PYRAZOLINE HETEROCYCLIC: A REVIEW

PYRAZOLINE HETEROCYCLIC: A REVIEW

Biswajit Dash and Shajidul Karim ^*

Department of Pharmaceutical Analysis & Quality Assurance, Himalayan Pharmacy Institute, Majhitar - 737136, East Sikkim, India.

ABSTRACT: Pharmaceutical chemistry is devoted to the discovery and development of new agents for treating diseases. Inorganic compound continues to be important in therapy, for example, as antacids, mineral supplements, and radiopharmaceuticals, but organic molecules with increasingly specific pharma-cological activities are clearly dominant. The five and six-membered heterocyclic nitrogen-containing systems such as pyrazole, imidazole, trizoles, thiozolidine, pyrazolidine, etc., are far by the most important in the ongoing research for more efficacious drugs in the fields such as anti-bacterial, fungicidal, anti-inflammatory, anticonvulsant, diuretics, and anti-histaminic, etc. Pyrazoline is a five-membered heterocyclic compound having two adjacent nitrogen atoms within the ring. It has only one endocyclic double bond and is basic in nature. Pyrazole derivatives have a long history of application in agrochemicals and pharmaceutical industry as herbicides and active pharmaceuticals. The recent success of pyrazole COX-2 inhibitors has further highlighted the importance of these heterocyclic rings in medicinal chemistry. Many scientists have synthesized novel pyrazoline derivatives. They have characterized the synthesized compounds by thin-layer chromatographic technique and analyzed the spectrum by IR, NMR, Mass spectra. Some compounds had been synthesized by the microwave method of synthesis, which is more convenient than the normal method of synthesis. Pyrazoline is a unique template that is associated with several biological activities. This literature high lightened research work of many researchers reported in literature for different pharmacological activities on pyrazole and pyrazoline compounds synthesized.

Pharmaceutical chemistry, Radiopharmaceuticals, Anti-inflammatory, Heterocyclic compound, COX-2 inhibitor

INTRODUCTION: Pharmaceutical chemistry is devoted to the discovery and development of new agents for treating diseases. Inorganic compound continues to be important in therapy, for example, as antacids, mineral supplements, and radio-pharmaceuticals, but organic molecules within caressingly specific pharmacological activities are clearly dominant.

The objective of medicinal chemistry is the design and production of compounds that can be used as medicine for the prevention, treatment, and cure of humans or animal diseases.

It is concerned with the invention, discovery, design, identification of biologically active compounds, the study of their pharmacokinetic and pharmacodynamic profiles, interpretation of their mode of action at the molecular level and the construction of structure-activity relationship (SAR), the relationship between chemical structure and pharmacological activity for a series of compounds. The five and six-membered heterocyclic nitrogen-containing systems such as pyrazole, imidazole, trizoles, thiozolidine, pyrazoli-dine, etc., are far by the most important in the ongoing research for more efficacious drugs in the fields such as anti-bacterials, fungicidal, anti-inflammatory, anticonvulsant, diuretics, and anti-histaminic, etc.

Pyrazole: The term Pyrazole was given by Ludwig Knorr in 1883. Pyrazole Fig. 1 refers to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions. Being so composed and having pharmacological effects on humans, they are classified as alkaloids, although they are rare in nature. In 1959, the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from seeds of watermelons.

FIG. 1: PYRAZOLE

Pyrazole derivatives have a long history of application in agrochemicals and pharmaceutical industry as herbicides and active pharmaceuticals. The recent success of pyrazole COX-2 inhibitors has further highlighted the importance of these heterocyclic rings in medicinal chemistry. A systematic investigation of this class of heterocyclic lead revealed that pyrazole-containing pharmacy active agents play an important role in medicinal chemistry. The prevalence of pyrazole cores in biologically active molecules has stimulated the need for elegant and efficient ways to make these heterocyclic lead ¹.

Pyrazoline: Pyrazoline is a five-membered hetero-cyclic compound having two adjacent nitrogen atoms within the ring. It has only one endocyclic double bond and is basic in nature. Among its various derivatives, 2-pyrazolines seem to be the most frequently studied pyrazoline type compounds. 2-Pyrazolines can be considered as a cyclic hydrazine moiety. From the X-ray study, it has been found that the structure of the five-membered dihydropyrazole ring has an envelope conformation.

C5 atom is deviated from the almost planar system of the other four atoms of the heterocyclic ring. It plays a crucial role in the development of theory in heterocyclic chemistry and is also extensively used as useful synthons in organic synthesis ^{2, 3, 4}.

