INTRODUCTION:

Heterocyclic compounds are a highly valuable and unique class of compounds. Amongst heterocyclic compounds, nitrogen-containing heterocycles are versatile lead compounds for designing potent bioactive agents because they are widely observed in natural products like vitamins, hormones and alkaloids^[1,2]. Pyrazole, a five membered simple aromatic ring comprises two nitrogen atoms at adjacent position as in the Figure 1.

Figure 1. Structure of pyrazole

Pyrazole derivatives exhibit a broad spectrum of biological activities, like antitubercular^[3], anti-AIDS^[4], anti-microbial^[5], antitumor^[6], anticancer^[7] and antifungal^[8]. In addition, pyrazoles have also been found as promising anti-hyperglycemic^[9], anti-depressant^[10], anti-convulsant[^11], anti-anxiety^[12] and insecticidal agents^[13].

Figure 2: Drugs containing pyrazole moiety

Several drugs containing pyrazole ring like Zaleplon (1) affects the nervous system, Zoniporide (2) selectively inhibits sodium-hydrogen exchanger isoform-1 (NHE-1), Celecoxib (3) functions as anti-inflammatory and analgesic agent, and Acomplia (4) the first selective CB1 receptor blocker have been developed which are given in Figure 2.

In light of the significance of pyrazoles in medicinal chemistry, the present review focuses on the synthesis of diverse pyrazole derivatives and their biological activities.

SOME GENERAL METHODS OF SYNTHESIS:

1. Cyclocondensation of hydrazine and its derivatives on 1,3-dicarbonyl compounds

Pyrazole which is also known as 1,2-diazole, was first synthesized by Knorr in 1883 by the condensation of hydrazines with 1,3-dicarbonyl compounds to give the following two isomers I and II^[14].

2. The 1,3-Dipolar Cycloaddition

Alkynes react with diazo compounds to afford 3,5-disubstituted pyrazoles^[15].

3. Reaction of α,β-unsaturated aldehydes and ketones with hydrazines

Another strategy for the synthesis of pyrazoles is the cyclocondensation of an appropriate hydrazine with a carbonyl compound having two electrophilic carbons at the 1 and 3 locations^[16].

BIOLOGICAL ACTIVITIES:

Derivatives of pyrazoles have played a crucial role in the history of heterocyclic chemistry and been used as important pharmacores and synthons in the field of organic chemistry and drug designing. This review summarizes the recent biological activities elucidated by the presence of pyrazole moiety in various synthesized compounds.

N. C. Desai et al. have synthesized two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety and assessed in vitro for their efficacy as antibacterial agents against gram-positive and gram-negative bacterial strains. Further, some of the compounds were endowed with low levels of cytotoxicity on a human cervical cancer cell line (HeLa) and a mouse embryonic fibroblast cell line (NIH 3T3) by MTT cytotoxicity studies^[17].

R = H, 4-Cl, 2,4-Cl₂, 4-CH₃, 4-OCH₃, 2-OH, 3-OH, 4-OH, 3-NO₂, 4-NO₂

F.-J. Meng et al. have synthesized novel pyrazole derivatives as potent neuraminidase inhibitors against influenza H1N1 virus^[18].

R = H, 4-Br, 4-F, 4-Cl, 3,4-OCH₃, 3-Cl, 4-OH, 2-Cl, 4-OCH₃, 4-CH₃

Pyrazoles incorporating triazolopyrimidines were synthesized by A. A. Abu-Hashem and M. A. Gouda and evaluated as antimicrobial^[19].

R = H, Ph

G. Manjunath et al. have designed and synthesized quinoline derivatives containing pyrazole moiety by condensation of 2-(quinolin-8-yloxy)acetohydrazide with various chalcones. These newly synthesized quinoline derivatives containing pyrazole moiety were screened for their minimum inhibitory concentration by antibacterial activity against two kinds of strains i.e. Staphylococcus aureus, Escherichia coli and antifungal activity against Aspergillus niger^[20].

R₁= H, 4-OCH₃, 2-OH; R₂= H, 4-OH, 2-OH, 4-Cl, 4-NO₂

Some new 3,4–disubstituted isocoumarins having bioactive pyrazole molecule at 3^rdposition of isocoumarin moiety were synthesized by P. Yadav et al., from isocoumarin -3- carboxylic acid hydrazide followed by cyclization with acetyl acetone and screened for antimicrobial and analgesic activities^[21].

R = CH₃, C₂H₅

Novel (Z)-1-(4-chlorophenyl)-2-(3,5-dimethyl-4-(substituited phenyldiazenyl)-1H-pyrazol-1-yl)ethanone derivatives were synthesized by K. S. Jacob et al. and evaluate their antimicrobial, anthelmintic and cytotoxic activity^[22].

R = 3-Cl , 4-Cl , 2,4-diCl , 3,4-diCl , 2,4,5-triCl , 3,4,5-triCl, 3-NO₂ , 4-NO₂, 3-OCH₃ , 4-OCH₃

P. A. Datar et al. have synthesized pyrazole-3-one compounds and were subjected to in vivo hypoglycemic activity using alloxan induced diabetic rats and metformin as a standard^[23].

