Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.


Introduction
Pyrazoles are five-membered heterocycles that constitute a class of compounds particularly useful in organic synthesis. They are one of the most studied groups of compounds among the azole family. Indeed, a huge variety of synthesis methods and synthetic analogues have been reported over the years.
The presence of the pyrazole nucleus in different structures leads to diversified applications in different areas such as technology, medicine and agriculture. In particular, they are described as inhibitors of protein glycation, antibacterial, antifungal, anticancer, antidepressant, antiinflammatory, anti-tuberculosis, antioxidant as well as antiviral agents [1,2].
In this review, we present descriptions and discussions on the most relevant synthesis methods and pharmacological properties of pyrazole-derived heterocyclic systems.

The Main Methods of Access to the Pyrazole Nucleus
Pyrazole is a π-excess aromatic heterocycle. Electrophilic substitution reactions occur preferentially at position 4 and nucleophilic attacks at positions 3 and 5 ( Figure 2). The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. The various access routes to the pyrazole nucleus have undergone numerous modifications since the first syntheses described by Knorr [11]. In this section, we will study this evolution and present the methods generally used to access substituted pyrazoles, that is to say: • Cyclocondensation of hydrazine and similar derivatives with carbonyl systems. • Dipolar cycloadditions. • Multicomponent reactions.

Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems
The leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an α,β-unsaturated ketone ( Figure 3).

The Main Methods of Access to the Pyrazole Nucleus
Pyrazole is a π-excess aromatic heterocycle. Electrophilic substitution reactions occur preferentially at position 4 and nucleophilic attacks at positions 3 and 5 ( Figure 2).

The Main Methods of Access to the Pyrazole Nucleus
Pyrazole is a π-excess aromatic heterocycle. Electrophilic substitution reactions occur preferentially at position 4 and nucleophilic attacks at positions 3 and 5 ( Figure 2). The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. The various access routes to the pyrazole nucleus have undergone numerous modifications since the first syntheses described by Knorr [11]. In this section, we will study this evolution and present the methods generally used to access substituted pyrazoles, that is to say: • Cyclocondensation of hydrazine and similar derivatives with carbonyl systems. • Dipolar cycloadditions. • Multicomponent reactions.

Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems
The leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an α,β-unsaturated ketone ( Figure 3).  The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. The various access routes to the pyrazole nucleus have undergone numerous modifications since the first syntheses described by Knorr [11]. In this section, we will study this evolution and present the methods generally used to access substituted pyrazoles, that is to say:

Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems
The leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an α,β-unsaturated ketone ( Figure 3).

Cyclocondensation of Hydrazine and Its Derivatives on 1,3-Difunctional Systems
The leading method used for obtaining substituted pyrazoles is a cyclocondensation reaction between an appropriate hydrazine acting as a bidentate nucleophile and a carbon unit like a 1,3-dicarbonyl compound, a 1,3-dicarbonyl derivatives or an α,β-unsaturated ketone ( Figure 3).  The cyclocondensation of the 1,3-dicarbonyl compounds with the hydrazine derivatives is a simple and rapid approach to obtain polysubstituted pyrazoles. The first synthesis of the substituted pyrazoles was carried out in 1883 by Knorr et al. [11] who reacted β-diketone 1 with hydrazine derivatives to give two regioisomers 2 and 3 (Scheme 1).

From Vinyl Ketones
The cyclocondensation reaction between an α,β-ethylenic ketone and a hydrazine derivative results in the synthesis of pyrazolines which, after oxidation, provide the pyrazole ring (Scheme 9).  (4-(tert-butyl) phenyl)hydrazine 30 in the presence of copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] (PF6) as catalysts, to access pyrazoline 31. The corresponding 1,3,5-trisubstituted pyrazole 32 was obtained after oxidation in situ of this pyrazoline. The reaction protocol gave 1,3,5-triarylpyrazoles in good yields (about 82%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization stands without the requirement of an additional oxidizing reagent. The catalyst can be reused more than four cycles without much loss in the catalytic activity (Scheme 10) [19]. Rao et al. described the condensation of an α,β-ethylenic ketone 29 with p-(4-(tert-butyl)phenyl) hydrazine 30 in the presence of copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] (PF6) as catalysts, to access pyrazoline 31. The corresponding 1,3,5-trisubstituted pyrazole 32 was obtained after oxidation in situ of this pyrazoline. The reaction protocol gave 1,3,5-triarylpyrazoles in good yields (about 82%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, and oxidative aromatization stands without the requirement of an additional oxidizing reagent. The catalyst can be reused more than four cycles without much loss in the catalytic activity (Scheme 10) [19]. In the inverse case where the substituent in position β is the largest, the regioselectivity decreases. Indeed, when β-aminoenones 50a, 50b and 50c were replaced by their position isomers 50d, 50e and 50f in the previous reactions, a drop in regioselectivity was observed (Scheme 18 and Table 2). Scheme 16. Synthesis of pyrazoles starting from α-benzotriazolylenones.
Alberola et al. [26] studied the regioselectivity of the reaction of various β-aminoenones on different monoalkyl, acetyl-, methoxycarbonyl-hydrazine and semicarbazide. Indeed, when the least bulky substituent is attached at the β position of the enone, high regioselectivity is obtained. This is the case of pyrazoles 51 and 52 which have been obtained with a regioselectivity greater than 90% from the reaction of alkylhydrazines (R1 = Me, t-Bu), in DMSO, with β-aminoenones 50a, 50b and 50c which possess the smallest group (CH 3 ) in the β position (Scheme 17 and Table 1). Alberola et al. [26] studied the regioselectivity of the reaction of various β-aminoenones on different monoalkyl, acetyl-, methoxycarbonyl-hydrazine and semicarbazide. Indeed, when the least bulky substituent is attached at the β position of the enone, high regioselectivity is obtained. This is the case of pyrazoles 51 and 52 which have been obtained with a regioselectivity greater than 90% from the reaction of alkylhydrazines (R1 = Me, t-Bu), in DMSO, with β-aminoenones 50a, 50b and 50c which possess the smallest group (CH3) in the β position (Scheme 17 and Table 1). Scheme 17. Synthesis of pyrazoles from β-aminoenones. In the inverse case where the substituent in position β is the largest, the regioselectivity decreases. Indeed, when β-aminoenones 50a, 50b and 50c were replaced by their position isomers 50d, 50e and 50f in the previous reactions, a drop in regioselectivity was observed (Scheme 18 and Table 2). Scheme 17. Synthesis of pyrazoles from β-aminoenones. In the inverse case where the substituent in position β is the largest, the regioselectivity decreases. Indeed, when β-aminoenones 50a, 50b and 50c were replaced by their position isomers 50d, 50e and 50f in the previous reactions, a drop in regioselectivity was observed (Scheme 18 and Table 2).

50c
t-Bu Me 72 t-Bu t- Bu 86 In the inverse case where the substituent in position β is the largest, the regioselectivity decreases. Indeed, when β-aminoenones 50a, 50b and 50c were replaced by their position isomers 50d, 50e and 50f in the previous reactions, a drop in regioselectivity was observed (Scheme 18 and Table 2). Scheme 18. Synthesis of pyrazoles from β-aminoenones. Scheme 18. Synthesis of pyrazoles from β-aminoenones. This phenomenon is all the more important as R and alkylhydrazine are more voluminous. In this context, in order to increase the regioselectivity (to increase the ratio 54/53) several experimental attempts have been carried out and have suggested that the selectivity would be improved if the reactions are catalyzed by acetic acid and carried out in DMSO or in ethanol.

The 1,3-Dipolar Cycloaddition
Other methods allowing access to the pyrazole nucleus involve [3 + 2] cyloaddition reactions between an alkyne (or an olefin) and 1,3-dipolar compounds such as the diazo compounds, the sydnones or the nitrilimines.

Cycloaddition of Diazocarbonyl Compounds
He et al. [27] investigated the action of ethyl α-diazoacetate 56 on phenylpropargyl 55 in triethylamine and in the presence of zinc triflate as a catalyst; the 1,3-dipolar cycloaddition reaction, leads to the corresponding pyrazole 57 in good yield (89%). The simple reaction conditions, straightforward procedure, synthetically useful products, good yielding, and easy manipulation make this method potentially useful in organic synthesis (Scheme 19).  This phenomenon is all the more important as R and alkylhydrazine are more voluminous. In this context, in order to increase the regioselectivity (to increase the ratio 54/53) several experimental attempts have been carried out and have suggested that the selectivity would be improved if the reactions are catalyzed by acetic acid and carried out in DMSO or in ethanol.

The 1,3-Dipolar Cycloaddition
Other methods allowing access to the pyrazole nucleus involve [3 + 2] cyloaddition reactions between an alkyne (or an olefin) and 1,3-dipolar compounds such as the diazo compounds, the sydnones or the nitrilimines.

Cycloaddition of Diazocarbonyl Compounds
He et al. [27] investigated the action of ethyl α-diazoacetate 56 on phenylpropargyl 55 in triethylamine and in the presence of zinc triflate as a catalyst; the 1,3-dipolar cycloaddition reaction, leads to the corresponding pyrazole 57 in good yield (89%). The simple reaction conditions, straightforward procedure, synthetically useful products, good yielding, and easy manipulation make this method potentially useful in organic synthesis (Scheme 19). Gioiello and co-workers described a facile one-pot procedure for the synthesis of pyrazole-5-carboxylates by 1,3-dipolar cycloaddition of ethyl diazoacetate 58 with α-methylene carbonyl 59 compounds utilizing 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) as base and acetonitrile as solvent. Pyrazoles 60 and 61 were obtained with excellent regioselectivity and good yields. In particular, when 58 was reacted with 59 (with R1 = R2 = Ph) in the presence of 1.7 eq. of DBU in acetonitrile under argon atmosphere at room temperature, ethyl 3,4-diphenyl-1Hpyrazole-5-carboxylate was obtained in 65% yield after flash chromatography. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition water elimination (Scheme 20) [28].
Under the same conditions, the reaction of various aryl α-diazoarylacetacetates on methyl propionate led to the formation of two regioisomers 63 and 64. After cyclization, minor compound 64 (4-12%) is obtained by migration of the ester group on nitrogen atom. The majority compound 63 (77-90%) would be obtained by migration of the aryl group to the adjacent carbon atom followed by a prototropic rearrangement (Scheme 21) [29]. Scheme 21. Synthesis of pyrazoles using 1,3-dipolar cycloaddition of α-diazoarylacetacetates.
In another approach, Qi and Ready developed a direct and efficient access towards 3-acylpyrazoles 67 that involves the copper-promoted cycloaddition of acetylides 65 with diazocarbonyl compounds 66 under mild conditions. A wide variety of substituents is tolerated at both the acetylide and the diazo compound. The method is a rare example of an inverse-electron-demand cycloaddition (Scheme 22) [30]. In another approach, Qi and Ready developed a direct and efficient access towards 3-acylpyrazoles 67 that involves the copper-promoted cycloaddition of acetylides 65 with diazocarbonyl compounds 66 under mild conditions. A wide variety of substituents is tolerated at both the acetylide and the diazo compound. The method is a rare example of an inverse-electron-demand cycloaddition (Scheme 22) [30]. Under the same conditions, the reaction of various aryl α-diazoarylacetacetates on methyl propionate led to the formation of two regioisomers 63 and 64. After cyclization, minor compound 64 (4-12%) is obtained by migration of the ester group on nitrogen atom. The majority compound 63 (77-90%) would be obtained by migration of the aryl group to the adjacent carbon atom followed by a prototropic rearrangement (Scheme 21) [29]. Scheme 21. Synthesis of pyrazoles using 1,3-dipolar cycloaddition of α-diazoarylacetacetates.
In another approach, Qi and Ready developed a direct and efficient access towards 3-acylpyrazoles 67 that involves the copper-promoted cycloaddition of acetylides 65 with diazocarbonyl compounds 66 under mild conditions. A wide variety of substituents is tolerated at both the acetylide and the diazo compound. The method is a rare example of an inverse-electron-demand cycloaddition (Scheme 22) [30]. Scheme 22. Synthesis of 3-acylpyrazoles using 1,3-dipolar cycloaddition of diazocarbonyl and acetylides.

The Sydnones
The pyrazoles ca obtained by a cycloaddition reaction of sydnones. Delaunay and co-workers presented the synthesis of the two regioisomeric 1,3,4,5-substituted pyrazoles 70 and 71 via a cycloaddition reaction between a sydnone 68 and alkyne 69. The reaction was completed within 15 h, Scheme 22. Synthesis of 3-acylpyrazoles using 1,3-dipolar cycloaddition of diazocarbonyl and acetylides.

The Sydnones
The pyrazoles ca obtained by a cycloaddition reaction of sydnones. Delaunay and co-workers presented the synthesis of the two regioisomeric 1,3,4,5-substituted pyrazoles 70 and 71 via a cycloaddition reaction between a sydnone 68 and alkyne 69. The reaction was completed within 15 h, giving rise to a 3:1 mixture of regioisomeric 5-iodopyrazoles 70 and 71 in 84% combined yield. The pyrazoles were easily separated by silica gel chromatography, and the structure assignment of the desired major isomer 70 (63% isolated yield) was made on the basis of the 1 H-NMR spectrum [31] (Scheme 23). On the other hand, Chen et al. [32] described the synthesis of a trisubstituted pyrazole 74, by 1,3-dipolar cycloaddition of arylsydnones 72 and α,β-unsaturated ketone 73 in dry xylene (Scheme 24). On the other hand, Chen et al. [32] described the synthesis of a trisubstituted pyrazole 74, by 1,3-dipolar cycloaddition of arylsydnones 72 and α,β-unsaturated ketone 73 in dry xylene (Scheme 24). On the other hand, Chen et al. [32] described the synthesis of a trisubstituted pyrazole 74, by 1,3-dipolar cycloaddition of arylsydnones 72 and α,β-unsaturated ketone 73 in dry xylene (Scheme 24).

Nitrilimines
Dadiboyena et al. described the synthesis of 1,3,5-trisubstituted pyrazole 78 by 1,3-dipolar cycloaddition of diphenylnitrilimine 75 with an alkene 76 in dichloromethane in the presence of triethylamine. The trisubstituted pyrazole 78, isolated in 88% yield, was the only product rather than the expected spiro-pyrazoline 77 (Scheme 25) [33]. The reaction yielded the corresponding pyrazole in 72% yield. The protocol is simple and practical, employing economical and readily available reagents (Scheme 26) [34]. The reaction yielded the corresponding pyrazole in 72% yield. The protocol is simple and practical, employing economical and readily available reagents (Scheme 26) [34].

In Situ Formation of Carbonyl Derivatives
Harigae and co-workers reported the preparation of 3,5-substituted pyrazole 86 in good yields (68-99%) with high regioselectivity in one pot by the treatment of terminal alkynes 83 with aromatic aldehydes 84, molecular iodine, and hydrazines. The present reaction is a simple and practical method for the preparation of various 1,3-disubstituted pyrazoles from easily available compounds (Scheme 27) [35].

In Situ Formation of Carbonyl Derivatives
Harigae and co-workers reported the preparation of 3,5-substituted pyrazole 86 in good yields (68-99%) with high regioselectivity in one pot by the treatment of terminal alkynes 83 with aromatic aldehydes 84, molecular iodine, and hydrazines. The present reaction is a simple and practical method for the preparation of various 1,3-disubstituted pyrazoles from easily available compounds (Scheme 27) [35].
Lizuka and Kondo demonstrate palladocatalyzed carbonylation of acetylenic acids on aryl iodides 92 in the presence of hexacarbonyl molybdenum as a source of CO and tri-tert-butylphosphine as a palladium ligand, to similarly access 1,3,5-substituted pyrazoles 93 with excellent yields (58-94%). The one-pot formation of pyrazole in the presence of methylhydrazine was also successful and aryl iodides with electron withdrawing groups were easily converted into pyrazoles (Scheme 29) [37]. a palladium ligand, to similarly access 1,3,5-substituted pyrazoles 93 with excellent yields (58-94%). The one-pot formation of pyrazole in the presence of methylhydrazine was also successful and aryl iodides with electron withdrawing groups were easily converted into pyrazoles (Scheme 29) [37].
Scheme 29. Synthesis of pyrazoles by one-pot reaction of aryl iodides, acetylenic acids and methylhydrazine.

In Situ Formation of β-Aminoenones
Kovacs et al. developed a novel process for the synthesis of 3,5-substituted pyrazoles 97 via cuprocatalyzed coupling between an alkyne 95 and an oxime 94 in dimethylformamide, which provides the β-aminoenone 96. The valuable β-aminoenone was transformed into pyrazoles with the addition of hydrazine in a straightforward one-pot procedure; the product 97 was isolated with 70% yield (Scheme 30) [38].

Scheme 29.
Synthesis of pyrazoles by one-pot reaction of aryl iodides, acetylenic acids and methylhydrazine.

In Situ Formation of β-Aminoenones
Kovacs et al. developed a novel process for the synthesis of 3,5-substituted pyrazoles 97 via cuprocatalyzed coupling between an alkyne 95 and an oxime 94 in dimethylformamide, which provides the β-aminoenone 96. The valuable β-aminoenone was transformed into pyrazoles with the addition of hydrazine in a straightforward one-pot procedure; the product 97 was isolated with 70% yield (Scheme 30) [38]. a palladium ligand, to similarly access 1,3,5-substituted pyrazoles 93 with excellent yields (58-94%). The one-pot formation of pyrazole in the presence of methylhydrazine was also successful and aryl iodides with electron withdrawing groups were easily converted into pyrazoles (Scheme 29) [37].
Scheme 29. Synthesis of pyrazoles by one-pot reaction of aryl iodides, acetylenic acids and methylhydrazine.

In Situ Formation of β-Aminoenones
Kovacs et al. developed a novel process for the synthesis of 3,5-substituted pyrazoles 97 via cuprocatalyzed coupling between an alkyne 95 and an oxime 94 in dimethylformamide, which provides the β-aminoenone 96. The valuable β-aminoenone was transformed into pyrazoles with the addition of hydrazine in a straightforward one-pot procedure; the product 97 was isolated with 70% yield (Scheme 30) [38]. 1,3,4,5-Substituted pyrazoles 105 were regioselectively synthesized in modest to good yields (26-92%) by Deng and Mani from hydrazone 103 and a nitroolefin 104 in methanol [41]. As a result of this work, the same authors proposed another strategy for synthesis based on the use of the same substrates and selectively leading to 1,3,4-substituted pyrazoles. In this new approach, the cyclocondensation of nitroolefins 104 with hydrazones 103 is carried out using a strong base such as t-BuOK. After treatment with a strong acid, the desired pyrazole 105 is obtained in the form of a single regioisomer in excellent yields (42-88%) (Scheme 33) [42]. Scheme 33. Synthesis of 1,3,4,5-Substituted pyrazole derivatives.