FIG. 2: PYRAZOLINE

FIG. 3: SINGLE CRYSTAL X-RAY STRUCTURE OF1-CARBOXAMIDO-2-PYRAZOLINE

Physico-chemical Properties: 2-pyrazoline is insoluble in water but soluble in propylene glycol because of its lipophilic character ³. It is known that the compounds of the 2-pyrazoline group that do not contain a substituent at the 1-position of the heterocyclic ring can react with benzaldehyde at high temperature (200 °C) and in an inert atmosphere to give 4-benzylidine derivatives. Pyrazoline derivatives, typical ICT (Intramolecular Charge Transfer) compounds, are known as a kind of fluorescent brightening agent because they have strong blue fluorescence in solution. They have a whole transport tendency. An intramolecular conjugated charge transfer process has been reported to exist in it in the excited state. In the conjugated part (–N1–N2–C3–) of the ring, the nitrogen atom at the 1-position and the carbon atom at the 3-position are, respectively, electron-donating and withdrawing moieties. The carbon atoms at 4- and 5-positions do not conjugate with the above-conjugated part. Its fluorescence spectrum exhibits a large redshift with an increase in the polarity of solvents. These compounds show stronger fluorescence because of the double bond hindering, which occurred due to cyclization.

Bulky groups in both the 4- and 5-positions improved both the fluorescence efficiency and the stability to the light of the molecule. It has significance for the design of pyrazoline whitening agents. Aryl group at position-5 is also responsible for spiroconjugated charge transfer quenching of pyrazoline fluorescence ^{5, 6, 7, 8}.

Spectrum of Activity: 2-Pyrazolines display a broad spectrum of potential pharmacological activities and are present in a number of pharmacologically active molecules such as phenazone/amidopyrene/methampyrone (analgesic and antipyretic), azolid / tandearil (anti-inflammatory), indoxacarb (insecticidal), anturane (uricosuric), etc. Considerable interest has been focused on the pyrazoline structure. The discovery of this class of drugs provides an outstanding case history of modern drug development and also points out the unpredictability of pharmacological activity from structural modification of a prototype drug molecule.

It is having a variety of medicinal applications ^{9, 10, 11, 12}. Pyrazoline derivatives were found to have potential antipyretic analgesic, tranquillizing, muscle relaxant, psycho analeptic, antiepileptic, anti-depressant, anti-inflammatory, insecticidal, and antimicrobial and anti-hypertensive activities. Their derivatives were also found to exhibit cytotoxic activity, the inhibitory activity of platelet aggregation, herbicidal activity, and cannabinoid CB1-receptor modulators. They also possess some potent receptor-selective biological activity like Nitric oxide synthase (NOS) Inhibitors. Pyrazoline interest extended to dyes and dye couplers to ^{13, 14}.

Literature Review:

Chemical Review: 2-pyrazoline is stable because it does not lose nitrogen as easily. The nitrogen present in the ring has 2 lone pairs of electrons. So, it acts as an electron donor group.

General Method of Preparation of Pyrazoline:

Method-1: 1, 3-Diketones, which were synthesized in situ from ketones and acid chlorides, were converted into pyrazoles by the addition of hydrazine.

This method allows a fast and general synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings ¹⁵.

Method-2: A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines proceeds at room temperature in N,N-dimethylacetamide and furnish espyrazoles in good yields ¹.

Method-3: Pyrazole or isoxazole derivatives are prepared by a palladium-catalyzed four-component coupling of a terminal alkyne, hydrazine (hydro-xylamine), carbon monoxide under ambient pressure, and an aryl iodide ¹⁷.

Method-4: In 1998, Powers et al. have synthesized pyrazoline derivatives by the reaction of chalcones and phenylhydrazine hydrochloride in the presence of sodium hydroxide in the absolute ethanol medium at 70 °C ¹⁸.

Method-5: Levai (2005), et al. have synthesized 3, 5-diaryl-2-pyrazolines by the reaction of chloro-chalcones with hydrazine derivatives in acetic acid by refluxing for 3 h ¹⁹.

Synthesis of Some new 2-Pyrazoline Derivatives: A chalcone of 2-acetyl thiophene (0.001 mol) dissolved in 20 mL of ethanol and phenylhydrazine hydrochloride (500 mg) was added to it. To this mixture, 0.3 mL of pyridine was added drop-wise at room temperature. After that, the mixture was refluxed for 5-6 h, and the solvent was evaporated completely. The reaction mixture was poured into ice-cold water. The solid mass that separated out was filtered, dried, and purified by column chromatography with ethyl acetate/ hexane and recrystallized from chloroform ²⁰.