R₁= R₂= H, R₃= NO₂

D. J. Wang et al. have synthesized 1,3,5-Trisubstituted-pyrazole derivatives containing a pyridyl moiety and evaluated their antibacterial activity against Escherichia coli, Staphylococcus aureus, Pyricularia oryzae and Rhizoctnia solani^[24].

R= H, CH₃, F, OCH₃, Ph

R. Rambabu et al. have synthesised a new series of substituted pyrazole derivatives by 1,3,4-benzoxazinone with active hydrogen atoms of an amino group by conventional synthetic methods to form quinazolinone nucleus. The compounds have been evaluated to determine their anti-tubercular profile and also were evaluated for antifungal and antimicrobial activity^[25].

Amarnath Velidandi et al. have synthesized novel pyrazole derivatives and evaluated antibacterial activity of novel compounds by the disc-diffusion method against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris^[26].

R= C₁₄H₂₉, C₁₆H₃₃, C₁₈H₃₇, R¹= CH₃, C₁₄H₂₉, C₁₆H₃₃, C₁₈H₃₇

B.V. Kendre et al. have synthesized a new series of pyrazole derivatives and screened for antibacterial, antifungal and anti-inflammatory activities^[27].

R = H, Ph, (NO₂)₂Ph

A novel series of 2-Chloroquinoline nucleus clubbed with the pyrazole ring were synthesized by P.B. Miniyar et al. and screened for antibacterial and antifungal activity^[28].

R=H, Br, F, NH₂, NO₂; R’= H, Br

A series of novel pyrazole amide derivatives were designed and synthesized by J. X. Mu et al. using multi-step reactions from phenylhydrazine and ethyl 3-oxobutanoate as starting materials and screened for their antifungal activity^[29].

R=2,4-F₂Ph, 4-NO₂Ph, 2,6-Cl₂Ph, 2-MePh, 4-Me,2-NO₂Ph, 4-Cl,2-NO₂Ph, 4-FPh, 3-MePh, 3-CF₃Ph, 4-ClPh, 4-OMe,2-NO₂Ph, 4-MePh, 3-ClPh

A series of novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates were synthesized by S.N. Thore et al. by condensation of various hydrazides with ketene dithioacetal. The synthesized compounds were screened for in vivo analgesic and anti-inflammatory activities^[30].

New active fluorine containing quinoline-pyrazole hybrid analogs were synthesized by N. Nayak et al. and evaluated for their antitubercular activity against MTB and antibacterial activity against three pathogenic bacterial strains^[31].

R ¹ = 4-F, 4-Cl, 3-Cl, 4-Br, 4-OCH₃, 4-CH₃, H; R² = 8-CF₃, 6-F, 6-OCH₃

Ravula et al. have synthesized a series of novel pyrazole derivatives and screened for in vitro antiproliferative activity against the HT-29 (human colon cancer) and MCF-7 (human breast cancer) cell lines by MTT assay. The following compound was found to exhibit good in vitro inhibitory activity against VEGFR-2 kinase^[32].

M. F. El Shehry et al. have synthesized quinoline derivatives bearing pyrazole moiety and were evaluated for antibacterial and antifungal activities where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi^[33].

X = CN, R = CH₃; X = CN, R = SCH₃; R = H, Ph

X = CN, R = 3-Cl-C₆H₄; X = COOEt, R = CH₃,

X = COOEt, R = SCH₃; X = CN, R = 2,4-Cl₂-C₆H₃

A series of novel compounds of type 3-(4-chlorophenyl)-5-((1-phenyl-3-aryl-1Hpyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one were synthesized by H. B’Bhatt and S. Sharma and were screened for in vitro antibacterial activity against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), and Staphylococcus pyogenes (MTCC 442) using commercially available antibiotics ampicillin as a standard drug^[34].

R’= H, CH₃, OH, NO₂, F, Cl, Br, OCH₃

A. Suresh et al. have prepared various 1-((1-(substituted)-1H-1,2,3-triazol-4-yl)methyl)-N,3-diphenyl-6,7- dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamides using click chemistry and screened for in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain and two ‘wild’ strains Spec. 210 and Spec. 192^[35]. The following compound is found to be most active compound.

A new series of 8-trifluoromethyl quinoline substituted pyrazole-3-carboxamides were synthesized by N. Nayak et al. from different primary and secondary amines and also screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain^[36]. Among them the following compound is found to be good active.

R. Kenchappa et al. have synthesized 6-substituted-3-(1-(4-substituted)-4-((Z)-(5,6- dimethoxy-1-oxo-1H-inden-2(3H)-ylidene)methyl)-1H-pyrazol-3-yl)-2H-chromen-2-one derivatives and screened for in vitro antioxidant activity. The selected compounds were also tested for in vivo antihyperglycemic activity against Streptozotocin– nicotinamide induced Adult Wistar rats^[37]. The following compound showed significant decrease in glucose concentration (115 and 138 mg/dL) with the dose of 100mg/kg.