In Situ Formation of Diazo Compounds
The Aggarwal team has developed a multicomponent process in which diazo 107 derivatives are generated in situ from various aldehydes 106 and tosylhydrazines, thus limiting the risks associated with the isolation of these compounds. These are then used in a 1,3-dipolar cycloaddition reaction to give corresponding pyrazoles 108 and 109 Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles in 24-67% Scheme 32. Synthesis of carboxaldehyde pyrazoles by Vilsmeier-Haack reaction.
1,3,4,5-Substituted pyrazoles 105 were regioselectively synthesized in modest to good yields (26-92%) by Deng and Mani from hydrazone 103 and a nitroolefin 104 in methanol [41]. As a result of this work, the same authors proposed another strategy for synthesis based on the use of the same substrates and selectively leading to 1,3,4-substituted pyrazoles. In this new approach, the cyclocondensation of nitroolefins 104 with hydrazones 103 is carried out using a strong base such as t-BuOK. After treatment with a strong acid, the desired pyrazole 105 is obtained in the form of a single regioisomer in excellent yields (42-88%) (Scheme 33) [42]. 1,3,4,5-Substituted pyrazoles 105 were regioselectively synthesized in modest to good yields (26-92%) by Deng and Mani from hydrazone 103 and a nitroolefin 104 in methanol [41]. As a result of this work, the same authors proposed another strategy for synthesis based on the use of the same substrates and selectively leading to 1,3,4-substituted pyrazoles. In this new approach, the cyclocondensation of nitroolefins 104 with hydrazones 103 is carried out using a strong base such as t-BuOK. After treatment with a strong acid, the desired pyrazole 105 is obtained in the form of a single regioisomer in excellent yields (42-88%) (Scheme 33) [42]. Scheme 33. Synthesis of 1,3,4,5-Substituted pyrazole derivatives.

In Situ Formation of Diazo Compounds
The Aggarwal team has developed a multicomponent process in which diazo 107 derivatives are generated in situ from various aldehydes 106 and tosylhydrazines, thus limiting the risks associated with the isolation of these compounds. These are then used in a 1,3-dipolar cycloaddition reaction to give corresponding pyrazoles 108 and 109 Diazo compounds derived from aldehydes Scheme 33. Synthesis of 1,3,4,5-Substituted pyrazole derivatives.

In Situ Formation of Diazo Compounds
The Aggarwal team has developed a multicomponent process in which diazo 107 derivatives are generated in situ from various aldehydes 106 and tosylhydrazines, thus limiting the risks associated with the isolation of these compounds. These are then used in a 1,3-dipolar cycloaddition reaction to give corresponding pyrazoles 108 and 109 Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles in 24-67% yields. Furthermore, the reaction of N-vinylimidazole and diazo compounds derived from aldehydes gave exclusively 3-substituted pyrazoles in a one-pot process with 32-79% yields (Scheme 34) [43]. Scheme 33. Synthesis of 1,3,4,5-Substituted pyrazole derivatives.

In Situ Formation of Diazo Compounds
The Aggarwal team has developed a multicomponent process in which diazo 107 derivatives are generated in situ from various aldehydes 106 and tosylhydrazines, thus limiting the risks associated with the isolation of these compounds. These are then used in a 1,3-dipolar cycloaddition reaction to give corresponding pyrazoles 108 and 109 Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles in 24-67% yields. Furthermore, the reaction of N-vinylimidazole and diazo compounds derived from aldehydes gave exclusively 3-substituted pyrazoles in a one-pot process with 32-79% yields (Scheme 34) [43].

Antibacterial and Antifungal Activity
Akbas et al. synthesized of series 1H-pyrazole-3-carboxylic acid derivatives ( Figure 4) and evaluated for their antibacterial activities against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas putida. The results showed that the compound 151 was the best compound in the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria [64]. A series of new pyrazoles containing a quinolinyl chalcone group were synthesized and assessed for antibacterial activity. Compound 152 was the most potent against bacterial and fungal strains [65].

Antibacterial and Antifungal Activity
Akbas et al. synthesized of series 1H-pyrazole-3-carboxylic acid derivatives ( Figure 4) and evaluated for their antibacterial activities against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas putida. The results showed that the compound 151 was the best compound in the series, exhibiting antibacterial activity against both Gram-positive and Gram-negative bacteria [64]. A series of new pyrazoles containing a quinolinyl chalcone group were synthesized and assessed for antibacterial activity. Compound 152 was the most potent against bacterial and fungal strains [65].  A series of pyrazole derivatives were synthesized and screened for their antibacterial properties against S. aureus, Bacillus subtilis, E. coli and P. aeruginosa. Among the tested compounds 158, 159, 160 and 161 ( Figure 5) have shown excellent antibacterial activity against all the tested bacterial strains as compared with the standard drug ceftriaxone, which was active at 3.125, 1.6125, 1.6125 and 1.6125 µ g/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa strains, respectively [68]. A series of pyrazole derivatives were synthesized and screened for their antibacterial properties against S. aureus, Bacillus subtilis, E. coli and P. aeruginosa. Among the tested compounds 158, 159, 160 and 161 ( Figure 5) have shown excellent antibacterial activity against all the tested bacterial strains as compared with the standard drug ceftriaxone, which was active at 3.125, 1.6125, 1.6125 and 1.6125 µg/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa strains, respectively [68]. A series of pyrazole derivatives were synthesized and screened for their antibacterial properties against S. aureus, Bacillus subtilis, E. coli and P. aeruginosa. Among the tested compounds 158, 159, 160 and 161 ( Figure 5) have shown excellent antibacterial activity against all the tested bacterial strains as compared with the standard drug ceftriaxone, which was active at 3.125, 1.6125, 1.6125 and 1.6125 µ g/mL against S. aureus, B. subtilis, E. coli, and P. aeruginosa strains, respectively [68].  A series of pyrazolylpyrazolines was synthesized and evaluated for their in vitro anti-microbial activity against two Gram-positive bacteria and two Gram-negative bacteria. The results schowed that the compound 162 was able to inhibit the growth of both the Gram-positive as well as Gram-negative bacteria [69]. A series of pyrazole derivatives were prepared and screened for their anti-bacterial and antifungal activities using ampicillin and norcadine as standard drugs. All the compounds were screened for their antimicrobial activities. The results for these derivatives showed good antibacterial activity for 163 and 164 [70].
B'Bhatt and Sharma synthesized a series of 3-(4-chlorophenyl)-5-((1-phenyl-3-aryl-1H-pyrazol-4yl)methylene)-2-thioxothiazolidin-4-ones. All the synthesized compounds were screened for in vitro antibacterial activity against E. coli, P. aeruginosa, S. aureus, and S. pyogenes and in vitro anti-fungal activity, these compounds were tested against C. albicans, A. niger and A. clavatus using ampicillin and griseofulvin as standard drugs. Compound 165 was found as a potent compound against E. coli, while compound 166 was found to be potent against S. aureus, S. pyogenes and was found to have very good activity against C. albicans [71].
1,3,4,5-Tetrasubstituted pyrazole derivatives were synthesized and tested for anti-microbial activity against S. aureus, E. coli, Aspergillus flavus and C. albicans. Compound 167 showed promising antibacterial and antifungal activity [72]. Padmaja et al. reported the synthesis and antimicrobial activity of substituted pyrazoles. Results showed that the compound with sulfone moieties 168 displayed the maximum activity [73]. Novel 1,5-diaryl pyrazole derivatives were synthesized and screened for their antimicrobial activity against E. coli, S. aureus, P. aeruginosa, K. pneumonia and for their antifungal activity against A. flavus, A. fumigates, P. marneffei and T. mentagrophytes. Compound 169 ( Figure 6) exhibited good antibacterial and antifungal activity with MIC value of 12.5 mg/mL [74]. A series of 1,3-diarylpyrazoles derivatives were synthesized and evaluated for their in vitro antibacterial activity against S. aureus, B. subtilis, E. coli, P. aeruginosa, and in vitro antifungal activity against A. niger and A. flavus. Compound 169 exhibited moderate antibacterial and antifungal activities against the tested bacteria and fungi [75]. A series of 3-(4-chlorophenyl)-4-substituted pyrazoles were synthesized and tested for antifungal activity against a pathogenic strain of fungi and antibacterial activity against Gram-positive and Gram-negative organisms. Among those tested, compound 171 ( Figure 6) showed good to excellent antimicrobial at MIC values of 0.0025 to 12.5 µg/mL against all the selected pathogenic bacteria and fungi [76]. 169 ( Figure 6) exhibited good antibacterial and antifungal activity with MIC value of 12.5 mg/mL [74]. A series of 1,3-diarylpyrazoles derivatives were synthesized and evaluated for their in vitro antibacterial activity against S. aureus, B. subtilis, E. coli, P. aeruginosa, and in vitro antifungal activity against A. niger and A. flavus. Compound 169 exhibited moderate antibacterial and antifungal activities against the tested bacteria and fungi [75]. A series of 3-(4-chlorophenyl)-4-substituted pyrazoles were synthesized and tested for antifungal activity against a pathogenic strain of fungi and antibacterial activity against Gram-positive and Gram-negative organisms. Among those tested, compound 171 ( Figure 6) showed good to excellent antimicrobial at MIC values of 0.0025 to 12.5 µ g/mL against all the selected pathogenic bacteria and fungi [76].  A series of novel imidazole derivatives containing substituted pyrazole moiety were synthesized by Vijesh et al. and screened for antifungal and antibacterial activities. Among the synthesized compounds, compound 172 was found to be potent antimicrobial agent [77]. Several pyrazole acyl thiourea derivatives were synthesized and antifungal activity against G. zeae, F. oxysporum, C. mandshurica. Compound 173 displayed good antifungal activities against the tested fungi [78]. A series of N-(substituted-pyridinyl)-1-methyl(phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives were synthesized by Wu et al. and evaluated in vitro against three kinds of phytopathogenic fungi (G. zeae, F. oxysporum, C. mandshurica). The results showed that the compound 174 displayed more than 73% inhibition activities against G. zeae at 100 µg/mL [79]. A series of 1,3-diaryl pyrazole derivatives bearing rhodanine-3-fatty acid moieties ( Figure 7) were synthesized and investigated for their in vitro antimicrobial activities against various Gram-positive and Gram-negative bacteria. Compound 175 was found active against the methicillin-resistant Staphylococcus aureus (MRSA) with a MIC of 2 mg/mL [80]. A series of novel pyrazole derivatives were synthesized by Desai et al. and screened for their in vitro antibacterial activity against S. aureus, S. pyogenes, E. coli, P. aeruginosa. The results indicated the compound 176 showed potent antibacterial activity against S. aureus, E. coli at 12.5 mg/mL [81]. Pyrido[1,2-a]benzimidazole derivatives bearing the aryloxypyrazole nucleus were synthesized and investigated for in vitro antimicrobial activity. Compound 177 was found active against employed pathogens [82]. Malladi et al. synthesized a series of new Schiff bases containing pyrazole rings and screened them for their antibacterial (S. aureus, B. subtilis, E. coli and P. aeruginosa) activity. The results revealed that, compound 178 exhibited significant antibacterial activity against the tested microorganisms with MIC value of 1.61 mg/mL [83]. A series of formyl-pyrazoles derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities. The compounds 179 exhibited promising antifungal and antibacterial activity with MIC values of 15-60 µg/mL against the different organisms tested [84]. The anti-bacterial activity of 5-aryloxypyrazole derivatives was reported by Song et al. Compound 180 showed good inhibitory activity against selected methicillin resistant and quinolone-resistant S. aureus (MRSA, QRSA) with MIC values in the range of 2-4 µg/mL [85]. Sayed and co-workers described the synthesis and antimicrobial activity of new pyrazole derivatives. The results revealed that the compound 181 showed significant antimicrobial activity against the tested microorganisms [86]. A series of novel 5-imidazopyrazole derivatives were synthesized and evaluated for their in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi. Compound 182 exhibited excellent antimicrobial activity as compared with the first line drugs [87]. exhibited significant antibacterial activity against the tested microorganisms with MIC value of 1.61 mg/mL [83]. A series of formyl-pyrazoles derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities. The compounds 179 exhibited promising antifungal and antibacterial activity with MIC values of 15-60 µ g/mL against the different organisms tested [84]. The anti-bacterial activity of 5-aryloxypyrazole derivatives was reported by Song et al. Compound 180 showed good inhibitory activity against selected methicillin resistant and quinolone-resistant S. aureus (MRSA, QRSA) with MIC values in the range of 2-4 µ g/mL [85]. Sayed and co-workers described the synthesis and antimicrobial activity of new pyrazole derivatives. The results revealed that the compound 181 showed significant antimicrobial activity against the tested microorganisms [86]. A series of novel 5-imidazopyrazole derivatives were synthesized and evaluated for their in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi. Compound 182 exhibited excellent antimicrobial activity as compared with the first line drugs [87].   [88]. Several pyrazole derivatives were synthesized and evaluated for their fungicidal activities against Botrytis cinerea, Rhizoctonia solani, Valsa mali Miyabe et Yamada, Thanatephorus cucumeris, Fusarium oxysporum, and Fusarium graminearum. The results indicated that the compound 184 showed the highest activity, with EC 50 values of 2.432, 2.182, 1.787, 1.638, 6.986 and 6.043 µg/mL against B. cinerea, R. solani, V. mali, T. cucumeris, F. oxysporum, and F. graminearum, respectively [89]. A series of 2,5-disubstitued-1,3,4-oxadiazole derivatives bearing a pyrazole moiety were synthesized and screened for their antibacterial activity against E. coli, S. aureus and P. aeruginosa, and for antifungal activity against A. flavus, C. keratinophilum and C. albicans. The evaluation of antimicrobial screening revealed that compounds 185 exhibited excellent activity [90]. A new series of quinazolin-4(3H)-one derivatives containing a (1,3-diphenyl-1H-pyrazol-4-yl) core were synthesized by Mehta et al. and screened for their antimicrobial, antifungal activities. The results showed that the compound 186 was found the most active against the tested pathogens [91]. A series of pyrazole derivatives containing 1,3,4-oxadiazoles moiety were synthesized by Ningaiah et al. and evaluated for their antimicrobial activity. Among the synthesized compounds, compound 187 showed good to moderate activity with MIC in the range of 20-50 µg/mL against bacteria and 25-55 µg/mL against fungi [92]. A series of pyrazole derivatives linked thiazole and imidazole were prepared and tested for antimicrobial activity. The compounds 188 and 189 exhibited excellent antibacterial and antifungal activities [93]. Du et al. synthesized a series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides and tested in vitro for their activities against seven phytopathogenic fungi. Among them N-(2-(5-bromo-1H-indazol-1-yl)-phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (190) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid [94].
for antimicrobial activity. The compounds 188 and 189 exhibited excellent antibacterial and antifungal activities [93]. Du et al. synthesized a series of novel 3-(difluoromethyl)-1-methyl-1H -pyrazole-4-carboxylic acid amides and tested in vitro for their activities against seven phytopathogenic fungi. Among them N-(2-(5-bromo-1H-indazol-1-yl)-phenyl)-3-(difluoromethyl) -1-methyl-1H-pyrazole-4-carboxamide (190) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid [94].  [96]. A series of new pyrazole derivatives were synthesized and evaluated for antimicrobial activity. Compound 193 showed the highest activities against tested organisms [97]. A series of isoxazolol pyrazole  [96]. A series of new pyrazole derivatives were synthesized and evaluated for antimicrobial activity. Compound 193 showed the highest activities against tested organisms [97]. A series of isoxazolol pyrazole carboxylate derivatives were synthesized and bioassayed in vitro against four types of phytopathogenic fungi (Alternaria porri, Marssonina coronaria, Cercospora petroselini and Rhizoctonia solani). The results showed that the compound 194 exhibited significant antifungal activity against R. solani, with an EC 50 value of 0.37 µg/mL [98]. A series of novel diterpene derivatives containing pyrazole ring were synthesized and investigated for their activity against S. aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Among the compounds tested, compound 195 showed the most potent activity with MIC values of 0.71-3.12 µg/mL against five multidrug-resistant S. aureus [99]. Elshaier et al. described the synthesis and antimicrobial activity of new series of pyrazole-thiobarbituric acid derivatives. Compound 196 was the most active against C. albicans with MIC = 4 µg/L, and exhibited the best activity against S. aureus, B. subtilis and E. faecalis with MIC = 16 µg/L [100]. A series of novel pyrazole-5-carboxylate derivatives containing a N-triazole scaffold were synthesized and screened for their in vitro antimicrobial activity against three Gram-positive and Gram-negative bacteria as well as three fungi. The results revealed that the compound 197 was more potent antibacterial activity against all bacterial strains, and showed excellent antifungal activities against A. niger and C. albicans in MIC = 4 µg/L [101]. Several new pyrazole derivatives incorporating a thiophene moiety were synthesized and evaluated for their antibacterial and antifungal activities. The results showed that compound 198 revealed a high degree of antibacterial activity towards Pseudomonas aeruginosa and inhibition effects against Escherichia coli [102].
The results revealed that the compound 197 was more potent antibacterial activity against all bacterial strains, and showed excellent antifungal activities against A. niger and C. albicans in MIC = 4 µ g/L [101]. Several new pyrazole derivatives incorporating a thiophene moiety were synthesized and evaluated for their antibacterial and antifungal activities. The results showed that compound 198 revealed a high degree of antibacterial activity towards Pseudomonas aeruginosa and inhibition effects against Escherichia coli [102]. derivatives and tested for their antimicrobial against bacterial strains E. coli and S. aureus. Data showed that pyrazole compound 204 was potent only at 0.075 mg/mL against the tested microorganisms [108]. A new series of pyrazole-containing s-triazine derivatives were synthesized by Sharma et al. and investigated for antimicrobial and antifungal activity against the growth of several microorganisms. Compound 205 exhibited antibacterial activity against bacterial strains: P. aeruginosa, M. luteus and methicillin-resistant S. aureu [109]. A series of pyridinium-tailored 5-trifluoromethylpyrazoles containing 1,3,4-oxadiazole moieties ( Figure 11) were constructed by Zhou et al. and evaluated in vitro for antimicrobial activities against three types of pathogenic bacteria and six fungal strains. Among these derivatives, compound 206 showed potent antibacterial effects against Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri with EC50 values within 0.467 and 0.600 µ g/mL, respectively [110]. Recently, Mondal et al. reported the syntheses and antimicrobial activity of some Ni(II), Cd(II) and Hg(II) complexes of a pyrazole containing Schiff base ligands. The results showed that the complex 207 demonstrated highest antimicrobial agents against both Gram positive and Gram negative bacteria [111]. A series of isoxazolyl thiazolyl pyrazoles were synthesized by Mor et al. and evaluated in vitro for antimicrobial activity. Amongst the newly synthesized compounds, compound 208 was found to exhibit the promising antibacterial activity against S. aureus [112]. A series of N-(1-methyl-1Hpyrazole-4-carbonyl)-thiourea derivatives were prepared and evaluated for antibacterial and antifungal activities. Compound 209 was found to be the most potent antimicrobial agent [113]. The synthesis and antibacterial activity of pyrazole derivative were described by Tanitame et al. Results showed that the compound 210 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases (MRSA, PRSA and VRE) with MIC = 1-2 µ g/mL [114]. Antibacterial activity of a-Acyl-pyrazole-3-carboxylic acids was described by Ç etin et al. Results showed that the compound 211 has very potent antibacterial activity against B.subtilis, S. aureus, E. coli, P. aeruginosa, and K. pneumonia [115]. A series of novel pyrazolyl alcohols were prepared and evaluated for their anti-bacterial activity. The compound 212 displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81 µ g/mL) [116]. A series of novel pyrazole  [111]. A series of isoxazolyl thiazolyl pyrazoles were synthesized by Mor et al. and evaluated in vitro for antimicrobial activity. Amongst the newly synthesized compounds, compound 208 was found to exhibit the promising antibacterial activity against S. aureus [112]. A series of N-(1-methyl-1H-pyrazole-4-carbonyl)-thiourea derivatives were prepared and evaluated for antibacterial and antifungal activities. Compound 209 was found to be the most potent antimicrobial agent [113]. The synthesis and antibacterial activity of pyrazole derivative were described by Tanitame et al. Results showed that the compound 210 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases (MRSA, PRSA and VRE) with MIC = 1-2 µg/mL [114]. Antibacterial activity of a-Acyl-pyrazole-3-carboxylic acids was described by Çetin et al. Results showed that the compound 211 has very potent antibacterial activity against B. subtilis, S. aureus, E. coli, P. aeruginosa, and K. pneumonia [115]. A series of novel pyrazolyl alcohols were prepared and evaluated for their anti-bacterial activity. The compound 212 displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81 µg/mL) [116]. A series of novel pyrazole oxime derivatives were synthesized and evaluated for fungicidal activities in vivo against Pseudoperonospora cubensis. Among the synthesized compounds, compound 213 (EC 50 = 0.51 µg/mL) showed excellent fungicidal activity against P. cubensis comparable or better than that of the control pyraclostrobin (EC 50 = 4.59 µg/mL) [117].

