A comprehensive study on synthesis and biological activities of Pyridazine Derivatives

 

Aamir Malik¹, Rakhi Mishra¹*, Rupa Mazumder¹, Avijit Mazumder¹, Prem Shankar Mishra²

¹Noida Institute of Engineering and Technology (Pharmacy Institute),

Greater Noida-201306, Uttar Pradesh, India.

²Galgotias University, Greater Noida-201306, Uttar Pradesh, India.

 

ABSTRACT:

Pyridazine and its derivative are very important compounds in nitrogen containing heterocyclic compounds due to their various reported pharmacological activities such as antibacterial, muscle relaxant, anti-depressant, antidiabetic, anti-hypertensive, analgesic, anti-tumor, antiviral, nephrotropic, antiinflammatory, anti-viral, anticancer, anti-aggregative, anti-epileptic. It also serves as building block in structure of many chemical constituent of natural compounds phytopharmaceuticals such as cinnolines, phthalazines and also attracting the interest of researchers and medicinal chemist due to its privilege structure which can bear substitution/functionalization easily. Different substituted pyridazine compounds have been synthesized by researchers using different reagents and diverse synthetic route. However most of the investigations available in literature are directed to its large number of biological activities with very less discussion on its various synthetic schemes yielding different type of its derivatives. With the purpose of focusing more on this lack of recent literature this review focuses on different derivative synthesis by using different reaction schemes. Now-a-days pyridazine is serving as ligand in many known chemical reactions and scaffold for drug discovery and development. The aim of this review paper is to encourage more studies on synthesis of pyridazine derivatives which in future will play a vital role for drug discovery.

 

 

 

INTRODUCTION:

Heterocyclic compounds are those which have one or more heteroatoms other than carbon in their structure such as nitrogen, oxygen and sulphur etc¹. They may be of different type like monocyclic, bicyclic, or fused ring bicyclic with carboxylic, amide or any other functional group at different positions². The heterocyclic compounds are vital organic compound due to their chemical, biological, and technical significance in various field of chemistry². Now a days many drug contains heterocyclic ring or combination of different heterocyclic ring as their main structural component⁴. Important biological molecules like DNA and RNA, chlorophyll, hemoglobin, vitamins and many other biological molecules have heterocyclic ring in their structure¹.

 

Heterocyclic compounds are also used as intermediates for many organic Synthesis. Five or six-membered rings heterocyclic compounds such as pyridazine, pyridine, pyrrole, furan, and thiophene are most commonly used in organic synthesis⁵.

 

Pyridazine is six membered nitrogen containing heterocyclic ring⁶. Pyridazine nucleus basically derived by substitution of two nitrogen atoms at 1-2 position on benzene ring. Pyridazine and its derivatives are the important heterocyclic compounds because of their multiple pharmacological activities⁵ and potential use in agricultural and medical chemicals⁷. Pyridazine and its derivatives in various research papers are reported to have wide class of activities like antimicrobial^8,9,10, anti- cancer¹¹, antitubercular¹², antidiabetic¹³, antihypertensive^14,15, anticonvulsant¹⁶, antipyretic¹⁷, insecticidal¹⁸ actions and can also be used as an Intermediates for synthesis of drug, agrochemicals¹⁹. Phthalazine and benzopyridazine in form of cinnoline are examples of pyridazine containing derivatives²⁰. 4-Amino cinnolines became of recent importance due to their antibacterial, antihistamine and insecticidal properties²¹.

 

Pyridazine cont Various position of pyridazine ring can be easily substituted by different functional groups which offers a remarkable feature to pyridazine for synthesis, designing and developing its new derivatives. This easy incorporation of substituents in pyridazine ring further leads to diversity in its pharmacological action²². Pyridazine and its derivatives have a systemic effect on the plants and active at very low concentration. Some of the investigated pyridazine derivatives have chemical structures related to those of the phytohormones²³. Phytochemicals are used as templates for lead optimization programs, which are intended to make safe and effective drugs²⁴.