Turkan et al. have synthesized a series of substituted pyrazol-4-yl-diazene derivatives and were found to be effective inhibitors against α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE)^[38].

R = H, CH₃, C₂H₅, Ph, 2,4-diMePh, ,4-diMePh, 4-BrPh, -NO₂Ph

A series of novel 1,3,4-trisubstituted pyrazole derivatives were synthesized by M. F. Harras et al. and evaluated for their cytotoxic activity against three different cancer cell lines namely HCT116, UO-31 and HepG2^[39].

R = H, CH₃, NO₂, Ph

A new series of benzimidazole linked pyrazole derivatives were synthesized by M.J. Akhtar et al. and were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2^[40].

R = 4-Cl, 4-Cl, 4-Cl, 4-OCH₃, 4-OCH₃, 4-OCH₃, 4-CH₃, 4-CH₃, 4-CH₃, 4-OH, 4-OH, 4-OH.

R¹ = 4-Cl, 4-Br, 4-F, 4-Cl, 4-Br, 4-F, 4-Cl, 4-Br, 4-F, 4-Cl, 4-Br, 4-F.

G. Verma et al. have synthesized pyrazole acrylic acid based oxadiazole derivatives and examined their antimalarial and anticancer activities^[41].

A series of novel 3,4-diaryl-1H-pyrazoles and 3,5-diaryl-1H-pyrazoles derivatives were synthesized C.-Y. Cui et al. and some of these novel compounds exhibited antifungal effects against Candida albicans SC5314^[42].

R¹ = R² = R⁴ = H, R³ = Ph

R² = R³ = H, R¹ = OH, R⁴ = 4-OCH₃Ph

R² = R³ = H, R¹= OH, R⁴ = 4-OHPh

R³=H, R¹=OH, R²=Glc, R⁴=Ph

H. Liu et al. have synthesized novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors^[43].

R¹ = H, Cl, Br, NO₂, CH₃

R² = H, N(Et)₂

R³ = H, F, Cl, CH₃

R⁴ = COOEt, COOH, CN

A series of bis-pyrazole derivatives were designed and synthesized by H. Dai et al., and their antitumor effects in vitro and in vivo were investigated^[44]. Among all the synthesized compounds the following one exhibits good activity.

P. A. Channar et al. synthesized new aryl pyrazole derivatives using 1,3-dicarbonyl motifs and investigated alkaline Phosphatase, nucleotide pyrophosphatase/phosphodiesterase and nucleoside triphosphate diphosphohydrolase inhibition studies with potential anticancer profile^[45]. The given compound exhibit good activity.

S. B. Jadhav et al. were synthesized a series of novel pyrazole derivatives and evaluated for their growth inhibitory activity against Mycobacterium smegmatis mc² 155 initially^[46].

R¹, R², R³= H, CH₃, OCH₃, F, Br

R⁴ = H, Cl, OCH₃

R⁵ = CN, CF₃

G. H. Sayed et al. have synthesized a series of novel pyrazole derivatives and screened for their antimicrobial activities against gram positive and gram negative bacteria using inhibition zone diameter measurements^[47]. Among them, the given compound shows good antibacterial activity.

Gaikwad et al. have synthesized some new pyrazolo[4,3-e]pyrimido[1,2-a]pyrimidin-3-amine derivatives and screened for their antimicrobial activity^[48].

R, R¹ = 4-Cl, 4-Br, H, 4-NO₂, 4-OCH₃

Novel series of the pyrazole-conjugated benzothiazole derivatives were synthesized by M. Bhat et al. and synthesized compounds exhibited moderate antimicrobial, antioxidant and excellent anti-TB activities^[49].

R = H, 4-OCH₃, 4-OH, 4 -CH₃, 4 -Cl, 4 -Br, 4 -NO₂, 3-NO₂, 4 -N(CH₃)₂

A series of 5-(Substituted-phenyl)-3-(furan-2-yl)-4,5-dihydro-1H-pyrazole were synthesized by Rajat K, et al. and were screened for their in-vitro antimicrobial activity against five bacterial strains Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermis, Escherichia coli and Pseudomonas aeruginosa, (Gram-negative) and on two fungal strains Aspergillus niger and Candida albicans by serial two-fold dilution method^[50].

R = 3,4-diOCH₃, 4-NO₂, 4-Br, 2,4-diOH, 4-OCH₃, 4-OH, 4-NH₂, 2-OH, 4-CH₃, 4-Cl, 2-Br-4-Cl, 2-Cl, 4-F, 2,4-diCl

Khumar et al. have synthesized novel series of 1-[5-(furan-2-yl)-4,5-dihydro-3-(4-morpholinophenyl)pyrazol -1-yl]ethanone from the 3-(furan-2-yl)-1-(4-morpholinophenyl)prop-2-ene-1-one by cyclization reaction and antimicrobial susceptibility tests of synthesized compounds are screened against Staphylococcus aureus and Escherichia coli ^[51].