Anticancer Activity
A new class of pyrazole-oxindole ( Figure 12) were synthesized and investigated for their antiproliferative activity on different human cancer cell lines. Among the active compound 214 manifested significant cytotoxicity and inhibited tubulin assembly with IC50 3 µM [118]. Xu et al. reported compound 215 as hPKM2 activator with (AC50 = 0.011 µ M) as the most active anticancer agent with IC50 of 5.94 and 6.40 µM against A549 and NCI-H1299 cell lines respectively [119]. Pyrazoles derivatives synthetized by Viale et al. were secrenned for their anti-proliferative activity. The comparative data once again demonstrate the good antiproliferative activity of these compounds, confirming that 216 may be considered as a good lead compound for subsequent development [120]. Several pyrazole derivatives were reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results indicated that the synthetized compound 217 exhibit potent cytostatic properties displaying IC50 values of 1.5 µM [121]. A series of pyrazolo[1,5-a]pyrazin-4(5H)-ones were synthesized and tested to determine their ability to inhibit the growth of A549 and H322 cancer cells. Results showed that the compound 218 exerted good activity, with an IC50 of of 24.2 and 29.4 µM against A549 and H322 cells lines, respectively [122]. Balbi et al. synthesized a series of pyrazole derivatives and studied their antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung carcinoma A549 cells, and murine P388 leukemia cells. compound 216 demonstated significant antiproliferative agent [123]. A series of substituted pyrazole compounds were synthesized and evaluated in vitro for their anticancer effects on a panel of 60 cellular lines. Results showed that the compound 219 presented significant growth inhibitory effects on the tested cancer cells [124]. A series of 3,5-diarylpyrazole derivatives were synthesized and evaluated for their anticancer activity against five cell lines (breast cancer, prostate cancer, promyelocytic leukemia, lung cancer, colon cancer). Compound 220 was identified as a potent anticancer agent against all selected cell lines [125].

Anticancer Activity
A new class of pyrazole-oxindole ( Figure 12) were synthesized and investigated for their antiproliferative activity on different human cancer cell lines. Among the active compound 214 manifested significant cytotoxicity and inhibited tubulin assembly with IC 50  The comparative data once again demonstrate the good antiproliferative activity of these compounds, confirming that 216 may be considered as a good lead compound for subsequent development [120]. Several pyrazole derivatives were reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results indicated that the synthetized compound 217 exhibit potent cytostatic properties displaying IC 50 values of 1.5 µM [121]. A series of pyrazolo[1,5-a]pyrazin-4(5H)-ones were synthesized and tested to determine their ability to inhibit the growth of A549 and H322 cancer cells. Results showed that the compound 218 exerted good activity, with an IC 50 of of 24.2 and 29.4 µM against A549 and H322 cells lines, respectively [122]. Balbi et al. synthesized a series of pyrazole derivatives and studied their antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung carcinoma A549 cells, and murine P388 leukemia cells. compound 216 demonstated significant antiproliferative agent [123]. A series of substituted pyrazole compounds were synthesized and evaluated in vitro for their anticancer effects on a panel of 60 cellular lines. Results showed that the compound 219 presented significant growth inhibitory effects on the tested cancer cells [124]. A series of 3,5-diarylpyrazole derivatives were synthesized and evaluated for their anticancer activity against five cell lines (breast cancer, prostate cancer, promyelocytic leukemia, lung cancer, colon cancer). Compound 220 was identified as a potent anticancer agent against all selected cell lines [125]. Miao and co-worker synthesized a series of pyrazoles derivatives ( Figure 13) and investigated the effects of all the compounds on A549 cell growth. The results showed that the compounds 221-229 possessed the highest growth inhibitory effect and induced apoptosis of A549 lung cancer cells [126][127][128][129][130][131][132][133][134].  Figure 14) and evaluated them for their antitumor activity. Compound 230 was reported as the most potent anticancer agent against Ehrlich ascites carcinoma tumor cells [135]. Several [1,2,4]triazolo[1,5-a]pyridine-bearing pyrazole Miao and co-worker synthesized a series of pyrazoles derivatives ( Figure 13) and investigated the effects of all the compounds on A549 cell growth. The results showed that the compounds 221-229 possessed the highest growth inhibitory effect and induced apoptosis of A549 lung cancer cells [126][127][128][129][130][131][132][133][134]. Miao and co-worker synthesized a series of pyrazoles derivatives ( Figure 13) and investigated the effects of all the compounds on A549 cell growth. The results showed that the compounds 221-229 possessed the highest growth inhibitory effect and induced apoptosis of A549 lung cancer cells [126][127][128][129][130][131][132][133][134].   Figure 14) and evaluated them for their antitumor activity. Compound 230 was reported as the most potent anticancer agent against Ehrlich ascites carcinoma tumor cells [135]. Several [1,2,4]triazolo[1,5-a]pyridine-bearing pyrazole moieties were prepared by Jin et al. and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The compound 231 exerted the maximun anticancer actvity with IC 50 of 0.57 nM [136]. Newhouse et al. reported the synthesis and anticancer activity of pyrazole derivatives. Results showed that the compound 232 exhibit excellent enzyme activity (B-Raf inhibitor) [137]. A series of novel 3-(1H-indole-3-yl)-1H-pyrazole-5-carbohydrazide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against A549, HepG-2, BGC823 and BT474 cell lines. Compound 233 exhibited more potent antiproliferative activity [138]. A new family of protein farnesyltransferase inhibitors, based on a phenothiazine containing pyrazole scaffold, was synthesized and evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel.  Compound 238 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. Compound 238 progressed to clinical evaluation in a Phase I oncology setting [143]. A series of new pyrazolo [3,4-d]pyrimidines were synthesized and investigated for their anti-tumor activity. Compound 239 was the most active compound with IC50 equal to 7.5 nM [144]. A series of pyrazolo [3,4-b]pyridine derivatives were prepared by El-Borai et al. and tested for antitumor activity against liver cell line. Compounds 240 showed the highest activity with IC50 3.43 µ g/mL [145]. Hanan et al. developed a new series of pyrazoles derivatives bearing pyrazolo[1,5-a]pyrimidine scaffold and optimized for their activity against Janus kinase 2 inhibitors. Compound 241 was identified as a   7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268), with IC50 values 0.01, 0.02 and 0.04 µM, respectively [150]. The same authors synthesized a series of pyrazolyl semicarbazidoandrrostane derivatives and tested their cytotoxicity activity, whereby compound 246 displayed excellent cytotoxicity with IC50 values 0.02, 0.01 and 0.03 µM against MCF-7, NCI-H460 and SF-268 cells, respectively [151]. Puthiyapurayil et al. reported the synthesis and anticancer activity of pyrazoles derivatives bearing a S-substituted-1,3,4-oxadiazole moiety. Amongst the tested compounds, the compound 247 was the most promising anticancer agent, with an IC50 value of 15.54 µM in MCF-7 cells, compared to doxorubicin as standard drug [152]. Small pyrazole derivatives were developed and evaluated in vitro for their anticancer activity on HCC-derived cell lines. The compound 248 selected as potential agents active against hepatocellular carcinoma (HCC) and showed a promising inhibitory growth efficacy (IC50 = 50 mM) in SNU449 cell line [153]. Synthesis and anticancer activities of new pyrazole derivatives bearing 1,2,4-oxadiazole moiety were reported by Vujasinovic et al. Therefore, , non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268), with IC 50 values 0.01, 0.02 and 0.04 µM, respectively [150]. The same authors synthesized a series of pyrazolyl semicarbazidoandrrostane derivatives and tested their cytotoxicity activity, whereby compound 246 displayed excellent cytotoxicity with IC 50 values 0.02, 0.01 and 0.03 µM against MCF-7, NCI-H460 and SF-268 cells, respectively [151]. Puthiyapurayil et al. reported the synthesis and anticancer activity of pyrazoles derivatives bearing a S-substituted-1,3,4-oxadiazole moiety. Amongst the tested compounds, the compound 247 was the most promising anticancer agent, with an IC 50 value of 15.54 µM in MCF-7 cells, compared to doxorubicin as standard drug [152]. Small pyrazole derivatives were developed and evaluated in vitro for their anticancer activity on HCC-derived cell lines. The compound 248 selected as potential agents active against hepatocellular carcinoma (HCC) and showed a promising inhibitory growth efficacy (IC 50 = 50 mM) in SNU449 cell line [153]. Synthesis and anticancer activities of new pyrazole derivatives bearing 1,2,4-oxadiazole moiety were reported by Vujasinovic et al. Therefore, compound 249 presents a good starting point for design of new, more potent and safer anticancer therapeutics [154].  Within just 253 compounds, identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase both wild type and clinically relevant mutants [158]. A series of pyrazoles derivatives bearing 4b-amidopodophyllotoxin rings were synthesized and evaluated for anticancer activity against five human cancer cell lines. Among the series, one of the compounds, 254, showed significant antiproliferative activity in A549 (lung cancer) cell line [159]. Koca [158]. A series of pyrazoles derivatives bearing 4b-amidopodophyllotoxin rings were synthesized and evaluated for anticancer activity against five human cancer cell lines. Among the series, one of the compounds, 254, showed significant antiproliferative activity in A549 (lung cancer) cell line [159]. Koca et al. a new series of acyl thiourea derivatives containing pyrazole ring were prepared and evaluated for their anticancer activity. Compound 255 was reported as the most potent anticancer agent [160]. Miyamoto et al. described the synthesis and anticancer activity of 1H-pyrazole-5-carboxamide deriavtives. Compound 256 emerged as a highly potent VEGF receptor 2 kinase inhibitor with an IC 50 value of 0.95 nM and suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC 50 of 0.30 nM [161]. A series of novel pyrazolo[1,5-a] [1,4]dia-zepin-4-one derivatives containing ferrocene scaffolds ( Figure 18) were synthesized and evaluated for their anticancer activity against A549, H322 and H1299 lung cancer cells. Of them, compound 257 possessed notable cytotoxicity and selectivity for A549 vs. H1299 and H322 lung cancer cells [162]. Zhu et al. prepared a series of novel carbothioamide-pyrazole derivatives and tested for their in vitro cytotoxic activities against four human tumor cell lines. Results indicated that compound 258 exhibited potent cytotoxicity (IC50 = 6.51 µ M) against Raji cell [163].
A series of novel isosteviol-fused pyrazole derivatives were synthesized and evaluated in vitro for their antiproliferative activities on four human malignant cell lines. Results [164]. A series of imidazo[2,1-b]thiazoles bearing pyrazole moieties were synthesized and tested in vitro for their anticancer activity. Result showed that compounds 260 had the highest anticancer effect against CNS SNB-75 and renal UO-31 cancer cell lines [165]. Sun et al. synthesized a series of 1H-pyrazole-4-carboxamide derivatives and evaluated for their antiproliferative activities as CDKs inhibitors. Among all the synthesized compounds, compound 261 inhibited CDK2 with an IC50 value 25 nM [166]. Novel pyrazole-benzimidazole derivatives were synthesized and evaluated for their anticancer activities against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The 262 demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities [167]. A series of novel 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid derivatives were synthesized and assessed for their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines). Compound 263 exhibited promising cytotoxic activity against all cell lines with IC50 values of 1.6 µ M, 3.3 µM and 1.1 µM for Huh7, MCF7 and HCT116 cells, respectively [168]. Cd(II) complexes of tridentate nitrogen donor ligand, 2,6-bis(3,4,5-trimethylpyrazolyl)pyridine ( Figure 19) were synthesized and tested for cytotoxic activity against the human carcinoma cell lines HEP3B (hepatocellular carcinoma), PC3 (prostate adenocarcinoma), MCF7 (breast adenocarcinoma) and Saos2 (osteosarcoma). The results showed that, complex 264 is the most cytotoxic complex for PC3 [169]. A series of pyrazoles derivatives were synthesized and evaluated for their ALK5 inhibitory activity. Among them, compound 265 inhibited ALK5 phosphorylation with an IC50 value of 0.018 µM [170]. Li [164]. A series of imidazo[2,1-b]thiazoles bearing pyrazole moieties were synthesized and tested in vitro for their anticancer activity. Result showed that compounds 260 had the highest anticancer effect against CNS SNB-75 and renal UO-31 cancer cell lines [165]. Sun et al. synthesized a series of 1H-pyrazole-4-carboxamide derivatives and evaluated for their antiproliferative activities as CDKs inhibitors. Among all the synthesized compounds, compound 261 inhibited CDK2 with an IC 50 value 25 nM [166]. Novel pyrazole-benzimidazole derivatives were synthesized and evaluated for their anticancer activities against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The 262 demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities [167]. A series of novel 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid derivatives were synthesized and assessed for their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines). Compound 263 exhibited promising cytotoxic activity against all cell lines with IC 50 values of 1.6 µM, 3.3 µM and 1.1 µM for Huh7, MCF7 and HCT116 cells, respectively [168].
Cd(II) complexes of tridentate nitrogen donor ligand, 2,6-bis(3,4,5-trimethylpyrazolyl)pyridine ( Figure 19) were synthesized and tested for cytotoxic activity against the human carcinoma cell lines HEP3B (hepatocellular carcinoma), PC3 (prostate adenocarcinoma), MCF7 (breast adenocarcinoma) and Saos2 (osteosarcoma). The results showed that, complex 264 is the most cytotoxic complex for PC3 [169]. A series of pyrazoles derivatives were synthesized and evaluated for their ALK5 inhibitory activity. Among them, compound 265 inhibited ALK5 phosphorylation with an IC 50 value of 0.018 µM [170].  [177]. A series of novel 4-pyrazolecyclopentylpyrimidines were prepared and evaluated in vitro as IGF-1R tyrosine kinase inhibitors. Compound 273 was found to be most active, with an IC50 value of 10 nM [178]. Several new series of benzenesulfonamide derivatives incorporating pyrazole were prepared by Ibrahim et al. and screened for anti-tumor activity against the metalloenzyme carbonic anhydrase and human isoforms hCA I, II, IX and XII. The in vitro evaluation demonstrated compounds 274 was found to inhibit hCA XII with Ki of 3.7 nM [179]. New arylpyrazole linked benzimidazole conjugates were synthesized and evaluated for their ability to inhibit the growth of sixty cancer cell line panel. Compound 275 exhibited significant growth inhibitory activity against most of the cell lines ranging from 0.3 to 3 µM and expressed appreciable cytotoxic potential [180]. A series of pyrazolylpyrazolines inhibitors. Among these compounds, compound 267 (IC 50 = 13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value = 0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 µM [172]. A series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones were developed and evaluated in vitro for their anticancer activity against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. Compound 268 revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency [173].
A series of novel 5-phenyl-1H-pyrazole derivatives were synthesized by Wang et al. and evaluated for their antiproliferative as potential BRAFV600E inhibitors. Among them, compound 269 exhibited the most potent inhibitory activity with an IC 50 value of 0.33 µM for BRAFV600E and has better antiproliferative activity against WM266.4 and A375 with IC 50 value of 2.63 and 3.16 µM, respectively [174]. Yao et al. reported compound 270 to have appreciable inhibitory activity against class I and IIb HDAC and in vitro anticancer activities against several cancer cell lines [175].
A series of novel pyrazolyl hydroxamic acid derivatives ( Figure 20) were synthesized and investigated in vitro for their anticancer activities against human lung cancer cell line A549. The results showed that the compounds 271 (10 µM) exerted more effective anti-proliferation activity against A549 cell line [176]. Abd El-Karim et al. synthesized a series of novel benzofuran-pyrazole and evaluated for their in vitro antiproliferative activity. Compound 272 exhibited remarkable growth inhibitory activity pattern against leukemia CCRF-CEM, MOLT-4, lung cancer HOP-92, colon cancer HCC-2998, CNS cancer SNB-75, melanoma SK-MEL-2, ovarian cancer IGROV1, renal cancer 786-0, RXF 393, breast cancer HS 578T and T-47D (GI 50 : 1.00-2.71 µM) [177]. A series of novel 4-pyrazolecyclopentylpyrimidines were prepared and evaluated in vitro as IGF-1R tyrosine kinase inhibitors. Compound 273 was found to be most active, with an IC 50 value of 10 nM [178]. Several new series of benzenesulfonamide derivatives incorporating pyrazole were prepared by Ibrahim et al. and screened for anti-tumor activity against the metalloenzyme carbonic anhydrase and human isoforms hCA I, II, IX and XII. The in vitro evaluation demonstrated compounds 274 was found to inhibit hCA XII with Ki of 3.7 nM [179]. New arylpyrazole linked benzimidazole conjugates were synthesized and evaluated for their ability to inhibit the growth of sixty cancer cell line panel. Compound 275 exhibited significant growth inhibitory activity against most of the cell lines ranging from 0.3 to 3 µM and expressed appreciable cytotoxic potential [180]. A series of pyrazolylpyrazolines were synthesized and evaluated for carbonic anhydrase inhibitory activity against cytosolic human isozymes. Compound 276 exhibited better inhibition profile against hCA II (Ki = 0.17 nM) [181].   [177]. A series of novel 4-pyrazolecyclopentylpyrimidines were prepared and evaluated in vitro as IGF-1R tyrosine kinase inhibitors. Compound 273 was found to be most active, with an IC50 value of 10 nM [178]. Several new series of benzenesulfonamide derivatives incorporating pyrazole were prepared by Ibrahim et al. and screened for anti-tumor activity against the metalloenzyme carbonic anhydrase and human isoforms hCA I, II, IX and XII. The in vitro evaluation demonstrated compounds 274 was found to inhibit hCA XII with Ki of 3.7 nM [179]. New arylpyrazole linked benzimidazole conjugates were synthesized and evaluated for their ability to inhibit the growth of sixty cancer cell line panel. Compound 275 exhibited significant growth inhibitory activity against most of the cell lines ranging from 0.3 to 3 µM and expressed appreciable cytotoxic potential [180]. A series of pyrazolylpyrazolines were synthesized and evaluated for carbonic anhydrase inhibitory activity against cytosolic human isozymes. Compound 276 exhibited better inhibition profile against hCA II (Ki = 0.17 nM) [181].    [189]. N-(Benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives were synthesized and evaluated for anticancer activity as MEK inhibitors. Among these compounds, compound 285 showed the most potent inhibitory activity with IC 50 of 91 nM for MEK1 and GI 50 value of 0.26 µM for A549 cells [190].
Nitulescu et al. synthesized new pyrazole thiourea derivatives ( Figure 21) and studied their apoptotic effects in human cancer cells. The results showed that the compound 278 exhibited the highest apoptosis-inducing effect [183]. The same author described the synthesis of new pyrazole derivatives as inhibitors of the cell cycle kinases. The compound 279 induced a significant increase of cells in G2/M phases in conjunction with an increased expression of cyclin A and cyclin B, emerging as a promising anticancer drug [184]. New pyrazole chalcones derivatives were described and assessed in vitro for their anticancer activity. The compound 280 was reported as potent anticancer agent with IC50 values of 18 and 47 µM against HeLa and MCF-7 cell lines, respectively [185]. A series of pyrazole derivatives containing benzimidazole moiety were synthesized and evaluated for their potential anti-proliferative activity against three human tumor cell lines. Compound 281 showed potent growth inhibition against A549, MCF-7, HeLa and HaCaT cell lines with IC50 values of 1.13, 0.95 and 1.57 µ M, respectively [186]. Steroidal derivatives containing a pyrazole moiety were synthesized and evaluated for anticancer activity against a human leukemia cell line (HL-60). Compound 282 displayed promising behavior by showing better anticancer activity [187]. Shi et al. synthesized a series of pyrazole-carboxamide derivatives and evaluated for anticancer activity. Compound 283 exhibited strong inhibitory activity against MGC-803 cells, and showed the most potent telomerase inhibitory activity [188]. A series of pyrazoles derivatives synthesized by Alam et al. and evaluated for topoisomerase IIa inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Compound 284 showed superior cytotoxicity with an IC50 value of 7.01 µM for HeLa, 8.55 µM for NCI-H460 and 14.31 µM for MCF-7 cancer cell lines [189]. N-(Benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives were synthesized and evaluated for anticancer activity as MEK inhibitors. Among these compounds, compound 285 showed the most potent inhibitory activity with IC50 of 91 nM for MEK1 and GI50 value of 0.26 μM for A549 cells [190].   [192]. Pyrazole-benzimidazole derivatives are novel potent active Chk2 inhibitors were described by Galal et al. Out of the synthesized compounds, compound 288 was reported as the most potent effects as Chk2 inhibitors with cytotoxic properties besides their potentiation effects on the cytotoxicity of both cisplatin and doxorubicin, and showed marked antitumor activity as single agent in breast cancer-bearing animals [193]. A novel series of 1H-pyrazole-3-carboxylate derivatives were synthesized and screened for antitumor activity against BEL-7404, HepG2, NCI-H460, T-24, A549 tumor cell lines. Compound 289 exhibited lower IC 50 value (129.75 µM) against HepG2 [194]. Li et al. synthesized novel steroidal pyrazole derivatives and evaluated for their cytotoxicity activity against 293T cell lines and three cancers cell lines: A549, Hela and MCF-7. Compound 290, showed the highest potency, with an IC 50 values of 0.87 µM and 0.53 µM for 293T cell lines and Hela cell lines, respectively [195]. A series of scopoletin-pyrazole hybrids were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines including HCT-116, Hun7 and SW620. Results showed that the compound 291 exhibited potent cytotoxic activities with IC 50 values below 20 µM [196]. A series of pyrazole derivatives bearing Sorafenib scaffold were synthesized by Wang et al. and evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compound 292 exhibited moderate to good activity toward c-Met and showed moderate to no activity against CRAF, EGFR, Flt-3 kinases, and showed strong antitumor activities against A549, HepG2 and MCF-7 cell lines with IC 50 values of 2.84, 1.85 and 1.96 µM, respectively [197]. Several new 4-(3,3-dimethyltriazeno)-5-benzamidopyrazole derivatives were prepared and tested at 10 µM for their vitro anti-leukemic activity against K562 and Raji cell lines. The most active compound 293 showed growth inhibition values of 97.8% and 99.4% against the K562 and Raji cell lines, respectively [198]. non-histone proteins in cellular level, and demonstrated a notable in vivo anti-tumor activity in HCT-116 xeno-grafted model [192]. Pyrazole-benzimidazole derivatives are novel potent active Chk2 inhibitors were described by Galal et al. Out of the synthesized compounds, compound 288 was reported as the most potent effects as Chk2 inhibitors with cytotoxic properties besides their potentiation effects on the cytotoxicity of both cisplatin and doxorubicin, and showed marked antitumor activity as single agent in breast cancer-bearing animals [193].  [198].