FIG. 4: SYNTHESIS OF SOME NEW 2-PYRAZOLINE DERIVATIVES

Synthesis of Pyrazoline from Recent Literature:

A one-pot synthesis of nitrogen-containing hetero-cycles from alkyl dihalides and primary amines and hydrazines occurs under microwave irradiation via a simple and efficient cyclo condensation in an alkaline aqueous medium ²¹.

Arylhydrazines regioselectively react with 3-butynol in the presence of a catalytic amount of zinc triflate to give aryl-substituted pyrazolines. The resulting products are easily oxidized in a one-pot procedure to the corresponding pyrazoles ²². Various 1 - acyl - 5 - hydroxyl - 4, 5 - dihydro -1H-pyrazoles have been prepared in good yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li₂CO₃ at room temperature to provide 1-acyl-4-iodo-1H-pyrazoles ²³.

A novel, efficient, and general domino reaction of 2-acylaziridines with the Huisgen zwitterions furnishes 2-pyrazolines. A possible mechanism for the domino sequence is proposed ²⁴.

Construction of Nitrogen Heterocycles Bearing an Aminomethyl Group by Copper-Catalyzed Domino Three-Component Coupling-Cyclization ²⁵.

Pharmacological Review: Pyrazoline derivatives are known to possess broad-spectrum pharmacological activities like antidepressant, anticonvulsant, antimicrobial (such as antibacterial activity and antifungal activity), antihypertensive activity, antitubercular activity, muscle relaxant, tranquilising activity, psychoanaleptic activity, antiamoebic activity ^{26, 27, 28}.

Antidepressant Activity: E. Palaska et al. (1996) have synthesized some 1, 3, 5-triphenyl-2-pyrazolines Fig. 5.

The methyl substitution at phenyl ring of position 3 of the pyrazoline ring enhanced the antidepressant activity. Replacement of the methyl group with chloro and bromo decreased the activity.

In addition, the introduction of a chloro substituent on the phenyl at position 5 decreases the anti-depressant activity ²⁷.

FIG. 5: SYNTHESIZE OF 1, 3, 5-TRIPHENYL-2-PYRAZOLINES

Erhan Palaska et al. (2001) have synthesized some 3, 5-diphenyl-2-pyrazolines derivatives Fig. 6. The antidepressant activity showed that 4-methoxy and 4-chloro substituents at phenyl at 3 position of pyrazoline ring enhanced the antidepressant activity, and the replacement of these substituents with bromo and methyl groups decreased the activity ²⁶.

FIG. 6: SYNTHESIZE SOME 3, 5-DIPHENYL-2-PYRAZOLINES DERIVATIVES

Rajendra Prasad: et al., (2005) have synthesized some 1, 3, 5-triphenyl-2-pyrazolines and 3-(2-hydroxynaphthalen - 1 - yl) - 1, 5 – diphenyl - 2 pyrazolines Fig. 7. The compounds possessing electron-releasing groups such as dimethylamino, methoxy and hydroxyl substituents, on both the aromatic rings at positions 3 and 5 of pyrazolines, considerably enhanced the antidepressant activity when compared to the pyrazolines having no substituents on the phenyl rings, and this is consistent with the observation made earlier by Parmar et al ²⁸.

FIG. 7: SYNTHESIZE OF SOME PYRAZOLINE

ZuhalOzdemi: et al (2007) have synthesized 3-(2-furyl)-pyrazoline derivatives and studied the antidepressant activities. A compound containing ethylthiocarbamoyl at 1 position of pyrazoline ring and compound containing allylthiocarbamoyl group at 1 position of pyrazoline group shows extensive antidepressant activity ²⁹.

Mohamed Abdel Aziz et al, (2009) synthesized novel pyrazole derivatives and screened them for anticonvulsant and antidepressant activities.

The derivatives 8aand 8b Fig. 8 showed comparable antidepressant activity by using tail suspension behavioral despair test and anticonvulsant activity for derivatives 9a, 9b, and 9 Fig. 9 by using PTZ induced seizures in mice ³⁰.

FIG. 8: SYNTHESIZED NOVEL PYRAZOLE DERIVATIVES

FIG. 9: SYNTHESIZED OF PYRAZOLE DERIVATIVE ABC

Anticonvulsant Activity: Zuhalet al., (2007) have synthesized some 3-(2-furyl)-pyrazoline deriva-tives. The anticonvulsant activities showed that compound containing pyrazoline group at position of pyrazoline and furyl group at position 3 show good anticonvulsant activity i.e., against MES-induced seizures. Compounds containing thio-carbamoyl group and its derivatives at position1 of pyrazoline show activity against MES and scMet.-induced seizures. Compounds having a 2-furyl substituent at the fifth position of the pyrazoline ring possess remarkable anticonvulsant activity ²⁸.