X = H, CH₃, Br

Zhou et al. have synthesized pyrazole containing biguanide derivatives and screened for in vitro cytotoxicity against human cancer cell lines ^[52].

R = H, 4-Cl, 4-F, 2-Cl, 4-CF₃

New series of pyrazole derivatives possessing amino/methanesulphonyl moiety were designed and synthesized by K. R. A. Abdel latif et al. All compounds were evaluated for both in vitro COX inhibition and in vivo anti-inflammatory activities and all of them were more potent against COX-2 than COX-1 isozyme and showed good in vivo anti-inflammatory activity^[53].

R = H, Cl, Br, NO₂, NHSO₂CH₃, OCH₃

A new series of hybrid structures containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO₂Me pharmacophore as selective COX-2 moiety was designed and synthesized by K. R. A. Abdellatif and also to be evaluated for both anti-inflammatory and anti-cancer activities^[54].

X = NO₂, Y = OCH₃; X = NO₂, Y = H; X = Br, Y = OCH₃

3-methyl-1-substituted-4-phenyl-6-[{(1E)-phenylmethylene}amino]1,4-dihyropyrano[2,3-c] pyrazole-5-carbonitrile derivatives were synthesized by M. Murahari et al. as selective COX-2 inhibitors^[55].

R = H, C₆H₅; R¹ = H, 4-OH, 4-OCH₃, 3,4-diOCH₃, 3,4,5-triOCH₃, 2-NO₂, 3-NO₂, 2-Cl, 3-Cl, 4-F; R² = H, OH.

A new series of pyrazole derivatives were prepared by D. M. Omran et al. were tested for in vitro anticancer activity on hepatocellular carcinoma cell line, HepG2^[56].

P. Taslimi et al. have synthesized pyrazole[3,4-d]pyridazine derivatives and examined their pharmacological activities such as NAD(P)H oxidase inhibitor, anticancer, and identified as a novel allosteric modulator of the adenosine A1 receptor^[57].

R₁ = Ph, OEt; R₂ = H, Ph, Ph(CH₃)₂(2,5), Ph(CH₃)₂(3,4), Ph(NO)₂(2,4), Ph(Cl)₃(2,4,6),Ph(CF₃)(4)

A series of substituted pyrazole compounds were synthesized by F. Turkana et al. and emerged as effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes^[58].

Ar = 3,4(CH₃)₂C₆H₃; R₁ = H, Et

F. Ran et al. have synthesized novel pyrazole derivatives as potential agents for treating mantle cell lymphoma ^[59]. The following compound showed potent effect in MCL cells with IC₅₀ values lower than 1 μM and antiproliferative activity.

L. Sun, et al. have synthesized 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors^[60]. The given compound found to have the best in vitro inhibition activity against PTP1B and the best selectivity between PTP1B and T-cell protein tyrosine phosphatase.

S. J. Takate et al. have synthesized a series of thiazolyl-pyrazole derivatives and they were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG)^[61].

R¹ = H, Cl; R² = H, Me; R³ = Br, Cl, Me; R⁴ = H, Me

T.-Y. Zhang, et al. have designed and synthesized a novel series of dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties and also evaluated in terms of their antibacterial and antifungal activities^[62]. The following compound exhibits good antibacterial activity.

W. Zhan et al. have synthesized a series of pyrazole-thiophene derivatives and observed good Akt inhibitory activities^[63].

R¹ = H, Cl, Br, Me, Vinyl, Et, carboxyl, CH₂OH, Ph, 4-Py; R² = 4-Cl, 3-F, 4-Cl-3-CF₃.

R. Romagnoli et al. have synthesized a series of 3-(3’,4’,5’-trimethoxyphenyl)-4-substituted 1H-pyrazole and their related 3-aryl-4-(3’,4’,5’-trimethoxyphenyl)-1-H-pyrazole regioisomeric derivatives and evaluated for their in vitro antiproliferative activity against six different cancer cell lines^[64]. The following compounds exhibit superior antiproliferative activity.

M. E. Monteiro et al. have synthesized pyrazole-imidazoline and pyrazole-tetrahydropyrimidine derivatives and highlighted them as promising novel drug candidates for the control of Chagas disease^[65].

R = H, 3-Cl, 3,5-diCl, 3,4-diCl, 4-Cl, 4-Br, 4-F, 3-Br, 4-OCH₃

New pyrazole derivatives were synthesized by G.S. Hassan et al. and evaluated for their COX-1 and COX-2 inhibitory activity in vitro. All compounds showed good inhibitory activity at a nanomolar level and most of the compounds exhibited selectivity towards COX-2 inhibition^[66].

X = CH₂, CH₂CH₂, CH(CH₃)

Nine novel difluoromethylpyrazole acyl urea derivatives were synthesized by L. Qiao et al. via seven steps conveniently. The in vivo fungicidal activities were determined against Corynespora mazei, Botrytis cinerea, Fusarium oxysporum, and Pseudomonas syringae^[67].

