INTRODUCTION:

Pyrazole is an heterocyclic aromatic compound characterised by five membered ring structure mainly composed of carbon and nitrogen. Heterocyclic compound are cyclic organic substance which contain ring system at least one atom other than carbon. Pyrazole is the name given by Ludwig Knorr in 1883. Pyrazole proved to be an interesting class of heterocyclics was described for the first time by Buchnev, who obtained it by decarboxylation of pyrazole 3, 4, 5-tricarboxilic acid in1889.

Synthesis of pyrazole by decarboxylation of pyrazole 3, 4, 5-tricarboxylic acid.:

Pyrazole ring can be represented by different tautomeric structural form as,

Tautomeric structures of the un-substituted pyrazole ring

3-n non-pyrazole and levo-3-(1-pyrazolyl) alanine are naturally occurring pyrazole derivatives.

Naturally occurring pyrazoles

Pyrazole is an five membered aromatic organic compound mainly composed of three carbon atom and two nitrogen atom in a adjacent positions and the unsubstituted parent compound.

Molecular Formula- C₃H₄N₂

Molecular weight- 68.077

Molar refractivity- 18.77 ± 0.3 cm³

Molar volume – 60.9 ± 3.0 cm³

Parachor value- 161.9 ± 3.0 cm³

Index of refraction- 1.528 ± 0.02

Surface tension- 48.6 ± 3.0 dyne/cm

Polarizability- 7.44 ± 0.5 10^-24cm³

Monoisotopic mass- 68.037448

Monoisotopic mass- 68.037448 Da Pyrazole derivatives are the subject of many research studies due to their widespread potential biological activities. Literature survey showed that pyrazole and its derivatives posses various pharmacological activities such as antimicrobial, antifungal, anti-influenza, antiangiogenic, analgesic, anaesthetic, anticancer, antitubercular, antioxidants, anti-inflammatory, insecticidal, herbicidal and hypotensive.

1.1 Antibacterial Activity:

The antibacterial activity of metal complexes was found in the order of Au, Cd and Hg > Cd, Zn > Pt, Pd and Ag> Ni. The average antibacterial action with respect to ligand is found in such pattern 2–(pyrazole -1-yl) pyridine > 1- (o-nitro phenyl) pyrazole, 1-(o- amino phenyl) pyrazole > 2- (3,5 –dimethyl pyrazole , o-(pyrazol–1-yl) benzoic acid ^[5]. Pyrazole ring fused with indole moiety gives highly potent, less toxic and more specific compound, which showed antibacterial activity,

Examples:

a. 1-[(2-methyl-1H-indole-3-yl) carbonyl] -3- substituted phenyl-1-H-pyrzole-4-carbaldhyde derivatives.

b. 3- Methoxybenzo furan and thizolidine-4-one substituted 1, 2, 4-triazole moieties ^[6].

1.2 Antifungal activity:

Most of newly synthesized pyrazole-thiazole compounds mainly showed antibacterial activity and hence used in treatment of Candida albicans ^[1].

Example:

a. 4-(2,4,5,6,7-terahydro-1-methyl-1-pyrazole[3,4,-C]pyridine-3-yl-thiazole-4-yl) benznitrile.

b. 3-(4-(2-fluprophenyl)thiazole-2-yl)4,5,6,7-tetrahyro-1-methyl-1-H-pyrazole[4,3-C] pyridine.

c. 4,5,6,7- tetrahydro-1-mthyl-3-(4-phenylthiazole-2-yl) 1-H-pyrazole [4, 4-C] pyridine.

Figure no. 1

According to WANG Wen-Yan, 1,3,4-thia(oxa) diazole substituted pyrazole derivatives showed antifungal activity against Rhizoctonia solun. Also series of pyrazole-4-carboxilic ester derivatives showed good antifungal activity ^{[2, 3]}.