 

These compounds are also used in treating sleep disorders including insomnia and for inducing sedation, hypnosis, anesthesia, sleep and muscle relaxation⁵. Kekule and chemical structure of pyridazine given in figure 1 and Some examples for marketed drugs containing pyridazine moiety are given in table number 1

 

Figure 1: Kekule structure and chemical structure of pyridazine

 

Table 1: Pyridazine Moiety Containing Marketed Drugs

S.No	Drug Name	Structure	Use
1	Hydralazine (Apresoline)		Antihypertensive
2	Azelastine		Bronchodilator
3	Minaprine		Anti-depressant
4	Pyridate		Herbicide
5	Credazine		Herbicide
6	Pyridafol		Herbicide
7	Cadralazine		Anti-hypertensive

BIOLOGICAL IMPORTANCE OF PYRIDAZINE AND DERIVATIVES:

Different pharmacological activities and synthesis scheme of pyridazine and its derivatives by the use of different substrates and reagants are reported below

 

Anti-Microbial^{25, 26}:

Athar J et al(2018); prepared starting material 3,6-dichlopyridazine (BM2) by reacting 3,6-pyridazine diol with phosphorous oxychloride. BM2 reacts with various anilines to give final compounds which are diphenylpyridazine analogs (AJ11-AJ30). The synthesized pyridazine derivatives (AJ11-AJ30) tested for antimicrobial activity using agar diffusion method 20 against bacterial and fungal stains (S.aureus, M.luteus, E.coli, P. aeruginosa, P. aurantiaca, T. rubrum, C. laurentii). Most of the compounds showed good broad-spectrum activity ranging from 7.8 to 500ug/ml. Compound AJ27 shows greater antimicrobial effect²⁷.

 

Fig 2: Scheme for synthesis of diphenylpyridazine derivatives

 

Mona H et al(2013) synthesized 3-diazo-4,5-diphenylpyrazolo[3,4-c]pyridazine (1) by diazotization of 3-amino-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine with sodium nitrite. Then compounds are treated with thiourea and undergo thiation to form thiouronium derivative which further undergo hydrolysis and acidification to give 3-mercapto-4,5-diphenyl-1H-pyrazolo [3,4-c] pyridazine. The newly synthesized compounds (2, 3, 4a-o) were tested for antimicrobial activity against various gram positive, gram negative and fungal strains by using agar plate diffusion technique. Most of the compounds showed more activity towards gram positive bacteria than gram negative bacteria and moderate activity towards fungal strain²⁸.

 

 

Fig 3: Chemical structure of 3-diazo-4,5-diphenylpyrazolo [3,4] pyridazine derivatives

Nadia G K et al (2015); synthesized different pyridazines by carrying reaction under basic condition and Synthesized pyridazine derivatives 2b-e, 3a-c and 4a-c tested for anti-microbial assay against S. aureus, E fecalis, E coli, K. pneumonia, Aspergillus flavus and C. albicans strains using gar well diffusion method. Compound 3a-c showed strong antibacterial activity, compounds 3a,c highly and 4a,c moderately active against fungal strains²⁹.

 

Fig 4: Chemical structure of pyridazine derivatives

 

S. Hurmath U et al(2016); carried out the synthesis of combination products of pyrazolo pyridazine derivatives (PZ-1 to PZ-6) by reacting various substituted anilines with sodium nitrite in the presence of HCl and water which result in the formation of diazonium salt which further treated with ethyl acetoacetate to give Ethyl 3 –oxo-2-(2-substituted phenyl hydrazinylidene) butanoate. The Ethyl 3 –oxo-2-(2-substituted phenyl hydrazinylidene) butanoate react with Chlorobenzene in the presence of anhydrous Aluminium chloride to give 3-Acetyl Cinnoline-4(1H)-one derivative. To Ethyl 3 –oxo-2-(2- phenylhydrazinylidene) butanoate, hydrazine hydrate/phenyl hydrazine is refluxed to give Pyrazolo benzpyridazine derivatives (PZ-1 to PZ-6). The synthesized pyridazine derivatives (PZ-1 to PZ-6) tested for anti-bacterial and anti-fungal activity and result shows moderate to good anti-bacterial and anti-fungal activity³⁰

 

 

Fig 5: Chemical structure of pyrazolo benzpyridazine derivatives

 

Anti-fungal Activity:

Lingling F et al(2020); Synthesized 3,6-disubstituted imidazo [1,2-b] pyridazine derivatives (4a-v) which later were tested for anti-fungal activity against phytopathogenic fungi Compounds were screened in vitro for their antifungal activities against phytopathogenic fungi (Fusarium solani, Botryosphaeria berengriana f. sp. Piricola, Corn Curvalaria Leaf Spot, Fusarium bulbigenum, Fusarium graminearum, Alternaria alternata, Pyricularia oryzae, Fusarium oxysporum f. sp. Vasinfectum and Alternaria brassicae) by using mycelium linear growth rate method. Compounds 4a, 4c, 4d, 4l and 4r exhibited excellent and broad-spectrum of antifungal activity compared with the two positive control hymexazol and carbendazim. Compounds 4i, 4j, 4k and 4n show similar activities as hymexazol. Compounds 4b, 4e, 4f, 4g and 4h show low antifungal activity³¹.