Kucukguzel et al. ¹³ synthesized a new series of 4-Arylhydrazono-2-pyrazoline-5-ones derivatives and evaluated for their anticonvulsant activity. Compound 6 showed 40% protection against pentylenetetrazole (PTZ) - induced seizures in albino Swiss mice^{. 31}. Singh et al.. synthesized several 3-(3-Acetoamino) phenyl-1, 5-substituted phenyl-2-pyrazolines [12] and evaluated for their anticonvulsant activity ³².

Antimycobacterial Activity: Mamolo et al., synthesized 5-Aryl-1-isonicotinoyl-3- (pyridin-2-yl)-4, 5-dihydro-1H-pyrazole derivatives 13 and tested for their in-vitro antimycobacterial activity. The compounds showed an interesting activity against a strain of M. Tuberculosis ³³. Ozdemiret al synthesized new 1-[(N, N-disubstituted thio-carbamoylthio) acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives 14 and evaluated for in-vitro antimycobacterial activity against M. Tuberculosis ³⁴. Zampieriet al synthesized several 1-(3, 5-Diaryl-4, 5-dihydro-1H-pyrazol-4yl)-1H-imidazole deriva-tives 15 and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of C. albicans and an interesting antitubercular activity against M. Tuberculosis ³⁵. Kiniet al., synthesized a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives 16 and determined their activity against the strain of Mycobacterium ³⁶.

Ali et al., synthesized a series of 5-(-4-(Substituted) phenyl) – 3 - (4 – hydroxyl – 3 - methylphenyl) -4, 5 – dihydro -1H-1- pyrazolyl – 2 - toluidino methanethione and 5-(Substituted) phenyl-3-(4-hydroxy – 3 - methylphenyl) - 4, 5-dihydro-1H-1- pyrazolyl-2-methoxyanilino methanethione17and tested for their in-vitro antitubercular activity against M. tuberculosis. Among the synthesized compounds, compound Anilino-3-(4-hydroxy-3-methylphenyl) – 5 - (2, 6 - dichlorophenyl) - 4, 5-dihydro-1H-1-pyrazolylmethanethione was found to be a more active agent against M. Tuberculosis ³⁷.

Babu et al. synthesized and evaluated biological activity of 1, 3, 5-Trisubstituted pyrazolines bearing benzofuran ¹⁸. They were found to be antitubercular, antimicrobial and antiinflammatory in nature ³⁸.

M Ali et al., (2007) have synthesized some novel pyrazoline derivatives and have evaluated the antitubercular activity. Compounds with hydroxy phenyl substituted showed more active when compared to the standard drug INH ³⁹.

Antimicrobial Activity: Samir Bondock et al., 2010, had synthesized a series of substituted pyrazole derivatives. The given compound 20 was found to exhibit the most potent in-vitro antifungal activity with MICs (6.25 μ/ml) against A. fumigatus & F. Oxysporum comparable with Chloro-amphenicol ⁴⁰. Smaail Radi et al., (2010) synthesized novel pyrazole derivatives and these derivatives were evaluated for their antimicrobial activity determined by agar plate diffusion technique. Antibacterial activity: Against antibacterial strains Escherichia coli and determined by agar plate diffusion method. Antifungal activity: Against two fungal strains Saccharomyces cerevisae and Fusarium oxysporum f. sp.ablicans. Streptomycin was used as reference compound in performing antimicrobial assay. These derivatives Fig. 8 were found to be most potent ⁴¹.

S. K. Sahu et al., (2008) synthesized novel pyrazoline derivatives. The derivatives a, b & c Fig. 25 showed potent Antimicrobial activity: Antibacterial activity; by muller hinton agar (Hi-media) plates by agar diffusion cup-plate method for Staphylococcus aureus, Salmonella typhi & E. coli. Antifungal activity; was tested on sabouraud dextrose agar plates by cup-plate method against Candida albicans & Aspergillus niger).

In both of these assays ciprofloxacin and cotrimazole was used as standard drugs. Also the compounds 2 c & 2 e Fig. 9 showed effective analgesic (by Tail flick method) and anti-inflammatory (by Carageenan induced rat paw edema method) ⁴².

FIG. 25: SYNTHESIZED PYRAZOLINE DERIVATIVES 

Davood Azarifar et al., (2002) have synthesized and characterized some new 3, 5-dinaphthyl substituted 2-Pyrazolines and studied their antimicrobial activity. All the compounds showed activity against the test organisms Klebsiella pneumonia and Staphylococcus aureus. Among these, one was found to be the most active since this compound could inhibit the microbial growth at lower concentrations ⁴³. Ozdemir et al synthesized several 1-(4-Aryl-2-thiazolyl)- 3 - (2 - thienyl) – 5 – aryl – 2 -pyrazoline derivatives 27 and investigated their antimicrobial activities against Escherichiacoli, Staphylococcus aureus, Salmonella typhimurium, Bacillus cereus, Streptococcus faecalis, Aeromona shydrophila, Candida albicans and Candida glabrata ⁴⁴.