R = 2-F, 3-F, 2,6-diEt, 2,6-diF, 2-CF₃, 2-Cl, 3,5-diCH₃, 2-OCF₃, 4-Et

A series of compound 3-chloro-4-(3-(4-fluorophenyl)-1-(2-phenylacetyl)- 1H-pyrazol-4-yl)-1-(substituted phenyl)azetidin-2-one were synthesized by Bhatt et al. from 1-(4- ((E)-(substituted phenylimino)methyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)-2-phenylethanone by the action of chloacetylchloride and TEA and evaluated for antibacterial activity^[68].

R = H, 2-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-F, 4-F, 4-NO₂, 2-OCH₃, 3-OCH₃, 2-Cl- 4-NO₂

J. A. McKenzie et al. have synthesized novel pyrazole ethandiamide compounds and in vitro assays performed to evaluate the compounds anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells^[69]. The following compound provides a structural foundation to the discovery of more potent neuroprotective drugs acting as inhibitors of adverse activation of microglia.

CONCLUSION:

This literature survey shows that pyrazole derivatives are pharmacologically very potent. The main goal of this review is focused on biological activities of pyrazole heterocyclic ring decorated with various functional groups. It has been noted so far that the structural modifications of the basic structure of pyrazole, have allowed the preparation of new derivatives with a broad spectrum of biological activity. For the moment, researchers have been drawn to the design of more potent pyrazole derivatives having wide diversity of biological activity in the quest for new drugs.

CONFLICT OF INTEREST:

There is no conflict of interest.

REFERENCES:

1. Srivastava M, Singh J, Singh SB, Tiwari K, Pathak KV and Singh J. Synthesis of novel fused heterocycleoxa-aza-phenanthrene and anthracene derivatives via sequential one-pot synthesis in aqueous micellar system. Green Chemistry. 2012; 14: 901.

2. Pai G and Chattopadhyay AP. N-arylation of nitrogen containing heterocycles with aryl halides using copper nanoparticle catalytic system. Tetrahedron Letters. 2016; 57: 3140.

3. Bekhit AA, Hassan AM, Abd El Razik HA, El-Miligy MM, El-Agroudy EJ and Bekhit AD. New heterocyclic hybrids of pyrazole and its bioisosteres: Design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents. Europian Journal of Medicinal Chemistry. 2015; 94: 30.

4. Sony JK and Ganguly S. A battle against AIDS: New pyrazole key to an older lock-reverse transcriptase. International Journal of Phamacy and Pharmaceutical Sciences. 2016; 8: 75.

5. Robin EM, David RG, Vijayalekshmi S. An antibacterial pyrazole derivative from Burkholderia glumae, a bacterial pathogen of rice. Phytochemistry. 2008; 69: 2704-2707.

6. Xia Y, Fan C, Zhao BX, Zhao J, Shin DS, Miao JY. Synthesis and structure–activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives as potential agents against A549 lung cancer cells. Europian Journal of Medicinal Chemistry. 2008; 43: 2347-2353.

7. Bandgar BP, Totre JV, Gawande SS, Khobragade CN, Warangkar SC, Kadam PD. Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer, anti-inflammatory agents. Bioorganic and Medicinal Chemistry. 2010; 18(16): 6149-6155.

8. Karthikeyan MS, Holla BS, Kumari NS. Synthesis and antimicrobial studies on novel chloro-fluorine containing hydroxy pyrazolines. Europian Journal of Medicinal Chemistry. 2007; 42: 30-36.

9. Kees KL, Fitzgerald JJ, Steiner KE, Mattes, Mihan B, Tosi T, Mondoro D and McCalebML. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and –pyrazolones. Journal of Medicinal Chemistry. 1996; 39: 3920.

10. Bailey DM, Hansen PE, Hlavac AG, Baizman ER, Pearl J, Defelice AF and Feigenson ME. 3,4- Diphenyl-1H-pyrazole-1-propanamine antidepressants. Journal of Medicinal Chemistry. 1985; 28: 256.

11. Michon V, Penhoat CHD, Tombret F, Gillardin JM, Lepage F and Berthon L. Preparation, structural analysis and anticonvulsant activity of 3- and 5-aminopyrazole N-benzoyl derivatives. European Journal of Medicinal Chemistry. 1995; 30: 147.

12. Jamwal A, Javed A and Bhardwaj V. A review on pyrazole derivatives of pharmacological potential. Journal of Pharmacy and Biosciences. 2013; 3: 114.

13. Heller ST and Natarajan SR. 1,3-Diketones from Acid Chlorides and Ketones : A Rapid and General One- Pot Synthesis of Pyrazoles. Organic Letters. 2006; 8: 2675.

14. Knorr L, Synthese von Pyrrolderivaten. Berichte der Deutschen Chemischen Gesellschaft. 1884; 17: 2032.

15. Aggarwal VK, Vicente JD, Bonnert RVJ. A Novel One-Pot Method for the Preparation of Pyrazoles by 1,3-Dipolar Cycloadditions of Diazo Compounds Generated in Situ. Organic Chemistry. 2003; 68: 5381.