Example:

a. Ethyl 1,3-dimethyl-5-methylthiol-H-pyrazole-4-carboxylate

b. 1,3,dimethyl-5-methylthio-1H-pyrazole-4-formhydrzide

c. Potassium 3-(1, 3- dimthyl-thio-1H-pyrazole-4- carbonyl) dithio-carbonate

1.3 Apoptotic activity:

E. TOTAN and his co-workers investigated the pro-apoptotic activities of two novel synthetic pyrazole derivatives, used in TH 2g colon cancer cell, which are characterised by point mutation in the P53 gene, which cause lack of functionality of the P53 protein ^[9].

Examples:

a. 5-(p-toluenesulfonyl) pyrazolo (4, 3-F) quinoline (Tospyrquin)

b. 5-chloro-3-(p-toluenesulfonyl) indazol (Tosind)

1.4 Anticonvulsant activity:

A several number of novel 4-(aryl/substituted aryl)-1-(un-substituted/aryl/substituted aryl) 3-phenyl-1-H pyrazoles have been synthesized by the reaction of 1-substitued phenyl-2, 3 dibromo-prop-1-ones and appropriate un-substituted and substituted hydrazines in ethanol. Anticonvulsant activity of all those compounds significantly reduces the electroshock-induced convulsion as compared to phenytoin, replacement of 1-H position pyrazole with phenyl and substituted phenyl increases the anticonvulsant activity ^[10].

Example:

a. 1-substitued phenyl-3-phenyl-prop-2-en -1-ones

b. 1-substitued phenyl-3-phenyl-2-3-dibromo-prop-1-ones

Compounds such as, 3-(4-amino-phenyl)-5-(3-nitrophenyl)-4,5-dihydro-pyrazole-1-carbothioic acid amide showed significant (75%) anticonvulsant activity while 3-(4- amino phenyl)-5-(3-nitro-phenyl 4,5-dihydro-pyrazole-1-carbothionic acid showed milder-intermediate activity ^[11].

1.5 Anti-inflammatory activity-^13-26

FA Yassin investigated anti-inflammatory activity of various pyrazole derivatives and hence they synthesized several newly pyrazolyl-pyridazine derivatives which shows anti-inflammatory action.

Example:

a. Ethyl 5-(3-oxo-5, 6-diphenyl-2, 3-dihydropyridazin-4-yl)-1H-pyrazole-3-carboxylate

b. 5-(3-oxa—5, 6-diphenyl-2-3-dihydropyridazin-4-yl)-1H-pyrazole-3-carbohydrazide

c. 5-(3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-yl)-1H-pyrazole-3-carboxilic acid

d. 5-(3-oxo-5,6-diphenyl-2,3-dihydropridazin-4-yl)-1H-pyrazole-3-carbonyl chloride

Non-steroidal anti-inflammatory drugs containing pyrazole nucleus are commonly used for the treatment of pain and inflammation by counteracting the cyclooxygenase enzyme

1.6 Antimicrobial activity:

Tarik EI- Sayed Ali synthesized some pyrazole derivatives, which showed antimicrobial activity against staphylococcus aureus and streptococcus pyrogens ^[28]. Some pyrazole derivatives showed antibacterial activity against Escherichia coli, Staphylococcus aureus, Corynebacterium diphtheria and Proteus aeruginosa ^[16].

Examples:

a. Bis{diethyl[phenylamino(3-phenyl-1H-pyrazole-4-yl)methyl]phosphonate}phosphine oxide

b. Bis{4-[2-ethoxy-2-oxido-5-phenyl-2,3-dihydro-1,2-oxaphosphol-3-yl]-3-phenyl-1Hpyrazole-1-yl} phosphine oxide

c. Bis{3-(4-biphenyl)-4-[2-ethoxy-6-phenylamino-2-oxido-3,4-dihydro-2h-1,4,5,2 thiadiazophosphine-3-yl]-1H-pyrazole-11yl} phosphine oxide

1.7 Anticancer activity:

Anticancer activity mainly carried out on the cancer cell lines namely HT-29 (colon cancer), A431 (skin cancer), MCF-7 (Breast cancer). The inhibition of the growth of the cell lines i.e., cytotoxicity was considered as anticancer activity. PG Baraldi et al investigated anticancer activity of T allimustine, Cinnamyl mustard derivatives ^[6].