Abdelwahab et al synthesized 1-(Benzofuran-2-yl)-4- nitro-3-arylbutan-1-ones and 3-(Benzofuran-2-yl)-4, 5- dihydro - 5-aryl - 1-[4-(aryl)-1, 3-thiazol-2-yl]-1H-pyrazoles 7 and evaluated their anti-bacterial and antifungal activities ⁴⁵. Stirrett et al., ²⁹ synthesized small molecules 29 with structural similarities to siderophores and evaluated them as novel antimicrobials against Mycobacterium tuberculosis and Yersinia pestis ⁴⁶.

FIG. 28: 1-(BENZOFURAN-2-YL)-4- NITRO-3-ARYLBUTAN-1-ONES AND 3-(BENZOFURAN-2-YL)-4, 5- DIHYDRO-5-ARYL-1-[4-(ARYL)-1, 3-THIAZOL-2-YL]-1H-PYRAZOLES 7

FIG. 29: SMALL MOLECULES OF PYRAZOLINE

Abunada et al. synthesized several 1, 3-Diaryl-5-(cyano-,aminocarbonyl- and ethoxycarbonyl) -2-pyrazoline, pyrrolo [3, 4-c]pyrazole-4, 6-dione and 1, 3, 4, 5-tetraaryl-2-pyrazoline derivatives 30 and screened their antimicrobial activities against E. coli, S. aureus, Asperagillus flavus and C. albicans ⁴⁷.

FIG. 30: PYRAZOLINE DERIVATIVES 30

Bhatt et al., synthesized different types of pyrazolines and cyan pyridines 31as potential antimicrobial agents. They found that these have remarkable activity against B. mega, B. subtilis, E. coli, and M. tuberculosis ⁴⁸.

FIG. 31: SYNTHESIZED DIFFERENT TYPES OF PYRAZOLINES

Bharmal et al., synthesized some pyrazoline derivatives as biologically active agents. All the compounds 32 showed antimicrobial activity against S. typhosaand A. niger ⁴⁸.

FIG. 32: SYNTHESIZED SOME PYRAZOLINE DERIVATIVES

Antiamoebic Activity:  Kakul Husainet.al., have synthesized some Novel Pd (II) complexes of 1-N-substituted 3-phenyl-2-pyrazoline derivatives.

They have shown that among all the cyclized ligands, the N-cyclo-octyl amine in this series showed a close value for antiamoebic activity with the reference drug metronidazole ⁴⁹.

Abid et al., synthesized a series of new 1-N-substituted cyclized pyrazoline analogues of thiosemicarbazones by cyclisation of Mannich bases with thiosemicarbazide were subsequently evaluated for their antiamoebic activity by microdilution method against the strain of Entamoeba histolytica.

A series of palladium (II) complexes of 1-N-substituted thiocarbamoyl - 3, 5 – diphenyl – 2 -pyrazoline derivatives were reported possessed better antiamoebic activity as compared to other ligands and complexes ⁵⁰.

FIG. 33: SERIES OF NEW 1-N-SUBSTITUTED CYCLISED PYRAZOLINE

Bhat and co-workers reported bis-pyrazolines 34 prepared by cyclization of chalcones with N-4 substituted thiosemicarbazides under basic conditions. The antiamoebic activity results showed that the compound with aromatic substituents at the thiocarbamoyl group was more active than those with the cyclic groups ⁵¹.

FIG. 34: BIS-PYRAZOLINES

Antiviral Activity: Osama I et al (2009) synthesized 4, 5-disubstituted pyrazole derivatives. The derivative containing R= Cl group Fig. 16 showed the potent antiviral activity against a broad panel of viruses in different cell cultures (HEL Cell cultures).

FIG. 35: 4, 5-DISUBSTITUTED PYRAZOLE DERIVATIVES

Analgesic, Antipyretic Activity: Flora F. Barsoum et al., (2009) synthesized bis (3- aryl-4, 5-dihydro-1H Pyrazole-1-thio carboxamide derivatives. The derivative 36 with substitution, A = 4-O (CH₂)2O-4’, R = Ph, showed potent antiinflammatory activity against carrageen an-induced rat paw edema test ^52.