16. Katritzky AR, Wang M, Zhang S, Voronkov MV. Regioselective Synthesis of Polysubstituted Pyrazoles and Isoxazoles. Journal of Organic Chemistry. 2001; 66: 6787.

17. Nisheeth CD, Hitesh MS, Ghanshyam MK, Hasit VV. Synthesis and Antibacterial and Cytotoxic Activities of New N‐3 Substituted Thiazolidine‐2,4‐dione Derivatives Bearing the Pyrazole Moiety. Archive der Pharmazie – Chemistry in Life Sciences. 2014; 347: 1–10.

18. Fan JM, Tao S, Wen ZD, Ming HL, Zhong ZT. Discovery of Novel Pyrazole Derivatives as Potent Neuraminidase Inhibitors against Influenza H1N1 Virus. Archive der Pharmazie – Chemistry in Life Sciences. 2016; 349: 168–174.

19. Hashem AA, Gouda MA. Synthesis and Antimicrobial Activity of Some Novel Quinoline, Chromene, Pyrazole Derivatives Bearing Triazolopyrimidine Moiety. Journal of Heterocyclic Chemistry. 2017; 54 (2): 850-858.

20. Manjunath G, Mahesh M, Bheemaraju G, Venkata RP. Synthesis of New Pyrazole Derivatives Containing Quinoline Moiety via Chalcones: A Novel Class of Potential Antibacterial and Antifungal Agents. Chemical Science Transactions. 2016; 5(1): 61-74.

21. Poonam Y, Nalini VP. Synthesis and evaluation of some bioactive compounds having oxygen and nitrogen heteroatom. Journal of Chemical Sciences. 2013; 125(1): 165–173.

22. Jacob KS, Ganguly S. Synthesis, anti microbial screening and cytotoxic studies of some novel pyrazole analogs. Journal of Applied Pharmaceutical Science. 2016; 6 (11):135-141.

23. Prasanna AD, Sonali RJ. Design and Synthesis of Pyrazole-3-one Derivatives as Hypoglycaemic Agents. International Journal of Medicinal Chemistry. 2015; Article ID 670181.

24. Wang DJ, Hua L, Yan FK, Yan JH, Xian HW. Synthesis and anti-microbial activities of 1,3,5-trisubstituted-pyrazole derivatives containing a pyridyl moiety. Journal of Chilean Chemical Society, 2015; 60 (1): 2857-2860.

25. Reddy R, Kumar PP, Rao JV, Subbarao J. Synthesis, characterization and biological evaluation of certain new pyrazole derivatives. International Journal of Chemical Sciences. 2015; 13(3): 1383-1392.

26. Sthalam VK, Bethanamudi P, Gadidasu KK, Kumar TR, Velidandi A. Synthesis, in vitro antibacterial activity and docking studies of newer pyrazole derivatives. Pharmacophore. 2015; 6 (4): 196-204.

27. Kendre BV, Landge MG, Bhusare SR. Synthesis and biological evaluation of some novel pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives bearing an aryl sulfonate moiety as antimicrobial and anti-inflammatory agents. Arabian Journal of Chemistry. 2019; 12 (8): 2091-2097.

28. Miniyar PB, Barmade MA, Mahajan AA. Synthesis and biological evaluation of 1-(5-(2-chloroquinolin-3-yl)-3-phenyl-1H-pyrazol-1-yl)ethanone derivatives as potential antimicrobial agents. J. Saudi Chemical Society. 2015; 19 (6): 655–660.

29. Mu JX, Shi YX, Yang MY, Sun ZH, Liu XH, Li BJ, Sun NB. Design, Synthesis, DFT Study and Antifungal Activity of Pyrazolecarboxamide Derivatives. Molecules. 2016; 21: 68–78.

30. Thore SN, Gupta SV, Baheti KG. Novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates: Synthesis and pharmacological activity. Journal of Saudi Chemical Sciences. 2016; 20 (3): 259–264.

31. Nayak N, Ramprasad J, Dalimba U. Synthesis and antitubercular and antibacterial activity of some active fluorine containing quinoline–pyrazole hybrid derivatives. Jornal of Fluorine Chemistry. 2016; 183: 59–68.

32. Ravula P, Vamaraju HB, Paturi M, Chandra JNGNS, Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR‐2 inhibitors. Archive der Pharmazie – Chemistry in Life Sciences. 2018; 351(1): 1700234.

33. Mohamed FES, Mostafa MG, Samir YA, Eman AF, Said AS, Yousry AA. Quinoline derivatives bearing pyrazole moiety: Synthesis and biological evaluation as possible antibacterial and antifungal agents. European Journal of Medicinal Chemistry. 2018; 143: 1463-1473.

34. Bhatt BH, Sharma S. Synthesis and antimicrobial activity of pyrazole nucleus containing 2-thioxothiazolidin-4-one derivatives. Arabian Journal of Chemistry. 2017; 10: S1590–S1596.