Anti-Inflammatory and Analgesic Activity
A new group of pyrazole derivatives were designed ( Figure 23) for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Results indicated that the compound 294 exhibited significant COX-II inhibition (78.91±0.80 %) [199]. A series of 1H-pyrazolyl derivatives were described by Bekhit

Anti-Inflammatory and Analgesic Activity
A new group of pyrazole derivatives were designed ( Figure 23) for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. Results indicated that the compound 294 exhibited significant COX-II inhibition (78.91±0.80 %) [199]. A series of 1H-pyrazolyl derivatives were described by Bekhit et al. and tested for their in vivo anti-inflammatory activity. Compound 295 exhibited anti-inflammatory activity comparable to that of indomethacin (LD 50 > 500 mg/Kg), and showed good selective inhibitory activity against COX-2 enzyme [200]. Bekhit et al. synthesized a series of novel pyrazolyl benzenesulfonamide derivatives bearing thiazolyl ring and evaluated for anti-inflammatory activity. Among the synthesized compounds, compound 296 exhibited higher anti-inflammatory activity than the reference compound (indomethacin) [201]. 3,5-Diaryl pyrazole derivatives were prepared and evaluated for anti-inflammatory activity. Compound 297 was identified as the potent ant-inflammatory agent against TNF-α and IL-6 at 10 µM concentration [125]. Girisha et al. synthesized a novel series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazolines and screened for analgesic and anti-inflammatory activity. Compound 298 showed good activity comparable with that of standard drugs pentazocin and diclofenac sodium, respectively [202]. Sharma et al. synthesized and evaluated pyrazolyl-pyrazoline derivatives for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Amongst the tested compounds, 299 showed pronounced anti-inflammatory activity (32%) that was comparable to nimesulide (36%) [69]. Synthesis and anti-inflammatory evaluation of new 2,3-dihydro-imidazo[1,2-b]pyrazole derivatives were reported by Brullo et al., in which compound 300 showed an interesting dual activity inhibiting both fMLP-OMe and IL8-induced chemotaxis with IC 50 values of 3.9 and 1.2 nM, respectively [203]. A novel series of pyrazoles containing benzenesulfonamides were synthesized by El-Moghazy et al., and evaluated in vivo for their anti-inflammatory activity. Compound 301 was found to be the most active anti-inflammatory agent (62.67% inhibition of edema) comparable to that of indomethacin (60.8% inhibition of edema) [204].
Molecules 2018, 23, 134 37 of 85 et al. and tested for their in vivo anti-inflammatory activity. Compound 295 exhibited anti-inflammatory activity comparable to that of indomethacin (LD50 > 500 mg/Kg), and showed good selective inhibitory activity against COX-2 enzyme [200]. Bekhit et al. synthesized a series of novel pyrazolyl benzenesulfonamide derivatives bearing thiazolyl ring and evaluated for anti-inflammatory activity. Among the synthesized compounds, compound 296 exhibited higher anti-inflammatory activity than the reference compound (indomethacin) [201]. 3,5-Diaryl pyrazole derivatives were prepared and evaluated for anti-inflammatory activity. Compound 297 was identified as the potent ant-inflammatory agent against TNF-α and IL-6 at 10 µM concentration [125]. Girisha et al. synthesized a novel series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1phenyl-1H-pyrazol-4-yl)-2-pyrazolines and screened for analgesic and anti-inflammatory activity. Compound 298 showed good activity comparable with that of standard drugs pentazocin and diclofenac sodium, respectively [202]. Sharma et al. synthesized and evaluated pyrazolyl-pyrazoline derivatives for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Amongst the tested compounds, 299 showed pronounced anti-inflammatory activity (32%) that was comparable to nimesulide (36%) [69]. Synthesis and anti-inflammatory evaluation of new 2,3-dihydro-imidazo[1,2-b]pyrazole derivatives were reported by Brullo et al., in which compound 300 showed an interesting dual activity inhibiting both fMLP-OMe and IL8-induced chemotaxis with IC50 values of 3.9 and 1.2 nM, respectively [203]. A novel series of pyrazoles containing benzenesulfonamides were synthesized by El-Moghazy et al., and evaluated in vivo for their anti-inflammatory activity. Compound 301 was found to be the most active anti-inflammatory agent (62.67% inhibition of edema) comparable to that of indomethacin (60.8% inhibition of edema) [204].  [205]. A series of dihydropyrazolyl-thiazolinone derivatives were synthesized and evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 303 displayed the most potent COX-2 inhibitory activity with IC50 of 0.5 µM [206]. 1,3,4-Trisubstituted pyrazole derivatives were synthesized and screened for the anti-inflammatory activity by carrageenan-induced paw edema method. Compounds 304 showed excellent anti-inflammatory actvity (≥84.2% inhibition) compared to that of the standard drug diclofenac (86.72%) [207]. Novel series of celecoxib analogs were synthesized and evaluated for COX-1/COX-2 inhibitory activity and assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivative  [205]. A series of dihydropyrazolyl-thiazolinone derivatives were synthesized and evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 303 displayed the most potent COX-2 inhibitory activity with IC 50 of 0.5 µM [206]. 1,3,4-Trisubstituted pyrazole derivatives were synthesized and screened for the anti-inflammatory activity by carrageenan-induced paw edema method. Compounds 304 showed excellent anti-inflammatory actvity (≥84.2% inhibition) compared to that of the standard drug diclofenac (86.72%) [207]. Novel series of celecoxib analogs were synthesized and evaluated for COX-1/COX-2 inhibitory activity and assessed for their anti-inflammatory activity and ulcerogenic liability in vivo. The 3-(pyridin-3-yl)pyrazole derivative 305 exhibited the highest anti-inflammatory activity and demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug [208]. Karrouchi et al. synthesized pyrazole-hydrazone derivatives and evaluated for their anti-inflammatory activity. The anti-inflammatory activity of 306 at the dose of 100 mg/kg showed excellent protection against inflammation (92.59% inhibition) in comparison with Indomethacin [209]. A series of 1-(4-substituted-phenyl)-3-phenyl-1H-pyrazole-4-carbaldehydes were prepared and tested for their anti-inflammatory and analgesic activities. Among the prepared compounds, compound 307 exhibited the maximum anti-inflammatory and analgesic activities [210]. A novel series of pyrazole derivatives were synthesized by Tewari et al. and evaluated in vivo for their anti-inflammatory activity. Among all compounds, 308 showed comparable anti-inflammatory activity to nimesulide [211]. 305 exhibited the highest anti-inflammatory activity and demonstrated about 40% reduction in ulcerogenic potential relative to the reference drug [208]. Karrouchi et al. synthesized pyrazole-hydrazone derivatives and evaluated for their anti-inflammatory activity. The anti-inflammatory activity of 306 at the dose of 100 mg/kg showed excellent protection against inflammation (92.59% inhibition) in comparison with Indomethacin [209]. A series of 1-(4-substituted-phenyl)-3-phenyl-1H-pyrazole-4-carbaldehydes were prepared and tested for their anti-inflammatory and analgesic activities. Among the prepared compounds, compound 307 exhibited the maximum anti-inflammatory and analgesic activities [210]. A novel series of pyrazole derivatives were synthesized by Tewari et al. and evaluated in vivo for their anti-inflammatory activity. Among all compounds, 308 showed comparable anti-inflammatory activity to nimesulide [211]. Several new pyrazole derivatives ( Figure 25) containing a quinolone moiety were synthesized and tested for their anti-inflammatory and ulcerogenic effect. The most active compound 309 was found to be superior to celecoxib, and demonstrated the highest anti-inflammatory activity as well as the best binding profiles into the COX-2 binding site [212]. Hussain et al. synthesized pyrazole derivatives and investigated them for their, anti-inflammatory and analgesic activities. Results indicated that the compound 310 (80.29% inhibition) showed anti-inflammatory activity almost equal to that of the standard drug, ibuprofen (80.38%). Compound 311 showed moderate analgesic activity in comparison to their standard drugs [213]. Surendra Kumar et al. reported the synthesis and anti-inflammatory activity of pyrazole derivatives. The derivative 312 showed significant anti-inflammatory activity when compared to the standard drug diclofenc sodium [214]. A series of 1,3-diaryl pyrazole derivatives bearing aminoguanidine moiety were synthesized and evaluated for and anti-inflammatory activities. Compound 313 showed the greatest anti-inflammatory activity (93.59% inhibition), which was more potent than the reference drugs ibuprofen and indomethacin [215]. Compound 314 were identified by Pelcman et al., as the most potent inhibitors of human 15-lipoxygenase [216]. Wang et al. identified a series of novel pyrazole containing benzamides as potent RORγ inverse agonists. Compound 315 was found to be more potent, selective and have adequate profiles RORγ inverse agonists [217]. A series of novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates were synthesized and were screened for in vivo analgesic and anti-inflammatory activities. Compound 316 exhibited significant analgesic and anti-inflammatory activities at a dose of 25 mg/kg [218]. Several new pyrazole derivatives ( Figure 25) containing a quinolone moiety were synthesized and tested for their anti-inflammatory and ulcerogenic effect. The most active compound 309 was found to be superior to celecoxib, and demonstrated the highest anti-inflammatory activity as well as the best binding profiles into the COX-2 binding site [212]. Hussain et al. synthesized pyrazole derivatives and investigated them for their, anti-inflammatory and analgesic activities. Results indicated that the compound 310 (80.29% inhibition) showed anti-inflammatory activity almost equal to that of the standard drug, ibuprofen (80.38%). Compound 311 showed moderate analgesic activity in comparison to their standard drugs [213]. Surendra Kumar et al. reported the synthesis and anti-inflammatory activity of pyrazole derivatives. The derivative 312 showed significant anti-inflammatory activity when compared to the standard drug diclofenc sodium [214]. A series of 1,3-diaryl pyrazole derivatives bearing aminoguanidine moiety were synthesized and evaluated for and anti-inflammatory activities. Compound 313 showed the greatest anti-inflammatory activity (93.59% inhibition), which was more potent than the reference drugs ibuprofen and indomethacin [215]. Compound 314 were identified by Pelcman et al., as the most potent inhibitors of human 15-lipoxygenase [216]. Wang et al. identified a series of novel pyrazole containing benzamides as potent RORγ inverse agonists. Compound 315 was found to be more potent, selective and have adequate profiles RORγ inverse agonists [217]. A series of novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates were synthesized and were screened for in vivo analgesic and anti-inflammatory activities. Compound 316 exhibited significant analgesic and anti-inflammatory activities at a dose of 25 mg/kg [218]. A new series of pyrazole-substituted were synthesized and investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique. Results revealed that, compound 317 seems to be the most effective prepared anti-inflammatory agent, revealing better activity (89.57% inhibition of edema) ( Figure 26) [219]. Several new 1H-pyrazole-4-acetates containing quinazolinone rings were synthesized and screened for their analgesic and anti-inflammatory activities. Compound 318 showed appreciable anti-inflammatory and analgesic activities [220]. Compound 319 was identified by Hall et al. as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain [221]. De Moura et al. identified new pyrazole-containing tetrazole compound 320 as a non-steroidal anti-inflammatory drug [222]. Some novel 1,3,4-trisubstituted pyrazoles were synthesized by Ragab et al. and screened for their anti-inflammatory and analgesic activities. Compound 321 was found to be the most active one as anti-inflammatory and analgesic agents [223]. Vijesh et al. described the synthesis and analgesic activity of new 1,2,4-triazole and benzoxazole derivatives containing pyrazole moieties. The results revealed that the compound 322 showed significant analgesic activity [224]. A series of new substituted pyrazoline derivatives linked to a substituted pyrazole scaffold were prepared by Vieka et al. and screened for their anti-inflammatory and analgesic activities. The results revealed that the compound 323 could be identified as the most active member within this study with a dual anti-inflammatory and analgesic profile [225]. A series of novel 5-methyl-2-phenylthiazole-4-substituted-pyrazole derivatives were synthesized and evaluated for their anti-inflammatory and analgesic activities. Derivative 324 exhibited moderate to good anti-inflammatory and analgesic activities [226].  A new series of pyrazole-substituted were synthesized and investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique. Results revealed that, compound 317 seems to be the most effective prepared anti-inflammatory agent, revealing better activity (89.57% inhibition of edema) ( Figure 26) [219]. Several new 1H-pyrazole-4acetates containing quinazolinone rings were synthesized and screened for their analgesic and anti-inflammatory activities. Compound 318 showed appreciable anti-inflammatory and analgesic activities [220]. Compound 319 was identified by Hall et al. as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain [221]. De Moura et al. identified new pyrazole-containing tetrazole compound 320 as a non-steroidal anti-inflammatory drug [222]. Some novel 1,3,4-trisubstituted pyrazoles were synthesized by Ragab et al. and screened for their anti-inflammatory and analgesic activities. Compound 321 was found to be the most active one as anti-inflammatory and analgesic agents [223]. Vijesh et al. described the synthesis and analgesic activity of new 1,2,4-triazole and benzoxazole derivatives containing pyrazole moieties. The results revealed that the compound 322 showed significant analgesic activity [224]. A series of new substituted pyrazoline derivatives linked to a substituted pyrazole scaffold were prepared by Vieka et al. and screened for their anti-inflammatory and analgesic activities. The results revealed that the compound 323 could be identified as the most active member within this study with a dual anti-inflammatory and analgesic profile [225]. A series of novel 5-methyl-2-phenylthiazole-4-substituted-pyrazole derivatives were synthesized and evaluated for their anti-inflammatory and analgesic activities. Derivative 324 exhibited moderate to good anti-inflammatory and analgesic activities [226]. A new series of pyrazole-substituted were synthesized and investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique. Results revealed that, compound 317 seems to be the most effective prepared anti-inflammatory agent, revealing better activity (89.57% inhibition of edema) ( Figure 26) [219]. Several new 1H-pyrazole-4-acetates containing quinazolinone rings were synthesized and screened for their analgesic and anti-inflammatory activities. Compound 318 showed appreciable anti-inflammatory and analgesic activities [220]. Compound 319 was identified by Hall et al. as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain [221]. De Moura et al. identified new pyrazole-containing tetrazole compound 320 as a non-steroidal anti-inflammatory drug [222]. Some novel 1,3,4-trisubstituted pyrazoles were synthesized by Ragab et al. and screened for their anti-inflammatory and analgesic activities. Compound 321 was found to be the most active one as anti-inflammatory and analgesic agents [223]. Vijesh et al. described the synthesis and analgesic activity of new 1,2,4-triazole and benzoxazole derivatives containing pyrazole moieties. The results revealed that the compound 322 showed significant analgesic activity [224]. A series of new substituted pyrazoline derivatives linked to a substituted pyrazole scaffold were prepared by Vieka et al. and screened for their anti-inflammatory and analgesic activities. The results revealed that the compound 323 could be identified as the most active member within this study with a dual anti-inflammatory and analgesic profile [225]. A series of novel 5-methyl-2-phenylthiazole-4-substituted-pyrazole derivatives were synthesized and evaluated for their anti-inflammatory and analgesic activities. Derivative 324 exhibited moderate to good anti-inflammatory and analgesic activities [226].  A series of pyrazole derivatives were synthesized ( Figure 27) by Chowdhury et al. All the compounds were evaluated for their anti-inflammatory potential using carrageenan-induced rat paw edema assay. Among the series compound 325 was found to possess potent anti-inflammatory potential (ED 50 value 61.2 mg/kg) [227]. In order to improve anti-inflammatory profile some modified and novel nitric oxide releasing coxib prodrugs were synthesize. In contrary to previously described results, compound 326 exhibited higher oral anti-inflammatory potency [228]. A series of novel pyrazole amalgamated flavones were synthesized and tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Among the synthesized compound 327 showed significant inhibitory profiles against COX-2, indicating that they are selective inhibitors for COX-2 [229]. Recently, novel, pyrazole-hydrazone derivatives as anti-inflammatory agents were synthesized and evaluated for their in vitro COX-1, COX-2 and 5-LOX enzymes inhibitition potential. Especially, Compound 328 (IC 50 = 0.58 lM) showed better COX-2 inhibitory activity than celecoxib (IC 50 = 0.87 lM) [230]. In search of novel anti-inflammatory motifs, several new pyrazole compounds were synthesized by Singh et al. and evaluated for cyclooxygenase inhibition against recombinant human COX-2 enzyme. Outcome of the study revealed that compound 329 having hydroxymethyl group ortho to sulfonamide group exhibited good inhibitory potency and selectivity toward COX-2 enzyme (SI = 297, COX-2 IC 50 = 0.036 mM) [231]. In order to explore the canine selective COX-2 inhibitory potential of N-methanesulfonylpyridinyl-substituted trifluoro-methylpyrazole derivatives, several compounds have been screened for their canine selective COX-2 inhibitory activity using in vitro canine whole blood (CWB) COX inhibition assay. Among all the synthesized derivatives, compound 330 was found to be most potent COX-2 inhibitor with high selectivity index (IC 50 = 0.06 mM, SI = 132) [232]. Cheng et al. synthesized some new N-methanesulfonyl pyridinyl-substituted pyrazole derivatives bearing heteroaryl moiety at 5-position of pyrazole and evaluated in vitro canine selective COX-2 inhibitory activity. Compound 331 is the most potent and selective canine COX-2 inhibitor (IC 50 = 0.012 mM) which displayed COX-1/COX-2 selectivity ratio greater than 4000-fold and thus provided an excellent efficacy profile for the treatment of pain and inflammation [233]. Sakya and coworkers evaluated canine selective COX-2 inhibitory potential of some new substituted pyrazole derivatives. The results revealed that among prepared compounds, the compound 332 (COX-2 IC 50 = 0.063 mM, SI = 262) was found to be most potent and COX-2 selective [234]. A series of pyrazole derivatives were synthesized ( Figure 27) by Chowdhury et al. All the compounds were evaluated for their anti-inflammatory potential using carrageenan-induced rat paw edema assay. Among the series compound 325 was found to possess potent anti-inflammatory potential (ED50 value 61.2 mg/kg) [227]. In order to improve anti-inflammatory profile some modified and novel nitric oxide releasing coxib prodrugs were synthesize. In contrary to previously described results, compound 326 exhibited higher oral anti-inflammatory potency [228]. A series of novel pyrazole amalgamated flavones were synthesized and tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Among the synthesized compound 327 showed significant inhibitory profiles against COX-2, indicating that they are selective inhibitors for COX-2 [229]. Recently, novel, pyrazole-hydrazone derivatives as anti-inflammatory agents were synthesized and evaluated for their in vitro COX-1, COX-2 and 5-LOX enzymes inhibitition potential. Especially, Compound 328 (IC50 = 0.58 lM) showed better COX-2 inhibitory activity than celecoxib (IC50 = 0.87 lM) [230]. In search of novel anti-inflammatory motifs, several new pyrazole compounds were synthesized by Singh et al. and evaluated for cyclooxygenase inhibition against recombinant human COX-2 enzyme. Outcome of the study revealed that compound 329 having hydroxymethyl group ortho to sulfonamide group exhibited good inhibitory potency and selectivity toward COX-2 enzyme (SI = 297, COX-2 IC50 = 0.036 mM) [231]. In order to explore the canine selective COX-2 inhibitory potential of N-methanesulfonylpyridinyl-substituted trifluoro-methylpyrazole derivatives, several compounds have been screened for their canine selective COX-2 inhibitory activity using in vitro canine whole blood (CWB) COX inhibition assay. Among all the synthesized derivatives, compound 330 was found to be most potent COX-2 inhibitor with high selectivity index (IC50 = 0.06 mM, SI = 132) [232]. Cheng et al. synthesized some new N-methanesulfonyl pyridinyl-substituted pyrazole derivatives bearing heteroaryl moiety at 5-position of pyrazole and evaluated in vitro canine selective COX-2 inhibitory activity. Compound 331 is the most potent and selective canine COX-2 inhibitor (IC50 = 0.012 mM) which displayed COX-1/COX-2 selectivity ratio greater than 4000-fold and thus provided an excellent efficacy profile for the treatment of pain and inflammation [233]. Sakya and coworkers evaluated canine selective COX-2 inhibitory potential of some new substituted pyrazole derivatives. The results revealed that among prepared compounds, the compound 332 (COX-2 IC50 = 0.063 mM, SI = 262) was found to be most potent and COX-2 selective [234].  Sakya et al. also evaluated in vitro canine selective COX-2 inhibitory activity of some new N-methanesulfonylpyridinyl-substituted pyrazole derivatives bearing ether/thioether substituents using CWB assay ( Figure 28). The results revealed that among alkyl ethers, the compound 333 showed highest inhibitory potency and selectivity for COX-2 enzyme (IC 50 = 0.09 mM, SI = 127) [235].
In a study, Aggarwal et al. explored the effect of 3/5-trifluoromethylpyrazole derivatives on in vivo anti-inflammatory potency at a dose level 50 mg/kg. Among all the tested compounds, 334 possessed very high anti-inflammatory potential 78% comparable to indomethacin (78%) after 3 h induction [236]. Knaus et al. synthesized and evaluated in vitro COX-1/COX-2 inhibitory potential of the celecoxib analogs having an azido group in place of the SO 2 NH 2 moiety. The compound 335 was emerged as a selective COX-2 inhibitor [COX-1 IC 50 > 100 µM, COX-2 IC 50 = 1.5 µM, SI = 64] and displayed good anti-inflammatory properties [237]. In continuation to previous results, Knaus and coworkers have synthesized a series of celecoxib analogs and evaluated for their in vitro COX-1/COX-2 inhibitory activity with an expectation to find an efficient class of anti-inflammatory agents. Results revealed that compound 336 bearing SO 2 N 3 group at para-position inhibited the activity of COX-1 enzyme selectively [COX-1 IC 50 = 3.3 µM, COX-2 IC 50 > 100, SI > 0.033] [238]. Some novel 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles derivatives have been synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among all the tested compounds, compound 337 optimal COX-2 inhibitory potency (IC 50 = 0.31 µM, ED 50 = 74.3 mg/kg) [239]. Other 4-substituted novel trifluoromethylpyrazole derivatives have also been evaluated for their anti-inflammatory and COX-2 inhibitory potential. Results revealed that compound 338 displayed a promising degree of activity with ED 50 value in the range 0.261 mmol/kg, in comparison to the standard drug, diclofenac (ED 50 = 0.358 mmol/kg) and resulted 89.7% inhibition of edema at dose level of 200 mg/kg [240]. A series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory and COX-1 and COX-2 inhibitory activities. Among investigated compounds, compound 339 was found to possess anti-inflammatory activity comparable to that of indomethacin and celecoxib, and exhibited COX-1/COX-2 selectivity [241]. Tewari et al. synthesized a series of pyrazole ester prodrugs analogues and evaluated in vitro for COX-2 inhibitory activity. The results indicated that compound 340 showed to possess maximum inhibitory effect when compared to control group [242]. A series of 1,3,4-trisubstituted pyrazole derivatives have been synthesized and evaluated for their cyclooxygenase (COX-1 and COX-2) inhibitory activity. Among these derivatives, compound 341 was the most potent and selective COX-2 inhibitor (IC 50 = 1.33 µM), with a significant selectivity index (SI > 60) [243].  [239]. Other 4-substituted novel trifluoromethylpyrazole derivatives have also been evaluated for their anti-inflammatory and COX-2 inhibitory potential. Results revealed that compound 338 displayed a promising degree of activity with ED50 value in the range 0.261 mmol/kg, in comparison to the standard drug, diclofenac (ED50 = 0.358 mmol/kg) and resulted 89.7% inhibition of edema at dose level of 200 mg/kg [240]. A series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory and COX-1 and COX-2 inhibitory activities. Among investigated compounds, compound 339 was found to possess anti-inflammatory activity comparable to that of indomethacin and celecoxib, and exhibited COX-1/COX-2 selectivity [241]. Tewari et al. synthesized a series of pyrazole ester prodrugs analogues and evaluated in vitro for COX-2 inhibitory activity. The results indicated that compound 340 showed to possess maximum inhibitory effect when compared to control group [242]. A series of 1,3,4-trisubstituted pyrazole derivatives have been synthesized and evaluated for their cyclooxygenase (COX-1 and COX-2) inhibitory activity. Among these derivatives, compound 341 was the most potent and selective COX-2 inhibitor (IC50 = 1.33 μM), with a significant selectivity index (SI > 60) [243].   (Figure 29). Compound 342 was found to be most active agent with a MIC value of 25 µg/mL [244]. A series of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazoles were synthesized by Almeida da Silva et al. and tested for their in vitro antimycrobial activity against Mycobacterium tuberculosis H37Rv, INH-resistant clinical M. tuberculosis isolates non-tuberculous mycobacteria. Amongst the synthesized compounds, compound 343 was found to be the most active agents against susceptible M. tuberculosis and several INH-resistant strains [245]. As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by Castagnolo [248]. A series of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide analogues were synthesized and evaluated for antitubercular activity. The compound 347 was found to be the most promising compound active against M. tuberculosis H37Rv and isoniazid resistant M. tuberculosis with MIC concentration 3.12 µM and 6.25 µM, respectively [249]. A new N-aryl-1,4-dihydropyridines derivatives bearing 1H-pyrazole ring were synthesized and evaluated for antitubercular activity. The lowest MIC value 0.02 µg/mL, was found for compound 348 making it more potent than first line antitubercular drug isoniazid [250]. As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against M. tuberculosis H37Rv. Amongst them, compound 349 displayed the most potency with IC 50 of 0.47 µM [251]. As a part to develop novel antitubercular agent, a series of 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesized by Pathak et al. and tested for antitubercular activity in vitro against M. tuberculosis H37Rv strain. Among them tested, compound 350 showed excellent antitubercular activity with MIC of 0.35 mg/mL [76].

