Abstract
Pyrazole, a five-membered heterocycle containing two nitrogen atoms, is extensively found as a core framework in a huge library of heterocyclic compounds that envelops promising agro-chemical, fluorescent and biological potencies. Attributed to its several potential applications, there is a rise in the significance of designing novel pyrazoles, disclosing innovative routes for synthesizing pyrazoles, examining different potencies of pyrazoles, and seeking for potential applications of pyrazoles. This review consists of two parts. The first part provides an overview on the recent developments in synthetic approaches to pyrazoles, which is related to the new or advanced catalysts and other ‘environment-friendly’ procedures, including heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions. The second part focuses on the recently reported novel biological affinities of pyrazoles. This systematic review covers the published studies from 1990 to date. It is expected that this review will be helpful in future research and for new thoughts in the quest for rational designs for developing more promising pyrazoles.
Graphic Abstract
The review consists of two parts: (i) an overview on the recent advances in synthetic approaches for the preparation of pyrazoles, including eco-friendly methodologies, heterogeneous catalytic systems, ligand-free systems, ultrasound and microwave-assisted reactions, and (ii) a summary of recently reported novel biological affinities of pyrazoles.
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1 Introduction
Heterocyclic compounds are a highly valuable and unique class of compounds. These compounds demonstrate a broad spectrum of physical, chemical and biological characteristics.[1, 2] In nature, heterocyclic compounds are widely distributed and display an important part in metabolism owing to their structural nucleus occurring in various natural products, including hormones, antibiotics, alkaloids, vitamins and many others.[3,4,5]
Amongst heterocyclic compounds, nitrogen-containing heterocycles are extensively found as a core framework in a huge library of heterocycles and show several employments in natural science and other areas of science.[6] Additionally, nitrogen-containing heterocycles have striking structural features and they are widely observed in natural products, for instance, vitamins, hormones and alkaloids.[7, 8] Pyrazole 1 is known to be one of the most potential families of nitrogen-containing compounds. Pyrazole derivatives exhibit a broad spectrum of biological profiles, for instance, anti-tubercular,[9] anti-AIDS,[10] anti-malarial,[8] anti-microbial,[11] antitumor,[12, 13] anticancer[14] and anti-fungal.[6] In addition, pyrazoles have also been found as promising anti-hyperglycemic,[15] anti-depressant,[16] anti-convulsant,[17] anti-pyretic,[18] anti-anxiety[19, 20] and insecticidal agents.[21] Bipyrazole shows diuretic, cytotoxic and cardiovascular efficacy.[19] It has achieved great attention since the privileged framework is frequently observed as a bioactive component in commercially available medicines, for example, Floxan 2 (anti-inflammatory medicine), pyrazomycin 3 (anti-cancer), difenamizole 4 (anti-inflammatory drug), and deramaxx 5 (NSAID) (Figure 1).[22, 23] It is also utilized in paint and photographic industries and in the development of heat resistant resins.[24] The corresponding 3-oxygenated derivative, pyrazolone 6, which has an additional keto-group, is the basic component in drugs such as metamizole sodium and phenylbutazone (both are non-steroidal anti-inflammatory medicines, generally used as powerful painkillers and fever reducers) (Figure 1).[19] Also, the benzo-fused derivative of pyrazole (i.e., tetrahydroindazole 7) is well-known to be biologically active, and used against cancer[25] and inflammation.[26] Indole 8, which is an isostere of indazole, is perhaps the most commonly found heterocyclic system in nature. For instance, the essential neurotransmitters in the central nervous system, serotonin and the crucial amino acid, tryptophan are two out of several important indole derivatives (Figure 1).[27]
Chemically, in the basic structure, pyrazole 1 has two nitrogen atoms at adjacent positions in the five-membered ring. The molecular formula of pyrazole 1 is \(\hbox {C}_{3}\hbox {H}_{4}\hbox {N}_{2}\) which has \(6~{\uppi }\) electrons delocalized over the ring forming an aromatic system. Pyrazole is closely linked to several of its reduced or oxidized forms such as pyrazoline (11, 12 and 13), pyrazolidine 9, and pyrazolone 10. Unlike pyrazole, pyrazoline, and pyrazolidine are not aromatic compounds due to the lack of conjugation and delocalization of \({\uppi }\) electrons (Figures 1 and 2).[28]
In synthetic chemistry, the development of novel and productive approaches for the synthesis of pyrazole derivatives along with their bioactivities examination is known to be an important and continuing challenge. This review provides an extensive summary of progress over the last decade for the formation of pyrazoles as well as their biological profile. We hope that this review will be useful for scientists working in the area of synthetic and medicinal chemistry.
