation contemplated us to synthesize some new derivatives of pyridazinones as good analgesic and anti-inflammatory agents.Various substituted pyridazinone derivatives possessing analgesic activity along with other useful pharmacological properties have been reported.Emorfazone (4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone) is a pyridazinone derivative which is currently used clinically in the management of pain and inflammation.Antinociceptive activity of 4-amino-2-methyl-6-phenyl-5-vinyl-3(2H)-pyridazinonewhich was found to be many fold potent than the emorfazone.A series of 2/3-substituted-6(4-methylphenyl)-4,5-dihydro-pyridaz-in3(2H)-ones and Pyridazine substituted Triazine were developed that allow efficient preparation of analogues with varied substitutions on the pyridazinone ring [28].Somepyridazine derivatives were evaluation of their analgesic and anti-inflammatory activities to obtainesafer non-steroidal anti-inflammatory agents (NSAIDs).The aryl propionic acid on reaction with phenyl hydrazine and hydrazine hydrate yielded the pyridazinone derivative,  5).The compounds were tested for their analgesic activity in mice and anti-inflammatory activity in Wistar albino rats.The results of in-vivo anti-inflammatory studies revealed that the compound 3 showed maximum inhibition in paw edema volume followed by compound 2 while the compound 3 exhibited excellent peripheral analgesic activity (74%) followed of the compound 4. Compounds 3 and 4 also showed a good central analgesic effect increased the reaction time to 90 minutes [28].
Compounds, 2 and 3, had smaller paw volume than the positive control and were found to be more potent.All the tested compounds except compound 4 exhibited the maximum reduction in paw volume at 120 min while 4 displayed the maximum protection at 90 min.It could be concluded that the anti-inflammatory activity of the synthesized compounds could be due to the inhibition of inflammatory mediators release and possibly due to the inhibition of COX synthesis similar to indomethacin.It was observed that substitution of 2-phenyl ring at p-position with -CH 2 OH in compound 4 decreases the anti-inflammatory activity.However, the best activity is shown by compound (2) having no substituent at second position of pyridazine ring.Further, replacing an oxo group at third position with a -chloro group does not lead to change in the activity.Compound (3) was found to be the most potent analgesic agent with respect to standard drug.Other compounds also showed moderate to good analgesic activity.The results indicated that pyridazine derivatives possess significant analgesic activity associated with NSAIDs properties.All title compounds exhibited anti-inflammatory activity that lasted for 90 min and the potency increased with time.Among the synthesized pyridazinones, compound 3 emerged as lead compound with good analgesic and anti-inflammatory activities at par with the reference drug.Most of the compounds were exhibited and analgesic effect by both peripheral and central mechanisms.The anti-inflammatory and analgesic potential of 2/3 substituted pyridazine derivatives was confirmed.However, further detailed investigations are needed to establish the safety, efficacy and mechanism of this promising class of heterocyclic compounds [28].The results of antibacterial exhibit that all compounds having comparable activity against the bacterial strain.Compounds 6b, 7b and 8b are the most active derivatives, which shows significant activity against these bacteria comparable to standard drug, ampicillin and chloramphenicol.All the final compounds were evaluated for antifungal activity against Candidaalbicans and Candidaneoformans and compared with standard drug fluconazole.The compounds 7a, 7b and 9b were found to be active derivatives of this series against the microorganism.It is concluded that compounds 6b, 7b and 8b are active against gram positive and gram negative bacteria.Compound 7a, 7b and 9b are potent antifungal drugs [29].products are cytotoxic to the HepA cell line in a dosedependent manner, with IC 50 values of 20.76 μg ml-1 and 9.2 μg ml-1, respectively.It is noteworthy that the cytotoxic effect of these products is weaker than that induced by adriamycin (IC 50 :1.2μg ml-1).The compound 24 was more cytotoxic than compound 23.Compound 24 exhibited significant cytotoxicity against the Hep cell line [31].
The [1,2,4]triazolo [4,3-b]pyridazine system has attracted great attention, it explore synthetic utility of compound I in the preparation of some other derivatives.In particular, interest in the preparation of the amino acid II [21].Reaction of I with hot 1 M sodium hydroxide solution took place on the ethoxycarbonyl group and at the position 6 of the triazolopyridazine system to give III, which underwent decarboxylation in hot ethanol affording benzamide IV (Scheme 2) [21].
Refluxing of I in diluted hydrochloric acid (1:1) for 4 h gave hydrochloride V.This compound was also prepared via a longer reaction sequence starting from hydrazide VI which was firstly transformed by heating in acetic acid into the chloromethyl substituted triazolopyridazine VII.Substitution of the chloro group with potassium phthalimide in hot N,N-dimethylformamide produced VIII, which hydrolyzed in hot hydrochloric acid to give V (Scheme 3).On the other hand, treatment of I with concentrated hydrochloric acid at room temperature for 15 days yielded acid IX, which similarly as III underwent decarboxylation by heating in ethanol giving benzamide X.The latter was also prepared by oxidative cyclization of hydrazone XI [34].Evidently, strong reaction conditions required for the elimination of the protective groups caused the decarboxylation of IX making impossible the preparation of the acid II (Scheme 4).Stable triazolopyridazine were obtained in reactions of 1 with hydrazine hydrate and ethylene glycol.Reaction with hot 80% hydrazine hydrate proceeded similarly as with sodium hydroxide at two electron deficient carbons, carbon 6 and carbonyl group, giving hydrazide XII, whereas treatment with hot ethylene glycol resulted in the formation of XIII.Both products might be suitable starting compounds for the preparation of some tricyclic systems, the former also for the peptide synthesis (Scheme 5).

CONCLUSION
Pyridazine is an important heterocyclic scaffold for designing medicinal agents with varying biological actions.
The easy functionalization at various ring positions makes them an attractive synthetic building block for designing, synthesis and discovery of new drugs.The incorporation of this versatile biologically accepted pharmacophore in established medicinally active molecules results in wide range of pharmacological effects.Further optimization of the chemical synthesis can possibly lead to more active molecules against fungal infections.Since all twelve compounds showed promising results, studies to establish their in vivo efficacy will be carried in the future.