Anti-Tubercular Activity
Manetti et al. identified new inhibitors of Mycobacterium tuberculosis ( Figure 29). Compound 342 was found to be most active agent with a MIC value of 25 µ g/mL [244]. A series of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-1H-1-isonicotinoyl-4,5-dihydropyrazoles were synthesized by Almeida da Silva et al. and tested for their in vitro antimycrobial activity against Mycobacterium tuberculosis H37Rv, INH-resistant clinical M. tuberculosis isolates non-tuberculous mycobacteria. Amongst the synthesized compounds, compound 343 was found to be the most active agents against susceptible M. tuberculosis and several INH-resistant strains [245]. As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by Castagnolo et al. and assayed as inhibitors of M. tuberculosis H37Rv. The pyrazole derivative 344, with the p-bromophenyl group at the N1 position, was showed to be very active (MIC = 4 µ g/mL) [246]. Velaparthi  The results showed that compound 346 bearing N-Me-piperazine and morpholine moieties proved to be very active with MIC = 4 µ g/mL [248]. A series of 3a,4-dihydro-3Hindeno[1,2-c]pyrazole-2-carboxamide analogues were synthesized and evaluated for antitubercular activity. The compound 347 was found to be the most promising compound active against M. tuberculosis H37Rv and isoniazid resistant M. tuberculosis with MIC concentration 3.12 µM and 6.25 µ M, respectively [249]. A new N-aryl-1,4-dihydropyridines derivatives bearing 1H-pyrazole ring were synthesized and evaluated for antitubercular activity. The lowest MIC value 0.02 µ g/mL, was found for compound 348 making it more potent than first line antitubercular drug isoniazid [250]. As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against M. tuberculosis H37Rv. Amongst them, compound 349 displayed the most potency with IC50 of 0.47 µM [251]. As a part to develop novel antitubercular agent, a series of 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesized by Pathak et al. and tested for antitubercular activity in vitro against M. tuberculosis H37Rv strain. Among them tested, compound 350 showed excellent antitubercular activity with MIC of 0.35 mg/mL [76].  displayed significant anti-tubercular activities against the M. tuberculosis H37Rv strain (MIC = 6.25 µ g/mL) [252]. A series of 1-[(4-benzyloxyphenyl)-but-3-enyl]-1H-azoles has been identified by Anand [260]. Novel 5-imidazopyrazoles incorporating 2-amino-3-cyano pyridine derivatives were synthesized and tested for their in vitro, anti-tuberculosis activity. Compound 360 displayed excellent inhibition (96% at 25 μg/mL) against anti-tubercular activity as compared to standard drugs [87]. A new category of polyhydroquinoline derivatives were synthesized were evaluated for their in vitro anti-tubercular activity against M. tuberculosis H37Rv strain. Compound 361 exhibited moderate anti-tuberculosis activity compared with the first line drugs. The outcome of the result revealed that, compound 361 was found to possess excellent activity (94% at 250 mg/mL and 100 mg/mL) against M. tuberculosis H37Rv [261]. Karad   Novel 5-imidazopyrazoles incorporating 2-amino-3-cyano pyridine derivatives were synthesized and tested for their in vitro, anti-tuberculosis activity. Compound 360 displayed excellent inhibition (96% at 25 µg/mL) against anti-tubercular activity as compared to standard drugs [87]. A new category of polyhydroquinoline derivatives were synthesized were evaluated for their in vitro anti-tubercular activity against M. tuberculosis H37Rv strain. Compound 361 exhibited moderate anti-tuberculosis activity compared with the first line drugs. The outcome of the result revealed that, compound 361 was found to possess excellent activity (94% at 250 mg/mL and 100 mg/mL) against M. tuberculosis H37Rv [261]. Karad et al. reported the synthesized and anti-tuberculosis activity against M. tuberculosis H37Rv of a novel series of fluoro-substituted pyrazolylpyrazolines. Good anti-tubercular activity was exhibited by compound 362 (96% at 250 mg/mL) [262]. Mehta et al. synthesized a new series of quinazolin-4(3H)-one derivatives containing a (1,3-diphenyl-1H-pyrazol-4-yl) core and screened for their anti-tubercular activities. Compound 363 was reported as the most active compound with MIC of 12.5 µg/mL against MTB H37Rv strain [91]. Various substituted 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone derivatives were synthesized by Pathak et al. and evaluated for their in vitro anti-tubercular activity against M. tuberculosis H37Rv strain. Compound 364 exhibited significant anti-tubercular activity at MIC value 12.5 µM concentration [263]. The design, synthesis, and in vitro anti-tubercular activity of compound 365 were reported by Villemagne and coworkers. The compound displayed moderate anti-tubercular activity (EC 50 > 10 µM) [264].  [263]. The design, synthesis, and in vitro anti-tubercular activity of compound 365 were reported by Villemagne and coworkers. The compound displayed moderate anti-tubercular activity (EC50 > 10 µM) [264].   [269]. Several 1,2,4-oxadiazole/pyrazole derivatives have been screened for anti-tubercular activity, and most of them showed weak to moderate activity. Amongst them, 1,2,4-oxadiazole pyrazole 371 displayed moderate potency against M. tuberculosis H37Rv strain [270]. A series of N-benzyl-4-((heteroaryl)methyl)-benzamides as a novel class of direct InhA inhibitors by high-throughput screening were identified by Guardia et al. These compounds displayed potent activity against MTB (MIC 90 : 6 to 125 µM), maintaining activity versus KatG mutant clinical strains (IC 50 : 12-31 µM) and emerging as a potential tool against MDR-TB and XDR-TB. The pyrazole derivative 372 (IC 50 = 0.04 µM) is a potent direct InhA inhibitor with moderate whole-cell activity and an encouraging safety profile, but unfortunately it was not efficacious in an in vivo murine model of TB infection [271]. Using a fragment-based approach, a novel series of potent and isoform selective inhibitors of the essential MTB enzyme CYP121 have been developed by Kavanagh [274]. A novel sila analogues of Rimonabant as potent anti-tubercular agents were identified by Ramesh et al. the sila analogue 376 was found to be the most potent anti-mycobacterial compound with MIC = 31 nM from this series with an excellent selectivity index [275]. Various 1-((1-(substituted)-1H-1,2,3-triazol-4-yl) methyl)-N,3-diphenyl-6,7dihydro-1H-pyrazolo [4,3-c]pyridine-5(4H)-carboxamides were prepared and screened for in vitro anti-tubercular activity against M. tuberculosis H37Rv strain. Among the compounds, 377 was found to be the most active compound with IC50 1.01 µM against MTB PS; it inhibited MTB with MIC 24.72 µM [276]. A new 2-aroyl- [1]benzopyrano [4,3-c]pyrazol-4(1H)-one derivatives containing hydrazide-hydrazone analogues were prepared and tested in vitro for their anti-mycobacterial activity against reference strain M. tuberculosis H37Rv. Compound 378 demonstrated significant MIC value 0.32 µ M, which was comparable to those of isoniazid [277]. A new bedaquiline derivatives containing a pyrazole moiety were identified by He et al. and tested for their inhibitory activities against ATP synthesis inhibition in mycobacteria. The results showed that compound 379 inhibited ATP synthesis with IC50 > 62.9 µM [278]. Various pyrazole derivatives derived from isoniazide pharmacophore along with coumarin scaffold were investigated for their anti-mycobacterial activity against MTB H37Rv by a resazurin MIC assay. Amongst them, compound 380 showed excellent activity at MIC 0.625 µ g/mL and exhibited 80% growth inhibition of MTB H37Rv [279]. A series of pyrazole derivatives were synthesized by Sriram et al. and subjected to in vitro screening against MTB H37Rv. The most potent analogue 381 exhibits MIC value of 3.13 µ g/mL compared to 3.25 and 50 µ g/mL for ethambutol and pyrazinamide [280].  [274]. A novel sila analogues of Rimonabant as potent anti-tubercular agents were identified by Ramesh et al. the sila analogue 376 was found to be the most potent anti-mycobacterial compound with MIC = 31 nM from this series with an excellent selectivity index [275]. 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 were prepared and screened for in vitro anti-tubercular activity against M. tuberculosis H37Rv strain. Among the compounds, 377 was found to be the most active compound with IC 50 1.01 µM against MTB PS; it inhibited MTB with MIC 24.72 µM [276]. A new 2-aroyl- [1]benzopyrano [4,3-c]pyrazol-4(1H)-one derivatives containing hydrazide-hydrazone analogues were prepared and tested in vitro for their anti-mycobacterial activity against reference strain M. tuberculosis H37Rv. Compound 378 demonstrated significant MIC value 0.32 µM, which was comparable to those of isoniazid [277]. A new bedaquiline derivatives containing a pyrazole moiety were identified by He et al. and tested for their inhibitory activities against ATP synthesis inhibition in mycobacteria. The results showed that compound 379 inhibited ATP synthesis with IC 50 > 62.9 µM [278]. Various pyrazole derivatives derived from isoniazide pharmacophore along with coumarin scaffold were investigated for their anti-mycobacterial activity against MTB H37Rv by a resazurin MIC assay. Amongst them, compound 380 showed excellent activity at MIC 0.625 µg/mL and exhibited 80% growth inhibition of MTB H37Rv [279]. A series of pyrazole derivatives were synthesized by Sriram et al. and subjected to in vitro screening against MTB H37Rv. The most potent analogue 381 exhibits MIC value of 3.13 µg/mL compared to 3.25 and 50 µg/mL for ethambutol and pyrazinamide [280]. The results showed that compound 383 exhibited excellent anti-tubercular activity with percentage inhibition of 96%, at a MIC < 6.25 μg/mL [282]. Labana et al. described the synthesis and anti-tubercular activity of benzopyran-annulated pyrano[2,3-c]pyrazoles derivatives. Results indicated that compound 384 showed excellent anti-tubercular activity with a percent inhibition growth around 93% [283]. According to the research by Encinas et al., benzofuran pyrazole derivatives showed considerable in vitro activity against MTB H37Rv, and compound 385 showed the most potency with MIC90 of 0.05 µM [284]. A series of quinolinyl heterocycles were evaluated for their anti-mycobacterial activity against M. smegmatis, and some quinolinyl pyrazole hybrids showed excellent anti-mycobacterial activity such as 386 (MIC = 14.66 µ g/mL) was as potent as isoniazide (MIC = 12.07 µ g/mL) [285].The in vitro abilities of quinazolinone pyrazole derivatives to inhibit growth of MTB H37Rv have been reported by Pandit et al. The results exhibited all hybrids showed considerable anti-TB activity, particularly, hybrid 387 (96%, MIC90 < 3.125 µ g/mL) warrant further investigation [286]. Dihydropyrimidine pyrazole derivatives were synthesized and evaluated for their in vitro anti-tubercular activity against MTB H37Rv, compound 388 were found to be the most active compounds in vitro with MIC of 0.02 µ g/mL, with the highest SI > 500 were more potent than INH (0.03 µ g/mL) [287].  The results showed that compound 383 exhibited excellent anti-tubercular activity with percentage inhibition of 96%, at a MIC < 6.25 µg/mL [282]. Labana et al. described the synthesis and anti-tubercular activity of benzopyran-annulated pyrano[2,3-c]pyrazoles derivatives. Results indicated that compound 384 showed excellent anti-tubercular activity with a percent inhibition growth around 93% [283]. According to the research by Encinas et al., benzofuran pyrazole derivatives showed considerable in vitro activity against MTB H37Rv, and compound 385 showed the most potency with MIC 90 of 0.05 µM [284]. A series of quinolinyl heterocycles were evaluated for their anti-mycobacterial activity against M. smegmatis, and some quinolinyl pyrazole hybrids showed excellent anti-mycobacterial activity such as 386 (MIC = 14.66 µg/mL) was as potent as isoniazide (MIC = 12.07 µg/mL) [285].The in vitro abilities of quinazolinone pyrazole derivatives to inhibit growth of MTB H37Rv have been reported by Pandit et al. The results exhibited all hybrids showed considerable anti-TB activity, particularly, hybrid 387 (96%, MIC 90 < 3.125 µg/mL) warrant further investigation [286]. Dihydropyrimidine pyrazole derivatives were synthesized and evaluated for their in vitro anti-tubercular activity against MTB H37Rv, compound 388 were found to be the most active compounds in vitro with MIC of 0.02 µg/mL, with the highest SI > 500 were more potent than INH (0.03 µg/mL) [287]. A series of 4-aminoquinolone piperidine amides were synthesized by Naik et al.