2 Aromaticity, chemical reactivity and physical properties of pyrazole
2.1 Aromatic character of pyrazole
Pyrazole 1 is a five-membered aromatic heterocyclic compound. Pyrazole is a pi-excessive heterocyclic system, which contains two nitrogen atoms; one is pyrrole type at position-1; while, other is pyridine type at position-2. Among the two nitrogens, one is basic and the other is neutral in nature. The aromatic nature in pyrazole systems appears from the unshared pair of electrons on the –NH nitrogen and the four pi-electrons. Pyrazole exists in three partially reduced forms, i.e., 1-pyrazoline 11, 2-pyrazoline 12 and 3-pyrazoline 13 (Figure 2).[29]
These are also aromatic systems attributed to their conjugated planar ring frameworks with six highly delocalized pi-electrons. It is found from various experimental investigations that the bond length between atoms at position 3 and 4 has a high value.[30] 2-Pyrazolines 12 are observed to be the most commonly examined pyrazoline-type heterocyclic systems (Figure 2).[31]
2.2 Chemical reactivity of pyrazole
The chemical reactivity of pyrazole 1 can be described by the effect of individual atoms. The nitrogen atom at position-2 with lone pair of electrons is moderately basic in nature and thus reacts with electrophilic centers of reagents. The nitrogen atom at position-1 is not reactive but gives up its \(\hbox {H}^{+}\) in the existence of the base. The combined effect of two nitrogen atoms reduces the charge density at carbon-3 and carbon-5, making them vacant for attack by electrophilic reagents. Removal of \(\hbox {H}^{+}\) at carbon-3 can take place in the existence of a strong base, ending in the opening of the ring. Addition of \(\hbox {H}^{+}\) ions to pyrazoles results in the formation of pyrazolium ions which are less likely to experience electrophilic attack at carbon-4, but an electrophilic attack at carbon-3 is facilitated. The anions of pyrazole are much less reactive toward nucleophilic attack, but the reactivity toward electrophiles is enhanced.[32] Owing to their planar conjugated ring skeletons with 6 highly delocalized pi-electrons, pyrazole molecules are aromatic heterocycles. Hence, various significant properties of pyrazoles have been investigated by matching with the properties of benzene analogues.[33] Like other nitrogen atom(s) involving heterocyclic compounds, different tautomeric forms (14 and 15) can also be written for pyrazole heterocycles. Unsubstituted pyrazole 1 can be illustrated in three tautomeric structures (Figure 3).[34]
5-Amino-3-(cyanomethyl)-1H-pyrazol-4-yl cyanide 16 is a pi-excessive aromatic monocyclic heterocyclic compound having two N-atoms in a 5-membered 1,2-diazole ring, there are three sites for electrophilic attack in pyrazole moiety 16 which is in tautomeric equilibrium with 17, the active methylene group and the amino group, whereas two such sites are also available for nucleophilic attack, the carbon atom of the conjugated nitrile group and the carbon atom of the non-conjugated nitrile group (Figure 4).[35]
2.3 Chemical and physical properties of pyrazole
Unsubstituted pyrazole 1 is a colorless solid with a melting point in the range of 69–70 \(^{\circ }\hbox {C}\). The boiling point of unsubstituted pyrazole is in the range of 186–188 \(^{\circ }\hbox {C}\) that is attributed to intermolecular H-bonding. The ionization potential of this molecule is 9.15 eV. It follows from a comparison with an azole (having ionization potential of 8.231 eV) that pyridine-like nitrogen-atom reduces the energy of the HOMO (highest occupied molecular orbital), indeed even more so than in the case of 1,3-diaza-2,4-cyclopentadiene (with ionization potential of 8.782 eV) (Table 1). The dipole moment (\({\upmu }\)) of pyrazole 1 in benzene is estimated to be 1.921 D (Debye). The value of \({\upmu }\) relies on the concentration of pyrazole 1 because cyclic dimers of pyrazole 1 develop at higher concentrations in compound 1. The \({\upmu }\) is directed from the center of the pyrazole to the bond between atoms 2 and 3. In most pyrazole reactions, a similarity with 1,3-diaza-2,4-cyclopentadienes is evident, and contrasts are also possible.[36, 37]