(A = 4-O (CH₂)2O-4’, R = Ph)

FIG. 36: BIS (3- ARYL-4, 5-DIHYDRO-1H PYRAZOLE-1-THIO CARBOXAMIDE DERIVATIVES

Ekta Bansal et al., (2001) have synthesized 1-acetyl-5-substituted aryl - 3 - (b-aminonaphthyl) – 2 -pyrazolines derivatives. They show that Compound substituted with phenyl ring having methoxy group at eitherortho or para positions exhibited the maximum percent inhibition of oedema ⁵³.

FIG. 37: 1-ACETYL-5-SUBSTITUTED ARYL-3-(B-AMINONAPHTHYL)-2-PYRAZOLINES

Rathish et al. synthesized new 1, 3, 5-trisubstituted pyrazolines bearing benzene sulphonamides 38 and evaluated their anti-inflammatory activity, several compounds demonstrated promising activity. Various 1-(4- sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines 39 were prepared and screened for cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibition ⁵⁴.

FIG. 38: COMPOUND ^{38, 39}

Amir et al., synthesized a series of 3-(4-Biphenyl)-5-substituted phenyl-2-pyrazolines and 1-Benzoyl-3-(4-biphenyl)-5-substituted phenyl-2- pyrazolines and screened for their anti-inflammatory and analgesic activity. Among the compounds studied, compound 40 showed more potent anti-inflammatory and analgesic activity than the standard drug, along with minimum ulcerogenic index ⁵⁵.

FIG. 40:  3-(4-BIPHENYL)-5-SUBSTITUTED PHENYL-2-PYRAZOLINES AND 1-BENZOYL-3-(4-BIPHENYL)-5-SUBSTITUTED PHENYL-2- PYRAZOLINES

Barsoum et al synthesized a variety of Bis (3-aryl- 4, 5-dihydro-1H-pyrazole-1-carboxamides) and screened for their anti-inflammatory properties and PGE2 inhibitory properties (at a dose level of 50 mg.kg-1) utilizing the in-vivo acute carrageenan-induced paw oedema standard method in rats. They exhibited that many of the tested compounds reveal considerable anti-inflammatory properties, especially [41.a and 41.b], which reveal remarkable activities relative to indomethacin (which was used as a reference standard at a dose of 10 mg.kg-1 of body weight). They exhibited lower ulcer index values than the used reference standard (indomethacin) ⁵⁶.

FIG. 41A: COMPOUND 41A, 41B: COMPOUND 41B

Rani et al ²² synthesized pyrazoline derivatives and evaluated them for their anti-inflammatory activity against carrageenan induced oedema in albino rats at a dose of 50 mg.kg-1 oral. All the compounds of this series showed promising anti-inflammatory activity. The most active compound of the series, 3-[1-Acetyl-5-(p-hydroxyphenyl)-2- pyrazolin-3-yl] indole ³² was found to be most potent, which had shown higher percent of inhibition of oedema, lower ulcerogenic liability, and acute toxicity than the standard drug phenylbutazone ⁵⁷.

FIG. 42: 3-[1-ACETYL-5-(P-HYDROXYPHENYL)-2- PYRAZOLIN-3-YL] INDOLE

Kelekc et al., synthesized a novel series of 1-Thiocarbamoyl - 3 - substituted phenyl-5-(2-pyrrolyl)-4, 5-dihydro-(1H)-pyrazole derivatives and tested for their in vivo anti-inflammatory activity by two different bio-assays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were also determined. The combined anti-inflammatory data from in-vivo animal models showed that compound 43 exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects ⁵⁸.

FIG. 43: 1-THIOCARBAMOYL-3-SUBSTITUTED PHENYL-5-(2-PYRROLYL)-4, 5-DIHYDRO-(1H)-PYRAZOLE

Khode et al., ²⁴ synthesized a novel series of 5-(Substituted) aryl – 3 - (3 - coumarinyl) – 1 - phenyl-2-pyrazolines and screened for in-vivo anti-inflammatory and analgesic activities at a dose of 200 mg.kg-1 of body weight. Among the 12 prepared compounds, Compound 44 exhibited significant anti-inflammatory activity in model of acute inflammation such as carrageenan-induced rat edema paw ⁵⁹.

FIG. 44: 5-(SUBSTITUTED) ARYL-3-(3-COUMARINYL)-1-PHENYL-2-PYRAZOLINES

Shoman et al., synthesized a group of NO-donating 2-pyrazoline derivatives 45 and evaluated for their anti-inflammatory activity using carrageenan-induced rat paw edema and compared it to a well-known NSAID, indomethacin, as a reference drug. The ability of the prepared compounds to induce gastric toxicity was also evaluated ⁶⁰. Kaplancikli et al., synthesized 1-[(Benzo-xazole / Benzimidazole-2-yl) thioacetyl] pyrazoline derivatives 46 and evaluated for antinociceptive activities ⁶¹.