Anti-Viral Activity
Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazine-4-one ribonucleozides ( Figure 35) were prepared by Manfredini et al. and tested in vitro for antiviral activities against herpes simplex type 1 (HSV-1), africain swine fever (ASFV), polio, coxsackie, vescicular stomatitis virus (VSV), and HIV-1. Among pyrazole nucleosides, compound 390 showed a selective and inhibited the HIV-1 multiplication in acutely infected C8166 cells [289]. In searching for derivatives of pyrazofurin that could display antiviral properties by means that do not require 5 -deoxypyrazofurin derivatives has been synthesized by Chen and Schneller and evaluated for their antiviral activity against a large number of viruses including herpes-, pox-, myxo-, toga-, arena-, rhabdo-, picorna-, reo-, and retroviruses. Compound 391 proved active against respiratory syncytial virus (in HeLa cells), vaccinia virus (in embryonic skin-muscle fibroblast cells), vesicular stomatitis virus (in HeLa cells), and influenza A virus (in Madin-Darby canine kidney cells) at concentrations ranging from 4 to 20 µg/mL [290]. A novel fluoropyrazole ribonucleoside has been synthesized and evaluated in vitro for their anti-influenza activity. The fluoropyrazole nucleoside 392 was found to have excellent activity against influenza A and B in vitro with I 50 values of 0.2 and 0.4 µg/mL, respectively [291]. Genin et al. discovered a novel 1,5-diphenylpyrazole class of HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Compound 393 was found to have good activity versus wild-type (IC 50 = 2.3 µM) and delavirdine-resistant P236L (IC 50 = 1.1 µM) reverse transcriptase (RT) [292]. Anovel series of 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs has been synthesized and were investigated for their in vitro effect on the replication of hepatitis-C virus (HCV) in HepG2 hepatocellular carcinoma cell line infected with the virus using the reverse transcription-polymerase chain reaction (RT-PCR) technique. The results revealed that compounds 394 were capable of inhibiting the replication of both the HCV RNA (+) and (−) strands at 10-100 µg/mL concentration range [293]. Some novel pyrazolo [4 ,3 :5,6]pyrano [2,3-d]pyrimidine derivatives were prepared and tested for antiviral activity against Herpes Simplex Virus type-1 (HSV-1). The obtained results revealed that the pyrazolopyranopyrimidine 395 showed the highest effect on HSV-1 than the other tested compounds, where its antiviral activity increased from 63% at concentration of 20 µg/10 5 cells to 95% at concentration of 40 µg/10 5 cells [294]. Sun et al. identified 1-methyl-3-(trifluoromethyl)-N-[4-(pyrrolidinylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide as a novel and potent inhibitor against multiple primary isolates of diverse measles virus (MV) genotypes currently circulating worldwide. The most active piperidine derivative 396, when subjected to a secondary virus titer reduction assay, revealed activity against live MV (0.012 ± 0.017 µM, strain Alaska) and no cytotoxicity [295]. A novel series of pyrazolaldoxime ester derivatives were synthesized by Ouyang et al. and evaluated for their antiviral activities against TMV. The results of bioassay showed that these title compounds exhibited weak to good anti-TMV bioactivity. Title compound 397 showed better biological activity and exhibited a higher affinity for TMV CP [296]. Some novel substituted pyrazole and pyrazolo [3,4-d]pyrimidine derivatives 2, 4, 8, and 9 were synthesized and tested for their antiviral activity against hepatitis-A virus (HAV) and herpes simplex virus type-1 (HSV-1). Compound 398 revealed the highest anti-HAV activity at a concentration of 20 µg/10 5 cells, in comparison with the other tested compounds [297]. genotypes currently circulating worldwide. The most active piperidine derivative 396, when subjected to a secondary virus titer reduction assay, revealed activity against live MV (0.012 ± 0.017 µ M, strain Alaska) and no cytotoxicity [295]. A novel series of pyrazolaldoxime ester derivatives were synthesized by Ouyang et al. and evaluated for their antiviral activities against TMV. The results of bioassay showed that these title compounds exhibited weak to good anti-TMV bioactivity. Title compound 397 showed better biological activity and exhibited a higher affinity for TMV CP [296]. Some novel substituted pyrazole and pyrazolo [3,4-d]pyrimidine derivatives 2, 4, 8, and 9 were synthesized and tested for their antiviral activity against hepatitis-A virus (HAV) and herpes simplex virus type-1 (HSV-1). Compound 398 revealed the highest anti-HAV activity at a concentration of 20 µ g/10 5 cells, in comparison with the other tested compounds [297].  [299]. In another study, the same authors described the design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNR-TIs) based on a pyrazole template. The compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants. Combining the best 3-and 5-substituents gave the 3,5-diethylpyrazole 402 as the most potent compound in this early series [300]. Sidique et al. described the design and synthesis of 3-substituted pyrazole ester derivatives which are active as allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase. Compound 403 was found to be more promising in comparison to the other one, with the IC50 value 1.96 µ M [301]. 4,4′-(Arylmethylene)bis(1H-pyrazol-5-ol) derivatives has been synthesized by Sujatha et al. and evaluated for in vitro antiviral activity against peste des petits ruminant virus (PPRV). Compound 404 emerged as the most interesting compound in this series exhibiting excellent antiviral activity against PPRV and found to be more potent than the standard drug ribavirin used [302]. Three series of novel pyrazole derivatives were synthesized by Riyadh et al. and  [299]. In another study, the same authors described the design and synthesis of a novel series of non-nucleoside HIV reverse transcriptase inhibitors (NNR-TIs) based on a pyrazole template. The compounds are active against wild type reverse transcriptase (RT) and retain activity against clinically important mutants. Combining the best 3-and 5-substituents gave the 3,5-diethylpyrazole 402 as the most potent compound in this early series [300]. Sidique et al. described the design and synthesis of 3-substituted pyrazole ester derivatives which are active as allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase. Compound 403 was found to be more promising in comparison to the other one, with the IC 50 value 1.96 µM [301]. 4,4 -(Arylmethylene)bis(1H-pyrazol-5-ol) derivatives has been synthesized by Sujatha et al. and evaluated for in vitro antiviral activity against peste des petits ruminant virus (PPRV). Compound 404 emerged as the most interesting compound in this series exhibiting excellent antiviral activity against PPRV and found to be more potent than the standard drug ribavirin used [302]. Three series of novel pyrazole derivatives were synthesized by Riyadh et al. and tested for anti-viral activity against HCV. Compound 405 was proved to be a notable anti-HCV activity with MIC value of 0.144 µg/mL [303]. Shih et al. identified novel pyrazole compound with potent and selective anti-influenza virus activity using a similar cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library, we found that 406 has potent inhibitory activity [304]. tested for anti-viral activity against HCV. Compound 405 was proved to be a notable anti-HCV activity with MIC value of 0.144 µ g/mL [303]. Shih et al. identified novel pyrazole compound with potent and selective anti-influenza virus activity using a similar cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library, we found that 406 has potent inhibitory activity [304].  Figure 37) as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. Compound 407 showed excellent intrinsic antiviral activity against WT, K103N, and Y181C mutants, and exhibited excellent activity in the cell base assay against the same panel of mutants with small shift in activity between 10% FBS and 50% NHS [305]. Several new pyrazole-and isoxazole-based heterocycles were synthesized by Dawood et al. and screened for their inti-viral activity against Herpes simplex type-1 (HSV-1). Among the tested compounds, compound 408 showed the highest activity and reduced the number of HSV-1 plaques by 69% [306]. A series of novel pyrazole amides containing α-aminophosphonate moiety were synthesized by Wu et al. and evaluated for their antiviral activity. The title compound 409 showed some curative activities (50.1%) against tobacco mosaic virus at 0.5 mg/mL [307]. A novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing pyrazole ring were reported by Di Francesco et al. Amongst these, the pyrazole analog 410 showed significantly improved intrinsic potency, both inhibiting NS5B polymerase with NTP IC50 = 0.5 µM and displayed interesting levels of anti-viral activity in the replicon assay, with EC50 = 7.8 µM [308]. Kim et al. identified a novel class of aryl substituted pyrazole compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-human immunodeficiency virus (HIV) activity using a cell-based full replication assay. The optimization of the antiviral activity leading to the discovery of compound 411 which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene [309]. Ndungu et al. the synthesis and a SAR strategy that led to the discovery of novel pyrazole derivatives as potent measles virus (MeV). Optimization of in vitro potency and aqueous solubility led to the discovery of pyrazole 412, a potent inhibitor of MeV (EC50 = 60 nM) with an aqueous solubility of approximately 60 μg/mL [310]. Compound 407 showed excellent intrinsic antiviral activity against WT, K103N, and Y181C mutants, and exhibited excellent activity in the cell base assay against the same panel of mutants with small shift in activity between 10% FBS and 50% NHS [305]. Several new pyrazole-and isoxazole-based heterocycles were synthesized by Dawood et al. and screened for their inti-viral activity against Herpes simplex type-1 (HSV-1). Among the tested compounds, compound 408 showed the highest activity and reduced the number of HSV-1 plaques by 69% [306]. A series of novel pyrazole amides containing α-aminophosphonate moiety were synthesized by Wu et al. and evaluated for their antiviral activity. The title compound 409 showed some curative activities (50.1%) against tobacco mosaic virus at 0.5 mg/mL [307]. A novel series of potent nucleoside inhibitors of Hepatitis C virus (HCV) NS5B polymerase bearing pyrazole ring were reported by Di Francesco et al. Amongst these, the pyrazole analog 410 showed significantly improved intrinsic potency, both inhibiting NS5B polymerase with NTP IC 50 = 0.5 µM and displayed interesting levels of anti-viral activity in the replicon assay, with EC 50 = 7.8 µM  A new series of 4-substituted 3-methyl-1,5-diphenyl-1H-pyrazoles ( Figure 38) has been synthesized by Tantawy et al. and evaluated in vitro for antiviral activity against herpes simplex virus type-1 grown on Vero African green monkey kidney cells through plaque-reduction assay method using acyclovir as a positive control. The results of the antiviral activity of the prepared compounds showed that compound 413 exhibited strong antiviral activity with IC50 value of 0.02 compared to the used reference drug [311]. A novel series of bis-pyrazole compounds were synthesized by Zhang et al. and tested for anti-viral activity against tobacco mosaic virus (TMV). Compound 414 showed higher activity superior to ningnanmycin at a concentration of 0.5 µ g/mL and equal activity at 0.1 µ g/mL [312]. Hwang et al. identified a series of 1,3,4-trisubstituted pyrazoles as potent hepatitis C virus (HCV) inhibitor by our phenotypic high-throughput screening using infectious HCVcc. Among them compound 415 was the most potent compound with EC50 value of 0.11 µM [313]. Mizuhara et al. synthesized a series of phenylpyrazole derivatives for the development of novel anti-HIV agents. Among the synthesized compounds, the 3,4-dichloro derivative 416 also exhibited more potent anti-HIV activity when (EC50 = 0.047 µ M) [314]. Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. Moreau et al. reported a rational approach to the discovery of macrocyclic acylsulfonamides bearing pyrazole moiety as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Compound 417 displayed most remarkable antiviral activity with an EC50 values of 0.14 and 1.0 nM against mutant D168V 1b and R155K 1a, respectively [315]. A series 24 compounds of diarylaniline analogues bearing pyrazole scaffold as non-nucleoside reverse transcriptase inhibitors (NNRTIs) were developed by Bhadoriya et al. using 3D-QSAR and pharmacophore modelling of NNRTIs. The survived 12 hits show new scaffolds 2,4-dihydropyrano[2,3-c]pyrazole 418 for anti-HIV-1 chemotherapy as NNRTIs [316]. A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines were synthesized by Fioravanti et al. and evaluated in vitro for cytotoxicity and antiviral activity against a large panel of viruses. Most of the tested compounds 419 interfered with RSV replication in the micromolar concentrations (EC50s ranging from 5 μM to 28 μM) [317]. A series of novel pyrazole fused heterocyclic derivatives were synthesized and evaluated for their catalytic DNA cleavage abilities and anti-BVDV activities. Among them, compound 420 showed the highest antiviral activity (EC50 = 0.12 mmol/L) and was 10 fold more than that of the positive control ribavirin (EC50 = 1.3 mmol/L) [318].  [314]. Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. Moreau et al. reported a rational approach to the discovery of macrocyclic acylsulfonamides bearing pyrazole moiety as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Compound 417 displayed most remarkable antiviral activity with an EC 50 values of 0.14 and 1.0 nM against mutant D168V 1b and R155K 1a, respectively [315]. A series 24 compounds of diarylaniline analogues bearing pyrazole scaffold as non-nucleoside reverse transcriptase inhibitors (NNRTIs) were developed by Bhadoriya et al. using 3D-QSAR and pharmacophore modelling of NNRTIs. The survived 12 hits show new scaffolds 2,4-dihydropyrano [2,3-c]pyrazole 418 for anti-HIV-1 chemotherapy as NNRTIs [316]. A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)anilines were synthesized by Fioravanti et al. and evaluated in vitro for cytotoxicity and antiviral activity against a large panel of viruses. Most of the tested compounds 419 interfered with RSV replication in the micromolar concentrations (EC 50 s ranging from 5 µM to 28 µM) [317]. A series of novel pyrazole fused heterocyclic derivatives were synthesized and evaluated for their catalytic DNA cleavage abilities and anti-BVDV activities. Among them, compound 420 showed the highest antiviral activity (EC 50 = 0.12 mmol/L) and was 10 fold more than that of the positive control ribavirin (EC 50 = 1.3 mmol/L) [318].   50 > 105.25). The compound has potential as lead compounds for further optimization into clinical anti-HIV-1 agents [323]. Novel pyrazole acyl thiourea derivatives were synthesized and tested for their anti-TMV activity. Amongst the new products compound 426 showed curative rates by 41.23% [78]. Pyrazolo [1,5-a] [328]. A series of pyrazole based compounds were synthesized by Zou et al. and identified them as novel C-terminus Beta-secretase 1 (BACE1) inhibitors. Further, modification over pyrazole scaffold lead to the identification of compound 432 as a potent inhibitor of BACE1 with IC50 value of 0.025 µM [329]. In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were synthesized by Han et al. and evaluated for anti-Alzheimer's activity. Results indicated that the most active analogs 433 exhibited higher inhibitory activities and exhibited significant brain Aβ-lowering effects as well as favorable aqueous solubility [330].   [328]. A series of pyrazole based compounds were synthesized by Zou et al. and identified them as novel C-terminus Beta-secretase 1 (BACE1) inhibitors. Further, modification over pyrazole scaffold lead to the identification of compound 432 as a potent inhibitor of BACE1 with IC 50 value of 0.025 µM [329]. In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were synthesized by Han et al. and evaluated for anti-Alzheimer's activity. Results indicated that the most active analogs 433 exhibited higher inhibitory activities and exhibited significant brain Aβ-lowering effects as well as favorable aqueous solubility [330].  [327]. A series of metabolically stable γ-secretase inhibitors selective for inhibition of the production of amyloid-β over notch were reported by Probst et al. Compound 431 both entered human clinical trials and lowered Aβ in the CSF of healthy human volunteers [328]. A series of pyrazole based compounds were synthesized by Zou et al. and identified them as novel C-terminus Beta-secretase 1 (BACE1) inhibitors. Further, modification over pyrazole scaffold lead to the identification of compound 432 as a potent inhibitor of BACE1 with IC50 value of 0.025 µM [329]. In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were synthesized by Han et al. and evaluated for anti-Alzheimer's activity. Results indicated that the most active analogs 433 exhibited higher inhibitory activities and exhibited significant brain Aβ-lowering effects as well as favorable aqueous solubility [330].   [2,3-c]pyrazole and evaluated for inhibition of acetylcholinesterase (AChE). Compound 435 bearing 3,4-dimethoxyphenyl group was the most potent compound against AChE, being more active than the reference drug tacrine [332]. Zanaletti et al. developed a new α7 nicotinic acetylcholine receptors (α7 nAChR) represented promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. Compound 436 was found a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models [333]. The same author reported the synthesis and α7 nAChR inhibitory activity of novel class of pyrazole derivative. Compound 437 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models [334]. Nencini et al. reported the design and synthesis of a pyrazole hybrid series of potent and selective agonists of α7 nicotinic acetylcholine receptor. The results revealed that compound 438 was the most potent inhibitor of α7 nAChR with an IC 50 value of 0.07 µM [335]. AstraZeneca AB developed diverse series of pyrazole derivatives as positive allosteric modulators (PAMs). Compound 439 expressed good activity by inhibiting nicotinic acetylcholine receptors (nAChRs) [336]. Janssen Pharmaceutica identified a new series of trisubstituted pyrazole derivatives to PAM types 1-4 related to their kinetic properties in whole-cell voltage-clamp recordings using the agonist choline at a concentration of 1 mM. The trisubstituted pyrazole 440 showed remarkable activity with a pEC 50 value of 7.11 (6268% efficacy) and a PAM type 4 profile [337].  [2,3-c]pyrazole and evaluated for inhibition of acetylcholinesterase (AChE). Compound 435 bearing 3,4-dimethoxyphenyl group was the most potent compound against AChE, being more active than the reference drug tacrine [332]. Zanaletti et al. developed a new α7 nicotinic acetylcholine receptors (α7 nAChR) represented promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. Compound 436 was found a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models [333]. The same author reported the synthesis and α7 nAChR inhibitory activity of novel class of pyrazole derivative. Compound 437 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models [334]. Nencini et al. reported the design and synthesis of a pyrazole hybrid series of potent and selective agonists of α7 nicotinic acetylcholine receptor. The results revealed that compound 438 was the most potent inhibitor of α7 nAChR with an IC50 value of 0.07 µM [335]. AstraZeneca AB developed diverse series of pyrazole derivatives as positive allosteric modulators (PAMs). Compound 439 expressed good activity by inhibiting nicotinic acetylcholine receptors (nAChRs) [336]. Janssen Pharmaceutica identified a new series of trisubstituted pyrazole derivatives to PAM types 1-4 related to their kinetic properties in whole-cell voltage-clamp recordings using the agonist choline at a concentration of 1 mM. The trisubstituted pyrazole 440 showed remarkable activity with a pEC50 value of 7.11 (6268% efficacy) and a PAM type 4 profile [337].     [340]. Several pyrazolopyrimidines were synthesized by Brigance et al. and evaluated as inhibitors of dipeptidyl peptidase-4 (DPP4). Among the synthesized compounds, the 444 displayed the greatest potency (Ki = 20 nM) and demonstrated excellent selectivity over the other dipeptidyl peptidases [341]. Choi et al. identified 1,3-diphenyl-1H-pyrazole derivatives as a new series of potent PPARγ partial agonists using an improved virtual screening method combining ligand-centric and receptor-centric methods. The pyrazole-based compound 445 showed relatively strong binding activities against PPARγ among the virtual candidates [342]. A novel class of 1,3,5-pyrazoles has been discovered by Shen et al. as potent human glucagon receptor antagonists. Compound 446 was identified as a potent human glucagon receptor antagonist with good pharmacokinetic profiles in four preclinical species, and showed excellent oral pharmacodynamics efficacy in rhesus monkeys and transgenic mice by blocking glucagon-induced hyperglycemia [343]. A series of 4-benzyl-1H-pyrazol-3-yl β-D-glucopyranoside derivatives were synthesized and evaluated for their inhibitory activity toward sodium glucose co-transporter 1 (SGLTs). Compound 447 was identified as potent and selective SGLT1 inhibitors, both of which showed improved in vitro intestinal stability over phlorizin, high solubility to water [344]. PPARγ partial agonists using an improved virtual screening method combining ligand-centric and receptor-centric methods. The pyrazole-based compound 445 showed relatively strong binding activities against PPARγ among the virtual candidates [342]. A novel class of 1,3,5-pyrazoles has been discovered by Shen et al. as potent human glucagon receptor antagonists. Compound 446 was identified as a potent human glucagon receptor antagonist with good pharmacokinetic profiles in four preclinical species, and showed excellent oral pharmacodynamics efficacy in rhesus monkeys and transgenic mice by blocking glucagon-induced hyperglycemia [343]. A series of 4-benzyl-1H-pyrazol-3-yl β-D-glucopyranoside derivatives were synthesized and evaluated for their inhibitory activity toward sodium glucose co-transporter 1 (SGLTs). Compound 447 was identified as potent and selective SGLT1 inhibitors, both of which showed improved in vitro intestinal stability over phlorizin, high solubility to water [344].  [346]. Yoshida et al. reported the discovery and preclinical profile of teneligliptin as a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Compound 450 (teneligliptin), at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats, and has been approved for the treatment of type 2 diabetes in Japan [347]. A series of pyrazole-based GPR119 agonists were designed by Futatsugi et al., a novel and potent GPR119 full agonist 451 was identified through a conformational restriction-core flipping strategy. Compound 451 was roughly 10-fold less potent than exemplars from other series [348]. Griffith et al. disclosed a series of acetyl-CoA carboxylase (ACC) inhibitors based on a spirocyclic pyrazololactam core. Compound 452 showed excellent oral bioavailability, moderate systemic clearance, and acceptable exposure in rat pharmacokinetic studies. The oral dosing of rats with 452 resulted in potent, dose-proportional inhibition of ACC activity as measured by incorporation of 14 C in DNL product [349]. Compound 450 (teneligliptin), at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats, and has been approved for the treatment of type 2 diabetes in Japan [347]. A series of pyrazole-based GPR119 agonists were designed by Futatsugi et al., a novel and potent GPR119 full agonist 451 was identified through a conformational restriction-core flipping strategy. Compound 451 was roughly 10-fold less potent than exemplars from other series [348]. Griffith et al. disclosed a series of acetyl-CoA carboxylase (ACC) inhibitors based on a spirocyclic pyrazololactam core. Compound 452 showed excellent oral bioavailability, moderate systemic clearance, and acceptable exposure in rat pharmacokinetic studies. The oral dosing of rats with 452 resulted in potent, dose-proportional inhibition of ACC activity as measured by incorporation of 14 C in DNL product [349].  [353]. A novel Zn mononuclear complex with 3-carboxy-pyrazole ligand has been prepared and evaluated in vivo for their antidiabetic activity. This compound 457 exhibits a potential in vivo anti-diabetic activity (62% reduction in blood glucose in the diabetic group treated compared with untreated diabetic) [354]. Kenchappa et al. reported the synthesis of coumarin derivatives containing pyrazole and indenone rings as potent anti-hyperglycemic agents. The compound 458 showed significant decrease in glucose concentration (115 and 138 mg/dL) with the dose of 100 mg/kg [355]. A series of substituted pyrazoles derivatives were synthesized by Doddaramappa et al. and tested in vitro for their anti-diabetic activity by measuring the α-amylase and α-glucosidase inhibitory potential. Among the synthesized compounds, compound 459 emerged as an excellent antidiabetic agent with IC50 values of 10 and 15 µ g/mL against α-amylase and α-glucosidase inhibitors, respectively [356].   [353]. A novel Zn mononuclear complex with 3-carboxy-pyrazole ligand has been prepared and evaluated in vivo for their antidiabetic activity. This compound 457 exhibits a potential in vivo anti-diabetic activity (62% reduction in blood glucose in the diabetic group treated compared with untreated diabetic) [354]. Kenchappa et al. reported the synthesis of coumarin derivatives containing pyrazole and indenone rings as potent anti-hyperglycemic agents. The compound 458 showed significant decrease in glucose concentration (115 and 138 mg/dL) with the dose of 100 mg/kg [355]. A series of substituted pyrazoles derivatives were synthesized by Doddaramappa et al. and tested in vitro for their anti-diabetic activity by measuring the α-amylase and α-glucosidase inhibitory potential. Among the synthesized compounds, compound 459 emerged as an excellent antidiabetic agent with IC 50 values of 10 and 15 µg/mL against α-amylase and α-glucosidase inhibitors, respectively [356]. showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys [351]. Yu et al. reported the lead optimization of pyrazole based GPR142 agonists. Structure−activity relationship studies indicated that amino-pyrazole-phenylalanine carboxylic acid 455, exhibited good agonistic activity (h-GPR142-EC50 = 0.052 µ M), high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability [352]. Bhosle et al. synthesized a new series of 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids having pyrazolyl pharmacophores and evaluated their anti-hyperglycemic activity. Among the prepared compounds, 456 have displayed significant anti-hyperglycemic activity at 100 mg/kg [353]. A novel Zn mononuclear complex with 3-carboxy-pyrazole ligand has been prepared and evaluated in vivo for their antidiabetic activity. This compound 457 exhibits a potential in vivo anti-diabetic activity (62% reduction in blood glucose in the diabetic group treated compared with untreated diabetic) [354]. Kenchappa et al. reported the synthesis of coumarin derivatives containing pyrazole and indenone rings as potent anti-hyperglycemic agents. The compound 458 showed significant decrease in glucose concentration (115 and 138 mg/dL) with the dose of 100 mg/kg [355]. A series of substituted pyrazoles derivatives were synthesized by Doddaramappa et al. and tested in vitro for their anti-diabetic activity by measuring the α-amylase and α-glucosidase inhibitory potential. Among the synthesized compounds, compound 459 emerged as an excellent antidiabetic agent with IC50 values of 10 and 15 µ g/mL against α-amylase and α-glucosidase inhibitors, respectively [356].  Hernández-Vázquez et al. reported the design, synthesis and anti-diabetic activity of novel N -arylidene pyrazole-3-carbohydrazides ( Figure 45). Compound 460 exhibited a remarkable hypoglycemic effect with a 90% of plasma glucose reduction [357]. A series of dihydropyrano [2,3-c] pyrazoles derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Compound 461 was the most potent analog of this series (IC 50 = 54.2 µM), when compared with standard drug, i.e., acarbose (IC 50 = 937.0 µM) [358]. A series of imidazolylpyrazoles were synthesized by Chaudhry et al. and tested for their α-glucosidase inhibitory activity. The in vitro enzyme inhibition indicated that the compound 462 showed significant inhibitory potentials and binding affinities (IC 50 = 23.95 µM) as compared to that of reference acarbose [359]. During current investigation concerning the synthesis of novel 1,5-diarylpyrazole derivatives as antidiabetic entities, Hernández-Vázquez et al. synthesized the hybrid 463, a novel dual compound that exhibited both anti-diabetic and in vitro antioxidant effects. Compound 463 showed a pronounced anti-hyperglycemic effect even at a dose of 5 mg/kg (p < 0.001) in a glucose tolerance test on normoglycemic rats [360]. Hernández-Vázquez et al. reported the design, synthesis and anti-diabetic activity of novel N′-arylidene pyrazole-3-carbohydrazides ( Figure 45). Compound 460 exhibited a remarkable hypoglycemic effect with a 90% of plasma glucose reduction [357]. A series of dihydropyrano [2,3-c] pyrazoles derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Compound 461 was the most potent analog of this series (IC50 = 54.2 µ M), when compared with standard drug, i.e., acarbose (IC50 = 937.0 µ M) [358]. A series of imidazolylpyrazoles were synthesized by Chaudhry et al. and tested for their α-glucosidase inhibitory activity. The in vitro enzyme inhibition indicated that the compound 462 showed significant inhibitory potentials and binding affinities (IC50 = 23.95 µ M) as compared to that of reference acarbose [359]. During current investigation concerning the synthesis of novel 1,5-diarylpyrazole derivatives as antidiabetic entities, Hernández-Vázquez et al. synthesized the hybrid 463, a novel dual compound that exhibited both anti-diabetic and in vitro antioxidant effects. Compound 463 showed a pronounced anti-hyperglycemic effect even at a dose of 5 mg/kg (p < 0.001) in a glucose tolerance test on normoglycemic rats [360].  Compound 467 showed an activity profile that can be improved through medicinal chemistry strategies [364]. This same author, synthesized a series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). Among the derivatives examined, compound 468 emerged as the most active on promastigotes forms of L. amazonensis, with an IC50 value of 15 μM [365]. A new series of pyrazolo [3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro anti-leishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that compound 469 exhibit better anti-leishmanial activity with IC50 3.63 and 2.32 μM, against the promastigote form and axenic amastigote form, respectively [366].