Example:

1.8 Antioxidant activity:

In order to neutralize the threat of free radicals to the tissues and cells, body enzymes take participating mainly includes Glutathione Peroxidase (GSH), Superoxide Dismutase (SOD) and Catalase. Antioxidants may intervene with these free radicals at different levels in the oxidative process. Siddhartha Tarun et al studied on antioxidant activity of some pyrazole-4-carboxaldehyde derivatives by DPPH and FRAP assay ^[27].

The compound, 3-(4- hydroxyl-phenyl) -1- phenyl-1-H- pyrazole-4-carbaldehyde was found to be higher potent for radical scavenging, may be due to the presence of electron releasing hydroxyl group. Other compounds also showed antioxidant activities such as,

a. 3-(3,4-dichlorophenyl)- 1-phenyl-1H-pyrazole-4-carbaldehyde

b. 3-(4-chlorophenyl—1-phenyl-1H-pyrazole-4-carbaldehyde

c. 3-(4-bromophenyl)—phenyl-1H-pyrazole-4-carbaldehyde

1.9 Ant-influenza activity:

Influenza viruses are major causes of morbidity and mortality around the world. Compound BPR1P00034 is the first pyrazole based anti-influenza compound, which showed potent sub-micromolar antiviral activity ^[28].

1.10 Insecticidal activity:

Several pyrazole derivatives tested for insecticidal activity by leaf dipped method. Insecticidal activity analysis of pyrazole derivatives showed significant activity against Armyworm (Mythimna Separate Walker) ^[29].

Examples:

1.11 Anaesthetic activity:

Local anaesthesia is due to blocking of voltage sensitive sodium channels result into loss of pain and sensation of particular body part. Some pyrazole derivatives also showed local anaesthetic effect ^[30].

Example:

a. 2-(pyrazol-1-yl)-4’-bromoacetanilide

b. 2-(3,5-dimethyl-pyrazol-1-yl)-4’-bromoacetanilide

c. 2-(3,5-dimethyl-pyrazole-1-yl)-2’-methyl-4’-bromoacetanilide

d. 2(3-phenyl-5-methyl-pyrazole-1-yl)-2’-methy7l-4’bromoactanilide

e. 2(3,5-dimethyl-pyrazole-1-yl)-2-fluroacetanilide

f. 2-(3,5-Dimthyl-pyrazol-1-yl)-4’-fluroacetanilide

12	R	R₁	R₂
a.	4’-Br	Me	Me
b.	2’-Me-4’Br	Me	Me
c.	2’-Me-4’Br	Me	C₆H₅
d.	2’F	Me	Me
e.	4’F	Me	Me
f.	4’Br	H	H

1.12 Acylating agents-

Acylation is one of the fundamental reaction in organic chemistry, which plays important role in the chemistry of biomolecules. Pyrazole derivatives are important synthons and reagent in organic synthesis and have found to be application in pharmaceuticals, agrochemicals, dyestuffs etc ^[31].

Example:

13	R₁
a.	Me
b.	Ph
c.	p-N₂-Ph
d.	Th (2-Thienyl)
e.	Py (4-Pyridinyl)

1.13 Analgesic activity:

The drugs that cause loss of pain are analgesics. Pyrazole derivatives are gaining importance in medicinal and synthetic chemistry due to their diverse type of biological properties. Mohammad at al evaluated various compounds for analgesic activity using acetic acid induced writhing method ^[14].

Examples:

a. 6-chloro-1-carboamidopyrazole [3, 4-b] quinoline

b. 6-methoxy-1- carboamidopyrazole [3, 4-b] quinoline

c. 6-methoxy-1-(2, 4-dinitrophenyl) pyrazolo [3, 4-b] quinoline

1.14 Herbicidal activity:

Noriaki kudo synthesised some diaryl-pyrazolecarboxylates, which showed good herbicidal activity against barnyard grass (Echinochloa oryzicola vasing). Herbicidal activities of synthesized (Noriaki kudo et al 1999) compounds were measured on the whole plant by green house assay ^[33].