2.4 Acid-base reactions
Unsubstituted pyrazole 1 displays acidity due to –NH group present at position-1. The \(\hbox {pK}_{\mathrm{a}}\) value of pyrazole 1 is experimentally calculated to be 14.211, which is equal to the \(\hbox {pK}_{\mathrm{a}}\) value of 1,3-diaza-2,4-cyclopentadiene (Figure 5). Pyrazolines (11, 12 and 13) are basic in nature. It is reported that in the excited state of Pyrazoline, an intermolecular conjugated charge transfer process exists. In the conjugated part (-C3-N2-N1-) of the ring of 1, the N-atom at the position-3 has, respectively electron withdrawing and donating capabilities. The carbon atoms at position-4 and position-5 are not conjugated intermolecularly with the remaining part of the ring of 1.[37]
3 Nomenclature of pyrazoles and related systems
Pyrazoles and related ring systems can be designated as 1H, 2H, 3H and 4H-pyrazoles. The 2H and 3H-pyrazoles (12 and 11) are called pyrazolines (2-pyrazoline 12 and 1-pyrazoline 11) and dihydropyrazoles. The designations 1H, 2H, 3H and 4H prior to the term ‘pyrazole’ show the position of the hydrogen atom, which resembles the lowest numbering system for the nitrogen or the location for saturation (Figure 6). The word ‘dihydro’ indicates the location of a formally reduced double bond. For dihydro 2H or 3H pyrazole, the entity must contain one double bond. In order to be named as 4H-pyrazole 14, which is aka. isopyrazole or cyclic azine, the entity must contain one tetrahedral carbon and two double bonds.[38]
4 Methodologies for the synthesis of pyrazoles
The pyrazole entity is a significant pharmacophore displaying a multitude of pharmacological and biological activities. Naturally, these broad biological activities render this class of compounds synthetically interesting. Consequently, new approaches for the development of this heterocyclic skeleton have attracted significant consideration during recent years. The development of methods for efficient construction of several pyrazole derivatives is the focus of this book chapter, which also includes the development of a new eco-friendly synthetic pathway to the construction of pyrazole derivatives. Also, benzo-fused and dihydropyrazolone analogues of pyrazole (i.e. indazoles and tetrahydroindazoles) are of interest in this context.
4.1 Recent green methodologies to construct the skeleton of pyrazole analogues
4.1.1 Microwave-mediated solvent-free approach
An innovative solvent-less microwave-based methodology to the construction of pyrazoles 22 from tosyl hydrazones 21 (generated in situ) of \(\alpha \),\(\beta \)-unsaturated carbonyls 19 having a beta-hydrogen in the presence of \(\hbox {K}_{2}\hbox {CO}_{3}\) and p-toluenesulfonyl hydrazide20 is recently disclosed by Anna Corradi et al. (Scheme 1). In this approach, activation was brought about with microwave irradiation (MWI). With the proposed microwave based solvent-less procedure, good results in terms of yields and reaction speed were observed, which indicate that this process is the eco-friendly, fast and simple synthetic route to attain pyrazoles 22 from \(\alpha \),\(\beta \)-unsaturated ketones19 having beta-hydrogen.[39]
4.1.2 One-pot deep eutectic solvent-based synthesis of polysubstituted pyrazoles
Polysubstituted pyrazoles 25 were efficiently synthesized by Beyzaei et al., through two-step one-pot procedure. In this technique, the reaction of 2,4-dinitrophenylhydrazine 25, malononitrile 23, and different aldehydes 24 in deep eutectic solvent (DES) were carried out.[40] In order to obtain optimized results and investigate the effectiveness of DES towards the synthesis of pyrazoles, some deep eutectic solvents having different molar ratios of potassium carbonate to glycerol were prepared and employed as reaction bath and catalyst in this synthetic approach. The finest results in terms of product yields and reaction times were achieved in molar ratios 1:4:14 of \(\hbox {K}_{2}\hbox {CO}_{3}/\hbox {glycerol}/\hbox {H}_{2}\hbox {O}\) (Scheme 2). In the existence of DES, the reaction times and productivity of reactions were improved considerably.