Anti-Leishmanial Activity
A new series of pyrazole derivatives were synthesized by Bekhit et al. and evaluated for their in vitro anti-leishmanial activity against Leishmania aethiopica promastigotes and amastigotes. The results showed that compound 470 had the highest anti-leishmanial activity, with an IC50 value of [367]. Mowbray et al. identified a novel series of amino-pyrazole ureas with potent in vitro  Compound 467 showed an activity profile that can be improved through medicinal chemistry strategies [364]. This same author, synthesized a series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). Among the derivatives examined, compound 468 emerged as the most active on promastigotes forms of L. amazonensis, with an IC 50 value of 15 µM [365]. A new series of pyrazolo [3,4-d]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro anti-leishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that compound 469 exhibit better anti-leishmanial activity with IC 50 3.63 and 2.32 µM, against the promastigote form and axenic amastigote form, respectively [366]. with a SI of 3, however, the IC50 obtained here was around four times higher (25 μM) [371]. A new series of pyrazole derivatives were prepared and tested in vitro for their anti-leishmanial activity. Compound 475 was found to be the most active (IC50 = 0.0112 µ g/mL) than the standards miltefosine (IC50 = 0.3 ± 0.04 µ g/mL) and amphotericin B deoxycholate (IC50 = 0.2 ± 0.02 µ g/mL) for Leishmania donovani [372]. Reviriego et al. reported the synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis. The diethyl ester 476 showed high efficiency against the mentioned protozoa [373].

Anti-Malarial Activity
A series of pyrazoles were described ( Figure 47) as part of efforts directed toward the synthesis of some potent antimalarial agents. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives 477 with IC50 = 0.149 µ mol/L [374]. Novel curcumin analogues bearing pyrazole ring were prepared and evaluated for their anti-malarial activity against CQ-S and CQ-R Plasmodium falciparum culture. Compound 478 was found to be the most potent analogue with IC50 values 0. 48  A new series of pyrazole derivatives were synthesized by Bekhit et al. and evaluated for their in vitro anti-leishmanial activity against Leishmania aethiopica promastigotes and amastigotes. The results showed that compound 470 had the highest anti-leishmanial activity, with an IC 50 value of [367]. Mowbray et al. identified a novel series of amino-pyrazole ureas with potent in vitro anti-leishmanial activity. Furthermore, compound 471 showed high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series [368]. A series of 4-(1H-pyrazol-1-yl)-benzenesulfonamides were synthesized and evaluated in vitro for their anti-leishmanial profile against Leishmania infantum and Leishmania amazonensis. Interestingly, 472 showed the best in vitro active profile against the infective L. amazonensis promastigotes and L. infantum forms, with IC 50 values of 0.059 and 0.070 mM, respectively [369]. Bekhit et al. prepared a novel series of 1H-pyrazole derivatives and tested for their in vitro anti-leishmanial activities against L. aethiopica promastigotes. The highest anti-leishmanial activity was exhibited by compound 473, with an IC 50 of 0.079 µg/mL [370]. Pyrazole derivatives were prepared and tested for their in vitro antiparasitic activity against promastigotes of Leishmania mexicana (Bel 21) and epimastigotes of Trypanosoma cruzi (DM28) using a modified MTT assay. Only 474 displayed selectivity on L. mexicana with a SI of 3, however, the IC 50 obtained here was around four times higher (25 µM) [371]. A new series of pyrazole derivatives were prepared and tested in vitro for their anti-leishmanial activity. Compound 475 was found to be the most active (IC 50 = 0.0112 µg/mL) than the standards miltefosine (IC 50 = 0.3 ± 0.04 µg/mL) and amphotericin B deoxycholate (IC 50 = 0.2 ± 0.02 µg/mL) for Leishmania donovani [372]. Reviriego et al. reported the synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis. The diethyl ester 476 showed high efficiency against the mentioned protozoa [373].

Anti-Malarial Activity
A series of pyrazoles were described ( Figure 47) as part of efforts directed toward the synthesis of some potent antimalarial agents. Further modification of the heterocyclic ring to give substituted aryl derivatives afforded potent antimalarial derivatives 477 with IC 50 = 0.149 µmol/L [374]. Novel curcumin analogues bearing pyrazole ring were prepared and evaluated for their anti-malarial activity against CQ-S and CQ-R Plasmodium falciparum culture. Compound 478 was found to be the most potent analogue with IC 50 values 0.48 and 0.45 µM against CQ-S and CQ-R, respectively [375]. Gonzalez Cabrera et al. identified an aminomethylthiazole pyrazole carboxamide lead 479 with good in vitro antiplasmodial activity [IC 50 : 0.08 µM (K1, chloroquine and multidrug resistant strain) and 0.07 µM (NF54, chloroquine-sensitive strain)] and microsomal metabolic stability from whole cell screening of a SoftFocus kinase library. Compound 479 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity [376]. Quirante et al. described the synthesis and in vitro antimalarial activities of platinum(II) and palladium(II) complexes with ligands derived from pyrazole. Compound 480 exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2) [377]. A new category of polyhydroquinoline derivatives containing pyrazole moieties were prepared by Kalaria et al. and evaluated for their in vitro antimalarial activity against Plasmodium falciparum. Among the tested compounds, compound 481 exhibited excellent antimalarial activity with an IC 50 value of 0.033 µg/mL [261]. A series of imidazopyridazine inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) has been explored and extended by Large et al. Diaminocyclohexane 482 showed a good in vitro potency and metabolic stability profile against Plasmodium falciparum (PfCDPK1 enzyme IC 50 = 0.056 µM, Pf anti-parasite EC 50 = 0.262 µM) [378]. A novel series of fluoro-substituted pyrazolylpyrazolines were synthesized and screened for their antimalarial activity against Plasmodium falciparum. Compound 483 displayed excellent activity with an IC 50 value of 0.022 µg/mL against P. falciparum stain as compared to quinine IC 50 = 0.268 µg/mL [262]. A new series of pyrazole derivatives were synthesized and evaluated for their in vivo antimalarial activity against Plasmodium berghei-infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum. Compound 484 had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC 50 values than chloroquine [367]. Belaji et al. reported the molecular modelling, synthesis, and antimalarial potentials of curcumin analogues containing pyrazole ring. The compound 485 showed the most significant result, with maximum schizonticidal (IC 50 = 1.48 µM) and parasiticidal activities (MKC; 3.87 = µM) [379].  [378]. A novel series of fluoro-substituted pyrazolylpyrazolines were synthesized and screened for their antimalarial activity against Plasmodium falciparum. Compound 483 displayed excellent activity with an IC50 value of 0.022 µ g/mL against P. falciparum stain as compared to quinine IC50 = 0.268 µ g/mL [262]. A new series of pyrazole derivatives were synthesized and evaluated for their in vivo antimalarial activity against Plasmodium berghei-infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum.
Compound 484 had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC50 values than chloroquine [367]. Belaji et al. reported the molecular modelling, synthesis, and antimalarial potentials of curcumin analogues containing pyrazole ring. The compound 485 showed the most significant result, with maximum schizonticidal (IC50 = 1.48 μM) and parasiticidal activities (MKC; 3.87 = μM) [379].

Anti-Parkinson Activity
Niswender et al. discovered a new pyrazolo [3,4-d]pyrimidines derivatives ( Figure 48) as novel modulators of the metabotropic glutamate receptor subtype 4 (mGluR4) positive allosteric modulators. Results indicated that the compound 486 showed a remarkable anti-parkinson activity [380]. A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has Results indicated that the compound 486 showed a remarkable anti-parkinson activity [380]. A series of N1-thiocarbamoyl-3,5-di(hetero)aryl-4,5-dihydro-(1H)-pyrazole derivatives has been synthesized by Chimenti et al. and tested for their ability to inhibit the activity of the A and B isoforms of human monoamine oxidase (hMAO). Compound 487 was found the most active of the series with IC 50 value of 2.75 µM and selectivity ratio of 25 [381]. Maher et al. synthesized a pyrazole structure 488 as aderivative of curcumin and was tested for its ability to enhance the activity of Ca 2+ /calmodulin dependent protein kinase II (CaMKII). Results indicated that the compound 488 enhanced the induction both long-term potentiation (LTP) in rat hippocampal slices and memory in a rat object [382]. Chan et al. identified a new aminopyrazole as a Leucine-Rich Repeat Kinase 2 (LRRK2) inhibitor. In in vivo rodent PKPD studies, compound 489 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration [383].  (493) as a novel radio-ligand for imaging of metabotropic glutamate receptor subtype 4 (mGluR4). In vitro autoradiography and ex vivo bio-distribution study in rat brains showed specific binding of compound 493 in the cerebellum, striatum, thalamus, cerebral cortex, and medulla oblongata, which showed dose-dependent decreases by administration with multiple dosing [387].  (493) as a novel radio-ligand for imaging of metabotropic glutamate receptor subtype 4 (mGluR4). In vitro autoradiography and ex vivo bio-distribution study in rat brains showed specific binding of compound 493 in the cerebellum, striatum, thalamus, cerebral cortex, and medulla oblongata, which showed dose-dependent decreases by administration with multiple dosing [387].

Agrochemical Activity
In the past few years, the interest in pyrazole derivatives has increased due to their proven usefulness as intermediates in the preparation of new biological materials. Specifically, pyrazole derivatives have a long history of application in the agrochemical industry as herbicides, insecticides, fungicides and acaracides. The pyrazole ring is present in many agrochemically important compounds, such as the pesticides, furametpyr [388], cyantraniliprole [389], cyenopyrafen [390], tebufenpyrad [391], tolfenpyrad [392], and fenpyroximate [388] (Figure 49).

Agrochemical Activity
In the past few years, the interest in pyrazole derivatives has increased due to their proven usefulness as intermediates in the preparation of new biological materials. Specifically, pyrazole derivatives have a long history of application in the agrochemical industry as herbicides, insecticides, fungicides and acaracides. The pyrazole ring is present in many agrochemically important compounds, such as the pesticides, furametpyr [388], cyantraniliprole [389], cyenopyrafen [390], tebufenpyrad [391], tolfenpyrad [392], and fenpyroximate [388] (Figure 49). Compound 495 showed 86% larvicidal activities against P. xylostella at the concentration of 0.1 mg/L, while the activity of compound 496 against M. separata was 80% at 1 mg/L [394]. Wu et al. reported the synthesis and insecticidal activities of novel pyrazole amide derivatives containing hydrazone substructures. In vivo tests indicated that the compound 497 exhibited good activity against different insect species, such as P. xylostella, H. armigera, C. pipiens pallens, N. lugens and R. maidis [395]. A series of new pyrazole oximes bearing substituted thiazole ring were prepared and tested for their insecticidal and acaricidal activities. The results of primary bioassay indicated that the compound 498 was more potent against Tetranychus cinnabarinus and Plutella xylostella than other analogues [396]. Song et al. synthesized a novel pyrazole derivatives and evaluated for their insecticidal activity against cotton bollworm (Helicoverpa armigera), diamondback moth (Plutella xylostella), bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), and spider mite (Tetranychus cinnabarinus). The results of bioassays indicated that the compound 499 showed high insecticidal activity against cotton bollworm was 60% at 5 mg/kg [397]. Fu et al. reported the synthesis and insecticidal activities of novel pyrazole oxime ether derivatives. Bioassays showed that at a 10 mg/L, the insecticidal activity of compounds 500 exceeded 90% [398].  Compound 495 showed 86% larvicidal activities against P. xylostella at the concentration of 0.1 mg/L, while the activity of compound 496 against M. separata was 80% at 1 mg/L [394]. Wu et al. reported the synthesis and insecticidal activities of novel pyrazole amide derivatives containing hydrazone substructures. In vivo tests indicated that the compound 497 exhibited good activity against different insect species, such as P. xylostella, H. armigera, C. pipiens pallens, N. lugens and R. maidis [395]. A series of new pyrazole oximes bearing substituted thiazole ring were prepared and tested for their insecticidal and acaricidal activities. The results of primary bioassay indicated that the compound 498 was more potent against Tetranychus cinnabarinus and Plutella xylostella than other analogues [396]. Song et al. synthesized a novel pyrazole derivatives and evaluated for their insecticidal activity against cotton bollworm (Helicoverpa armigera), diamondback moth (Plutella xylostella), bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), and spider mite (Tetranychus cinnabarinus). The results of bioassays indicated that the compound 499 showed high insecticidal activity against cotton bollworm was 60% at 5 mg/kg [397]. Fu et al. reported the synthesis and insecticidal activities of novel pyrazole oxime ether derivatives. Bioassays showed that at a 10 mg/L, the insecticidal activity of compounds 500 exceeded 90% [398]. Compound 495 showed 86% larvicidal activities against P. xylostella at the concentration of 0.1 mg/L, while the activity of compound 496 against M. separata was 80% at 1 mg/L [394]. Wu et al. reported the synthesis and insecticidal activities of novel pyrazole amide derivatives containing hydrazone substructures. In vivo tests indicated that the compound 497 exhibited good activity against different insect species, such as P. xylostella, H. armigera, C. pipiens pallens, N. lugens and R. maidis [395]. A series of new pyrazole oximes bearing substituted thiazole ring were prepared and tested for their insecticidal and acaricidal activities. The results of primary bioassay indicated that the compound 498 was more potent against Tetranychus cinnabarinus and Plutella xylostella than other analogues [396]. Song et al. synthesized a novel pyrazole derivatives and evaluated for their insecticidal activity against cotton bollworm (Helicoverpa armigera), diamondback moth (Plutella xylostella), bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), and spider mite (Tetranychus cinnabarinus). The results of bioassays indicated that the compound 499 showed high insecticidal activity against cotton bollworm was 60% at 5 mg/kg [397]. Fu et al. reported the synthesis and insecticidal activities of novel pyrazole oxime ether derivatives. Bioassays showed that at a 10 mg/L, the insecticidal activity of compounds 500 exceeded 90% [398].  A series of novel N-(2,2,2)-trifluoroethylpyrazole derivatives ( Figure 51) were synthesized and tested for their herbicidal activity. The bioassay results indicated that the compound 501 showed the best preemergence herbicidal effects against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape at the dosage of 150 g·ha −1 in greenhouse [399]. Dai et al. synthesized a new series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety and evaluated for their insecticidal and acaricidal activities against Plutella xylostella, Aphis craccivora and Tetranychus cinnabarinus. Results showed that the compound 502 possessed excellent acaricidal activity against T. cinnabarinus and displayed potential insecticidal activity against P. xylostella and A. craccivora [400]. Li et al. reported Synthesis and fungicidal activities of new pyrazole derivatives. The test results indicated that the compound 503 exhibited strong fungicidal activities against Pyricularia oryzae, Phytophthora infestans, Pseudoperonospora cubensis, and Erysiphe graminis [401]. Fustero et al. described the synthesis of new fluorinated tebufenpyrad analogs with acaricidal activity. Among the synthesized compounds, two of these compounds 504 and 505 display a fertility inhibition superior to that of tebufenpyrad [402]. Two series of new pyrazoles, namely pyrazolo[1,5-a] [1,3,5]triazine-2,4-dione and pyrazolo- [1,5-c] [1,3,5]thiadiazine-2-one derivatives, were synthesized as potential inhibitors of the photosynthetic electron transport chain at the photosystem II level. Among the pyrazolo[1,5-a] [1,3,5]triazine-2,4-dione derivatives, those including cyclohexyl substituents like 506 showed maximal activity [403]. A series of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety were designed and synthesized by Zhao et al. and tested for their insecticidal activity. The results of bioassays indicated that the target compounds possessed excellent activities against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens) and diamondback moth (Plutella xylostella). Especially, the foliar contact activity against bean aphid of compound 507 at 2.5 mg/kg was 89% [404]. A series of novel N-(2,2,2)-trifluoroethylpyrazole derivatives ( Figure 51) were synthesized and tested for their herbicidal activity. The bioassay results indicated that the compound 501 showed the best preemergence herbicidal effects against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape at the dosage of 150 g·ha −1 in greenhouse [399]. Dai et al. synthesized a new series of pyrazole oxime derivatives containing a 5-trifluoromethylpyridyl moiety and evaluated for their insecticidal and acaricidal activities against Plutella xylostella, Aphis craccivora and Tetranychus cinnabarinus. Results showed that the compound 502 possessed excellent acaricidal activity against T. cinnabarinus and displayed potential insecticidal activity against P. xylostella and A. craccivora [400]. Li et al. reported Synthesis and fungicidal activities of new pyrazole derivatives. The test results indicated that the compound 503 exhibited strong fungicidal activities against Pyricularia oryzae, Phytophthora infestans, Pseudoperonospora cubensis, and Erysiphe graminis [401]. Fustero et al. described the synthesis of new fluorinated tebufenpyrad analogs with acaricidal activity. Among the synthesized compounds, two of these compounds 504 and 505 display a fertility inhibition superior to that of tebufenpyrad [402]. Two series of new pyrazoles, namely pyrazolo[1,5-a] [1,3,5]triazine-2,4-dione and pyrazolo- [1,5-c] [1,3,5]thiadiazine-2-one derivatives, were synthesized as potential inhibitors of the photosynthetic electron transport chain at the photosystem II level. Among the pyrazolo[1,5-a] [1,3,5]triazine-2,4-dione derivatives, those including cyclohexyl substituents like 506 showed maximal activity [403]. A series of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety were designed and synthesized by Zhao et al. and tested for their insecticidal activity. The results of bioassays indicated that the target compounds possessed excellent activities against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens) and diamondback moth (Plutella xylostella). Especially, the foliar contact activity against bean aphid of compound 507 at 2.5 mg/kg was 89% [404].

Conclusions
Pyrazoles represent a major pharmacophore with various biological properties, and some pyrazole-containing derivatives have already been used for therapeutic purposes. This literature review shows that pyrazole derivatives are pharmacologically very potent and, therefore, their design and synthesis is the potential area of research. 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, with the most important structural variations concerning the substituents at the 1-position, the carbon at the 3-position and the substituent at the 5-position. Previous studies have shown that the structural modification on the different positions of

Conclusions
Pyrazoles represent a major pharmacophore with various biological properties, and some pyrazole-containing derivatives have already been used for therapeutic purposes. This literature review shows that pyrazole derivatives are pharmacologically very potent and, therefore, their design and synthesis is the potential area of research. 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, with the most important structural variations concerning the substituents at the 1-position, the carbon at the 3-position and the substituent at the 5-position.
Previous studies have shown that the structural modification on the different positions of the basic molecule allows for improving its pharmacological profile, giving it antimicrobial, anticonvulsant, analgesic, anti-inflammatory, anti-viral, anti-malarial and anti-cancer properties. For the moment, researchers have been drawn to the design of more potent pyrazole derivatives having great diversity of biological activity.