Anticancer Activity: Peng-cheng LVet al., (2010) synthesized a series of pyrazole derivatives. The compound 47 having R1= 3, 4- 2CH3 and R2=4-OCH3 substitution own high antiproliferative activity ⁶². Havrylyuk et al., ⁵ synthesized several novel thiazolone-based compounds containing 5-Aryl-3-phenyl-4, 5-dihydro-1Hpyrazol- 1-yl framework and tested for in-vitro anticancer activity. Most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal and prostate, and breast cancer cell lines. The most efficient anticancer compound 48 was found to be active with selective influence on colon cancer cell lines ⁶³.

Bhat et al., synthesized a series of substituted pyrazoles ⁴⁹ and evaluated for in-vitro cytotoxic activity against a panel of human cancer cell lines. Out of 93 compounds screened, 8 compounds showed marked activity ⁶⁴. Manna et al., synthesized a series of substituted pyrazolines (1-Acetyl - 3, 5 – diphenyl - 4, 5 – dihydro - (1H)-pyrazole) and evaluated for their anticancer activity and for their ability to inhibit P-glycoprotein-mediated multidrug resistance by direct binding to a purified protein domain containing an ATP-binding site and a modulator interacting region. Compounds 50a and 50b have been found to bind to P-glycoprotein with greater affinity ⁶⁵.

Hypotensive Activity: Turan-Zitouni et al., synthesized some 1-(4-Arylthiazol-2-yl)-3, 5-diaryl-2-pyrazoline derivatives 51 and investigated their hypotensive activity by the tail-cuff method using clonidine as reference standard ⁶⁶.

FIG. 51: 1-(4-ARYLTHIAZOL-2-YL)-3, 5-DIARYL-2-PYRAZOLINE

ACE-Inhibitory Activity: Macro Bonesi et al., (2010) synthesized a series of pyrazole derivatives Fig. 5 and investigated their potential activity as Angiotensin-I-converting enzymes inhibitory activity by performing assay. This derivative of pyrazole Fig. 52 showed effective ACE-inhibitory activity ⁶⁷.

R1 R2 NO₂ OCH₃

FIG. 52: DERIVATIVE OF PYRAZOLE

Cholesterol Inhibitory Activity: Jeong et al ⁶¹ synthesized a series of 3-(3, 5-Di-tert-butyl-4- hydroxyphenyl) – 5 - (multi - substituted 4-hydroxyphenyl)-2-pyrazolines 53 and evaluated their inhibitory action on acyl-CoA: cholesterol acyltransferase ⁶⁸.

FIG. 53: 3-(3, 5-DI-TERT-BUTYL-4- HYDROXY-PHENYL) – 5 - (MULTI-SUBSTITUTED 4-HYDROXY-PHENYL)-2-PYRAZOLINES

Cannabinoid CB1 Receptor Antagonists: Cannabinoid CB1 receptor antagonists are currently the subject of intensive research due to their highly promising therapeutic prospects. NCEs having CB1 antagonistic properties have recently been disclosed by several pharmaceutical companies and some academic research groups; Srivastava et al. prepared a number of analogues of diaryl dihydropyrazole-3-carboxamides 54 and evaluated them for appetite suppression and bodyweight reduction in animal models ⁶⁹.

FIG. 54: DIARYL DIHYDROPYRAZOLE-3-CARBOX-AMIDES

Nitric Oxide Synthase Inhibitor: Nitric oxide synthase (NOS) is an enzyme in the body that contributes to synaptic transmission from one neuron to another, to the immune system and to dilating blood vessels. It does so by synthesis of nitric oxide (NO) from the terminal nitrogen atom of L-arginine in the presence of NADPH. There are three known isoforms of NOS; two are constitutive (cNOS) i.e., neural (nNOS) & endothelial (eNOS), and the third is inducible (iNOS), which is associated with biological functions brain and other parts of the body. Camacho et al. designed and synthesized 19 new nNOS inhibitors with a 4,5-dihydro-1H-pyrazole structure 55 in an attempt to find new compounds with neuroprotective activity.

Compounds 1-cyclopropanecarbonyl-3-(2-amino-5 - chlorophenyl) - 4, 5 - dihydro-1H-pyrazole and 1-cyclopropanecarbonyl – 3 - (2 – amino – 5 –methoxyphenyl)- 4,5-dihydro-1H-pyrazole show the highest activities with inhibition percentages of 70% and 62%, respectively. Similarly, Carriónet al. reported preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1Hpyrazoles 56 and 1-alkyl-3-benzoyl-1H-pyrazoles 57 as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS) ⁷⁰.

Steroidal Activity: Zhang et al., designed and synthesized a novel series of pyrazolines 58 and evaluated by in-vivo screening as tissue-selective androgen receptor modulators (SARMs).