 

 

Fig 6: Chemical structure of 3,6-disubstituted imidazo[1,2-b] pyridazine derivatives

 

Jian W et al (2009); reported for synthesis of 5-Chloro-6-Phenylpyridazin-3(2H)-one derivatives and tested for antifungal activity. Synthesized pyridazine derivatives 3a-3h, 4, 6a-6i, 7a-7c than tested for fungicidal activities in vitro against G. zeae, F. oxysporum and C. mandshurica. Most of the compounds possessed weak to good antifungal activities, compounds 3e, 3h, 7b, 7c show good antifungal activities³².

 

Fig 7: Chemical structure of 5-Chloro-6-Phenylpyridazin-3(2H)-one derivatives

 

Muscle Relaxant Activity:

Kanruna RP et al (2017); reported for the synthesis of pyridazine derivatives (8a-j) by taking starting material 3,6-dichloro pyridazine (1) which reacts with conc. Ammonia to produce 3-amino-6-chloro- pyridazine. The synthesized compound 8a-j tested for in vivo locomotor activity by using photoactometer and rotarod apparatus. Compounds 8e, 8a, 8f, 8g and 8d shows faster onset of action 93.27%, 90.58%, 70.6%, 64.82% and 46.53% respectively, compounds 8j, 8i, 8h, 8b and 8c shows prolonged depressant action with 80.34%, 74.38%, 71.2%, 65.59% and 63.01%. Compounds 8a-j show good motor coordination 8a, 8e, 8g, 8f, and 8d show rapid onset of falling of motor coordination with 98.28%, 96.44%, 96.11%, 94.72% and 69.29% during ½ h, respectively. Compounds 8j, 8i, 8h, 8b and 8c showed 96.88%, 96.27%, 96.11%, 75.28% and 69% falling of voluntary motor movements in mice during 1 h respectively³³.

 

Fig 8: Chemical structure of pyridazine derivatives

 

Anti convulsant activity:

Mohammad A et al(2016); prepare β-tolol Propionic Acid (1a) and 4-Chloro Benzoyl Propanoic Acid (1b) by reacting appropriate aryl hydrocarbons, AlCl₃ and succinic anhydride .All the synthesized compounds (3a-e), (3f-j) evaluated for anticonvulsant agents against MES-induced convulsion method. Result found that the compounds 3e and 3j exhibited highest Anticonvulsant Activity³⁴.

 

Fig 9: Chemical structure of 4-benzylidene-6-(4-substituted-aryl)-4,5-dihydropyridazin-(2h)-ones derivatives

 

Ramaiah S et al(2003); Synthesized novel 1-Substituted-1,2-dihydro pyridazine-3,6-diones derivatives (4a-l, 5a-j) possessing anticonvulsant activity. The synthesis of Pyridazine-3,6-Dione (1) involve the reaction of maleic anhydride and hydrazine monohydrate in ethanol and acetic acid under reflux and recrystallised with methanol–ether. Compound 1 then treated with epichlorohydrine in the presence of silver chloride, sodium iodide and methanol then recrystallised to give 1-(2^/,3^/-Epoxypropyl)-1,2-dihydropyridazine-3,6-dione (2). Compound 2 and amine refluxed with methanolic potassium hydroxide and filtered which then recrystallized using various solvents resulting in the formation of 1-Substituted-1,2-dihydro-pyridazine-3,6-dione(4a-l). 1-(3^/-Chloropropyl)-1,2-dihydro-pyridazine-3,6-dione (3) prepared by refluxing 1,2-dihydropyridazine-3,6-dione with 1-bromo-3-chloro propane in the presence of silver chloride, sodium iodide and methanol and recrystallization with chloroform–ether. Compound 3 and amine refluxed with methanolic potassium hydroxide then filtered and recrystallized using various solvents resulting in the formation of 1-Substituted-1,2-dihydro-pyridazine-3,6-diones (5a-j). The synthesized compounds(4a-l) and (5a-j) tested in vivo for the anticonvulsant activity. Compounds 4h, 4c and 4d show good anticonvulsant activity against maximal electroshock (MES)-induced convulsions³⁵.

 

Fig 10: Chemical structure of 1-Substituted-1,2-dihydro pyridazine-3,6-diones derivatives

 

Anti-Diabetic activity:

Tata VRK et al; synthesize 6-methoxyimidazo[1,2-b] pyridazine derivatives (7a-l) by taking starting material 3,6-dichloropyridazine (1). Amination of 1 in the presence of ‘a’ produced 6-Chloropyridazin-3-ylamine. The 6-methoxyimidazo[1,2-b]pyridazine derivatives (7a–l) tested for the antidiabetic activity, it is observed that most of the compounds shows anti-diabetic activity. Compounds 7b (69.87%), 7f (69.0%), 7h (68.79%), and 7l (68.61%) showed good hypoglycemic activity when compared to the standard drug insulin (50 mg/kg b.w)³⁶.