35. Amaroju S, Kalaga MN, Srinivasarao S, Napiorkowska A, Augustynowicz KE, Murugesan S, Chander S, Krishnan R, Sekhar CKVG. Identification and development of pyrazolo[4,3-c]pyridine carboxamides as Mycobacterium tuberculosis pantothenate synthetase inhibitors. New Journal of Chemistry. 2017; 41: 347–357.

36. Nayak N, Ramprasad J, Dalimba U. Design, Synthesis, and Biological Evaluation of New 8‐Trifluoromethylquinoline Containing Pyrazole‐3‐carboxamide Derivatives. Journal of Heterocyclic Chemistry. 2017; 54: 171–182.

37. Kenchappa R, Bodke YD, Chandrashekar A, Sindhe MA, Peethambar SK. Synthesis of coumarin derivatives containing pyrazole and indenone rings as potent antioxidant and antihyperglycemic agents. Arabian Journal of Chemistry. 2017; 10 (2): S3895–S3906.

38. Turkan F, Cetin A, Taslimi P, Gulçin İ. Archive der Pharmazie – Chemistry in Life Sciences. 2018; 1–7.

39. Marwa FH, Sabour R. Design, synthesis and biological evaluation of novel 1,3,4-trisubstituted pyrazole derivatives as potential chemotherapeutic agents for hepatocellular carcinoma. Bioorganic Chemistry. 2018; 78: 149–157.

40. Akhtar MdJ, Khan AA, Ali Z, Dewangan RP, Rafi Md, Hassan QMd, Akhtar SMd, Siddiqui AA, Partap S, Pasha S, Yar MS. Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors. Bioorganic Chemistry. 2018; 78: 158–169.

41. Verma G, Chashoo G, Ali A, Khan MF, Akhtar W, Ali I, Akhtar M, Alam MM, Shaquiquzzaman M. Synthesis of pyrazole acrylic acid based oxadiazole and amide derivatives as antimalarial and anticancer agents. Bioorganic Chemistry. 2018; 77: 106–124.

42. Cui CY, Liu J, Zheng HB, Jin XY, Zhao XY, Chang WQ, Sun B, Lou HX. Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the discovery of promising reversal agents of fluconazole resistance in Candida albicans. Bioorganic & Medicinal Chemistry Letters. 2018; 28 (9): 1545–1549.

43. Liu H, Ren ZL, Wang W, Gong JX, Chu MJ, Ma QW, Wang JC, Lv XH. Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity. European Journal of Medicinal Chemistry. 2018; 157: 81-87.

44. Dai H, Ge S, Guo J, Chen S, Huang M, Yang J, Sun S, Shi Y, Ling Y. Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage. European Journal of Medicinal Chemistry. 2018; 143: 1066-1076.

45. Channar PA, Afzal S, Ejaz SA, Saeed A, Larik FA, Mahesar PA, Lecka J, Sévigny J, Erben MF, Iqbal J. Exploration of carboxy pyrazole derivatives: Synthesis, alkaline phosphatase, nucleotide pyrophosphatase/phosphodiesterase and nucleoside triphosphate diphosphohydrolase inhibition studies with potential anticancer profile. European Journal of Medicinal Chemistry. 2018; 156: 461-478.

46. Jadhav SB, Fatema S, Sanap G, Farooqui M. Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives. Journal of Heterocyclic Chemistry. 2018; 55 (7): 1634-1644.

47. Sayed GH, Azab ME, Anwer KE, Raouf MA, Negm NA. Pyrazole, pyrazolone and enaminonitrile pyrazole derivatives: Synthesis, characterization and potential in corrosion inhibition and antimicrobial applications. Journal of Molecular Liquids. 2018; 252: 329-338.

48. Milind VG, Rahul DK, Shrikant VH, Kadam SN, Ajay NA, Bhaskar SD. Synthesis of Pyrazolo [4,3-e] Pyrimido [1,2-a] Pyrimidin-3-Amine Derivatives and their Antimicrobial Activity. Journal of Pharmaceutical, Chemical and Biological Sciences. 2018; 5(4): 376-385.

49. Mahesh B, Belagali SL. Synthesis, characterization and biological screening of pyrazole-conjugated benzothiazole analogs. Future Medicinal Chemistry. 2018; 10 (1): 71-87.

50. Sunil K, Rajat K. Synthesis and Antimicrobial Activity of 5-(Substituted-Phenyl)-3-(Furan-2- Yl)-4,5-Dihydro-1H-Pyrazole Compounds Using Silver Trifluro Methane Sulphonate as Catalyst. Der Pharmacia Lettre. 2018; 10 (8): 57-67.

51. Khumar SAB, Ezhilarasi MR, Prabha B. Molecular Docking Study of Novel Synthesized Pyrazole Derivatives and their Antibacterial Activity. Asian Journal of Chemistry. 2018; 30 (4): 741-746.