Examples:

a. N-methyl-4-chlro-1-(2, 5-diflurophenyl) 5-phenylpyrazole-3-carboxamide

b. N-methyl-4-chlro-1-(2, 5diflurophnyl)-5- phnylpyrazole-3-carboximide

c. Methoxymethyl-4-chlro-1-(2,5iflurophenyl)-5-(4-flurophenyl)-pyrazole-3-carboxylate

Ethoxymethyl-4-chloro-1-(2, 5diflurophenyl)-5-4-flurophenyl-pyrazole-3-carboxylate 15	Y	COZR
a.	H	COMNHMe
b.	H	CONHOMe
c.	H	CON (iso-Pr) (2,4-F₂C₂H₃)
d.	H	CO₂CH₂Ot

1.15 Antitubercular activity:

Tuberculosis is a common and often deadly infectious disease caused by mycobacterium, usually Mycobacterium tuberculosis in human. Vimal Patel synthesized some pyrazole derivatives by claisen-Schmidt condensation method, which showed antitubercular activity ^[34].

Example:

5-(Substituted phenyl)-N, 3diphnyl-4,5-dihydropyrazole-1-carbothioamide

1.16 Antiangiogenic property:

Angiogenesis is the process of new blood vessel formation. During the last decades, several molecules containing various azaheterocyclic rings including the pyrazole moiety are used. Several compounds elicited a dose dependent inhibition of endothelial cell proliferation in which 50% inhibition concentration ranging from 6-44 micrometer. Endothelial cell migration is an essential step in the formation of new blood vessels. Following compounds showed in-vitro anti-angeogenic activities are,

Examples:

a. 1-(4-hydroxyphenyl)-3-(3’’, 4’’-dihyroxyphenyl)-1H-pyrazole-4-carboxaldehyde

b. 1-(4’-hydroxyphenyl)-3 (3’’-hydroxyphenyl) 1-H-pyrazole-4-carboxaldehyde

c. (E)-Ethyl-3-(4’’-hydroxyphenyl)-(3-phnyl-1H-pyrazole-4-yl) acrylate

d. (E)- Ethyl -3-(1’ (4’’-hydroxyphenyl)-1H-pyrazol 4-yl) acrylate

17	R₁
a.	H
b.	OH

1.17 Antiviral activity, Antidiabetic activity, Hypotensive agent:

Sachacha SP showed antiviral action of several phenyl 1-3-(substituted fluro phenyl) 5-hetero aryl -2-pyrazoline derivative against sunn hemp rosette. Froesch EE has reported antidiabetic activity in the 5-methyl pyrazole -3-carboxilic acid. Smith DL reported 3,5 dimethyl pyrazole and 3-methyl pyrazole-5-carboxilic acid exhibited hypoglycemic activity. Arya VP et al synthesized several pyrazolidine derivatives and reported the hypotensive activity ^[6].

CONCLUSION:

In summary, all pyrazole and its derivatives showed prominent pharmacological activities such as antimicrobial, antifungal, anti-influenza, antiangiogenic, analgesic, anaesthetic, anticancer, antitubercular, antioxidants, anti-inflammatory, insecticidal, herbicidal and hypotensive. So pyrazole and its derivatives plays very important role in treatment of varies disorders and hence one of the important medicinal compound.

ACKNOWLEDGEMENT:

The authors expresses their sense of gratitude towards management of Satara College of Pharmacy, Degaon, Satara for providing all obligatory facilities necessary to carry out present work.

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Received on 29.05.2014 Modified on 26.07.2014

Res. J. Pharm. Dosage Form. & Tech. 7(1): Jan.-Mar. 2015; Page 74-81

DOI: 10.5958/0975-4377.2015.00011.7