 

Fig 11: Chemical structure of 6-methoxyimidazo[1,2-b] pyridazine derivatives

Anti-cancer activity:

Salwa E et al (2017); synthesized pyridazine containing compounds 2a–f, 3a, b, 4a, b, 5a, b, 6a and b, and tested for antitumor activity in vivo against Ehrlich’s ascites carcinoma (EAC) solid tumor grown in mice. The starting material 3,6-dichloropyridazine and sulfaguanidine reacts to give an intermediate 1. Reaction of 1 with different aromatic amines yields compounds 2a–f. Nucleophilic substitution of 1 with either meta or para phenylenediamine yield the compounds 3a and b. By reacting 3a with either acetyl chloride or 3-chloropropionyl chloride form 4a and b respectively. Reaction of 3a and b with different isothiocyanates yield the corresponding compounds 5a, b, 6a and 6b. The synthesized pyridazine derivates tested for antitumor activity in vitro using colon cancer cell line (HCT-116) and breast cancer cell line (MCF-7) applying Sulforhodamine B stain (SRB) colorimetric assay. Compounds 2e, 4b and 5b show greater antitumor activity than by imatinib, compounds 2a, b, e, f, 4a, b, 5b and 6b show comparable activity to that produced by imatinib^37,38,39,40.

 

Fig 12: Scheme for the synthesis of pyridazine containing compounds

 

Anti-Tubercular Activity:

Paidi KR et al(2017); synthesized a series of pyridazine derivatives with different substitutions from 3,6-dichloro pyridazine (1) which on subsequent reactions gave 6-chloropyridazin-3-amine (2). Then compound 2 and chloroacetaldehyde react to yield 6-chloroimidazo [1,2-b] pyridazine (3), which further react with conc. sulphuric acid and fuming nitric acid to give 6-chloro-3-nitroimidazo [1,2-b] pyridazine (4). A solution of 4-hydroxy-3-methoxy benzaldehyde and sodium hydride in tetrahydrofuran prepared which react with compound 4 to give 4-(3-nitroimidazo [1,2-b] pyridazin-6-yloxy)-3-methoxybenzaldehyde (5). Compound 5 react with corresponding hydrazide in ethanol to give compounds (6a-6l)²². The synthesized compounds (6a-6l) have been tested against Mycobacterium tuberculosis H37Rv strain ATCC 27294 using the microplate alamar blue assay, compound 6a was found to be most active against M. tuberculosis strain at MIC of 6.25 µg/mL⁴¹.

 

Fig 13: Scheme for the synthesis of pyridazine derivatives

 

CONCLUSION:

During the past few decades, increased interest in the synthesis and properties of pyridazines has been observed. Its functionalized derivatives shows antibacterial, antitumor, antiviral and antidiabetic activities, anti-inflammatory, antioxidant, antitubercular, antiviral, antidepressant, anticonvulsant, anticancer and other activities^42,43,44. Sometimes The incorporation of two moieties increases biological activity of both and thus it was of value to synthesize some new heterocyclic derivatives having two moiety in the same molecule⁴⁵. Heterocyclic synthesis has emerged as powerful technique for generating new molecules useful for drug discovery. Heterocyclic compounds provide scaffolds on which pharmacophores can arrange to yield potent and selective drugs⁴⁶.

 

Derivatives are obtained by following different reaction scheme⁴⁷ which promotes to study the substituted pyridazine derivatives hoping to get more understanding about pyridazine and its synthesis schemes⁴⁸. The easy substituion at various ring positions of pyridazine makes it an attractive synthetic building blocks for designing and developing its novel compounds⁴⁹. Pyridazine analogues act as useful ligands for different targets and suggested as “privileged structure” for drug discovery⁵⁰.

 

In this current review we have discussed about various pyridazine derivatives which were synthesised by use of different starting material, reagants and synthetic scheme. Also in the review pharmacological evaluation of synthessied pyridazine was reported which shows that pyridazine nucleus shows a wide range of pharmacological activity with easy substitution at various ring positions which in current and future era can attract the interest of medicinal chemist.

 

ACKNOWLEDGEMENT:

The authors are thankful to Dr. Avijit Mazumder (Director Pharmacy Institute, NIET, Greater Noida) and to management of Noida Institute of Engineering and Technology for providing all facilities and sources for collection of this review data.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 12.06.2020           Modified on 03.07.2020

Accepted on 27.07.2020         © RJPT All right reserved