Structure-activity relationships (SAR) were investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 positionare optimal for AR agonist activity. Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-endometriotic activities. Non-steroidal mime-tics of mifepristone and progesterone are important templates for modulation of the progesterone receptor (PR).

Jones et al., identified 4-substituted pyrazolines derivatives 59 by docking of compounds into a PR homology model, and when the same was synthesized and tested, exhibited functional antagonism of PR ⁷¹.

Antioxidant Activity: Babu et al., ⁶³ synthesized a series of pyrazoline derivatives and evaluated for antioxidant activity against standard drug ascorbic acid. Compound 60 showed excellentantioxidant activity as compared with ascorbic acid ⁷².

Polarity Probes Activity: Svechkarev et al., ⁵³ synthesized two novel 1, 3, 5-Triphenyl-2-pyra-zoline moiety containing derivatives of 3- hydroxychromone [61a, 61b] and discussed the prospects of the practical application of these compounds exhibiting high solvatofluorochromism into analytical chemistry and biophysics as effective ratiometric polarity probes proceeding from the data on their fluorescent properties ⁷³.

Amine Oxidase Inhibitory Activity: Manna et al. ⁶² synthesized a novel series of 1-Acetyl-3, 5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives and investigated for the ability to inhibit selectively MAOs, swine kidney oxidase, and bovine serum amine oxidase. 1-Acetyl-3-(2,4-dihydroxyphenyl)-5-(3-methylphenyl)-4,5- dihydro-(1H)-pyrazole ⁶² showed to be a potent monoamine oxidase inhibitor.

FIG. 62: 1-ACETYL-3-(2,4-DIHYDROXYPHENYL)-5-(3-METHYLPHENYL)-4,5- DIHYDRO-(1H)-PYRAZOLE

MAO-inhibitory Activity: Chimenti et al. ⁵⁷ synthesized a series of N1-propanoyl-3, 5-diphenyl-4, 5-dihydro-(1H)-pyrazole derivatives ⁵⁵ and assayed as inhibitors of MAO-A and MAO-B isoforms.

These showed inhibitory activity with micromolar values and MAO-A selectivity and found to be useful as co-adjuvants in the treatment of Parkinson’s disease (PD) and Alzhei-mer’sdisease.

Photoluminescence (PL) activity: Wang et al ⁵¹ synthesized 5 - (9 - Anthryl) – 3 - (4 - nitrophenyl)-1-phenyl - 2-pyrazoline (ANPP) ⁴⁹ and screened its photoluminescence property.

RESULTS AND DISCUSSION: In the present review, interest is focused on the profile of various pharmacological activities pyrazoline and its derivatives. Many scientists have synthesized novel pyrazoline derivatives. They have characterized the synthesized compounds by thin-layer chromato-graphic technique and analyzed the spectrum by IR, NMR, Mass spectra. Some compounds had been synthesized by the microwave method of synthesis, which is more convenient than the normal method of synthesis. The different biological activities were evaluated by in-vitro and in-vivo methods. In the present literature, it is seen that pyrazoline derivatives have been found to possess considerable biological activities, which stimulated the research activity in this field. Pyrazoline derivatives have prominent effects, such as antimicrobial, antimycobacterial, antifungal, anti-amoebic, anti-inflammatory, analgesic, anti-depressant, and anticancer activities. The neuro-toxicity study reveals that the synthesized pyrazoline derivatives have zero toxicity. It is one of the tools for the design of some novel pyrazoline derivatives. The pharmacokinetic study includes the % oral absorption, CNS activity etc which are also more prominent in pyrazoline derivatives. Some of the pyrazoline derivatives were also patented.

CONCLUSION: Pyrazoline is a unique template that is associated with several biological activities. This literature highlighted the research work of many researchers reported in the literature for different pharmacological activities on pyrazole and pyrazoline compounds synthesized. The review has presented comprehensive details of pyrazole and pyrazoline analogues, potent compounds reported for particular pharmacological activity. From the literature, we came to know that pyrazoline derivatives are having a broad spectrum of biological activities. Many new compounds have been made and patented, but still, there are new aspects to explore. So, it is concluded that the pyrazoline nucleus is one of the basic pharmacophores for the design of new drug development.

ACKNOWLEDGEMENT: The author is grateful to thank Dr. Biswajit Dash for guiding me.

CONFLICTS OF INTEREST: The author did not have any conflict of interest.

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    Dash B and Karim S: Pyrazoline heterocyclic: a review. Int J Pharm Sci & Res 2021; 12(5): 2570-88. doi: 10.13040/IJPSR.0975-8232.12(5).2570-88.

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