52. Zhou S, Xu L, Cao M. Anticancer properties of novel pyrazole‐containing biguanide derivatives with activating the adenosine monophosphate‐activated protein kinase signaling pathway. Archive der Pharmazie – Chemistry in Life Sciences. 2019; 352 (9): 1900075.

53. Abdellatif KRA, Abdelall EKA, Lamie PF, Labib MB, Nahaas ESE, Abdelhakeem MM. New pyrazole derivatives possessing amino/methanesulphonyl pharmacophore with good gastric safety profile: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory activity and histopathological studies. Bioorganic Chemistry. 2020; 95: 103540.

54. Khaled RAA, Wael AAF, Mostafa YA, Zaher DM, Omar HA. Thiohydantoin derivatives incorporating a pyrazole core: Design, synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities. Bioorganic Chemistry. 2019; 91: 103132.

55. Murahari M, Mahajan V, Neeladri S, Kumar MS, Mayur YC. Thiohydantoin derivatives incorporating a pyrazole core: Design, synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities. Bioorganic Chemistry. 2019; 86: 583-597.

56. Dina MO, Ghaly MA, Messery SME, Farid AB, Latif EA, Ihsan AS. Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based derivatives, biological evaluation, DNA binding, and molecular modeling studies. Bioorganic Chemistry. 2019; 88: 102917.

57. Taslimi P, Türkan F, Cetin A, Burhan H, Karamane M, Bildirici I, İlhami G, Şen F. Pyrazole[3,4-d]pyridazine derivatives: Molecular docking and explore of acetylcholinesterase and carbonic anhydrase enzymes inhibitors as anticholinergics potentials. Bioorganic Chemistry. 2019; 92: 103213.

58. Turkan F, Cetin A, Taslimi P, Karaman M, İlhami G. Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorganic Chemistry. 2019; 86: 420–427.

59. Ran F, Liu Y, Zhang D, Liu M, Zhao G. Discovery of novel pyrazole derivatives as potential anticancer agents in MCL. Bioorganic & Medicinal Chemistry Letters. 2019; 29 (9): 1060–1064.

60. Sun L, Wang P, Xu L, Gao L, Li J, Piao H. Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors. Bioorganic & Medicinal Chemistry Letters. 2019; 29 (10): 1187–1193.

61. Takate SJ, Shinde AD, Karale BK, Akolkar H, Nawale L, Sarkar D, Mhaske PC. Thiazolyl-pyrazole derivatives as potential antimycobacterial agents. Bioorganic & Medicinal Chemistry Letters. 2019; 29 (10): 1199–1202.

62. Zhang TY, Zheng CJ, Wu J, Sun LP, Piao HR. Synthesis of novel dihydrotriazine derivatives bearing 1,3-diaryl pyrazole moieties as potential antibacterial agents. Bioorganic & Medicinal Chemistry Letters. 2019; 29 (9): 1079-1084.

63. Zhan W, Che J, Xu L, Wu Y, Hu X, Zhou Y, Cheng G, Hu Y, Dong X, Li J. Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors. European Journal of Medicinal Chemistry. 2019; 180: 72-85.

64. Romagnoli R, Oliva P, Salvador KM, Camacho ME, Padroni C, Brancale A, Ferla S, Hamel E, Ronca R, Grillo E, Bortolozzi R, Rruga F, Mariotto E, Viola G. Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors. European Journal of Medicinal Chemistry. 2019; 181: 111577.

65. Monteiro ME, Lechuga G, Lara LS, Souto BA, Vigan_o MG, Bourguignon SC, Calvet CM, Oliveira Jr. FOR, Alves CR, S Silva F, Santos MS, Pereira MCS. Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease. European Journal of Medicinal Chemistry. 2019; 182: 111610.

66. Hassan GS, Rahman ADE, Abdelmajeed EA, Refaey RH, Salem AM, Nissan YM. Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease. European Journal of Medicinal Chemistry. 2019; 171: 332-342.

67. Li Q, Zhi WZ, Peng PC, Cheng XT, Jian QW, Liang H, Xing HL, Yong GZ. Synthesis, Crystal Structure, Antifungal Activity, and Docking Study of Difluoromethyl Pyrazole Derivatives. Journal of Heterocyclic Chemistry. 2019; 56 (9): 2536-2541.

68. Bhatt JJ, Suresh KD, Mrugesh HT. Synthesis, characterization and anti-microbial activity of pyrazole capped 2-azitidinone derivatives. RJLBPCS. 2019; 5(1): 647-662.

69. Jordan AMcK, Reham FB, Azhaar TA, Omkar K, Kalun B, Frederic M, Edward GN, Andis K. Synthesis and Evaluation of Novel Pyrazole Ethandiamide Compounds as Inhibitors of Human THP-1 Monocytic Cell Neurotoxicity. Cells. 2019; 8 (7): 655-666.

Received on 11.05.2020 Modified on 04.06.2020

Asian J. Research Chem. 2020; 13(5):383-394.

DOI: 10.5958/0974-4150.2020.00072.3