4.1.3 Catalyst-free and eco-friendly formation of phthalide-fused pyrazole derivatives
A promising catalyst-free and eco-friendly procedure for the formation of phthalide-fused pyrazole derivatives 30 through condensation of acetylenic ester 27, hydrazine monohydrate 28 and phthalaldehydic acid 29 in water at 100 \(^{\circ }\hbox {C}\) for one day is disclosed by A. Bazgir and co-workers.[41] The course of work-up of these eco-friendly reactions required only filtration and subsequent washing with excess methanol (Scheme 3). Further, this method shows remarkable characteristics, for instance, application of \(\hbox {H}_{2}\hbox {O}\) as a solvent, uncomplicated workup of products, and reduced waste formation without employing any catalyst or additive.
4.1.4 Eco-friendly formation of 1,4-dihydropyrano[2,3-c]pyrazoles through biodegradable catalyst maltobiose
A novel and highly effective technique for four-component one-pot preparation of highly derivatized 1,4-dihydropyrano[2,3-c]pyrazoles 33 using phenylhydrazine or hydrazine monohydrate 32, acetoacetic ester 31, malononitrile 23 and aldehydes 24 under thermal and solvent-less conditions with maltobiose as a catalyst has been unveiled by Kangani et al.[42] The reaction efficiently proceeded to produce the respective products 33 (Scheme 4). Use of inexpensive and non-toxic materials, short reaction times, simple and clean work-up, non-hazardous catalyst, minimum pollution of the environment, operational simplicity and excellent yields of the pyrazoles are the benefits of this technique.
4.1.5 Eco-friendly TBAB-based formation of pyrazoles under solvent-less conditions
Soltanzadeh et al., disclosed a green, environment-friendly, novel and inexpensive technique for the production of a library of pyrazoles 37.[43] The reaction took place in the existence of N’-benzoylbenzohydrazide 34, 35, isocyanide 36 and tetrabutylammonium bromide (TBAB; a commercially available organic ionic salt) at r.t. under solvent-less conditions for 0.5–12 h (Scheme 5). Operational simplicity, excellent yields of the pyrazoles (75–86%) and short times of reaction are the merits of this technique.
4.1.6 Eco-friendly development of pyrazole frameworks using IL [bmim]OH
A unique and appropriate technique for the preparation of 4H-pyrano[2,3-c]pyrazole derivatives 39 by three-component condensation reaction of malononitrile23, aryl-aldehydes 24 and pyrazolone 38 or four-component condensation reaction of malononitrile 23, hydrazine monohydrate, aromatic aldehydes 24 and acetoacetic ester 31 using [bmim]OH 40 as ionic liquid (IL) at 50–60 \(^{\circ }\hbox {C}\) has been disclosed by Khurana et al.[44] The procedure was expressed to be environmentally benign and efficient in terms of excellent yields, ease of recovery, low reaction times and recyclability of reaction medium (Scheme 6).
4.1.7 Synthesis of pyrazole derivatives by 1-methylimidazolium trinitromethanide: a nano-IL
In the report of Zolfigol et al., an effective and green NIL catalystviz., 1-methylimidazolium trinitromethanide \(\{[\hbox {HMIM}]\hbox {C}(\hbox {NO}_{2})_{3}\}\) 42 was employed in the formation of 5-amino-pyrazole-4-carbonitriles 44 by the three-component condensation reaction of malononitrile 23, aryl aldehydes 24, and phenyl hydrazine 41 under solvent-less conditions at r.t. (Scheme 7). 1,4-Dihydropyrano-[2,3-c]-pyrazoles 43 were also prepared via four-component condensation reaction of malononitrile 23, aryl aldehydes 24, ethyl acetoacetate 39 and phenyl hydrazine 41 under similar reaction conditions.[45] The disclosed reactions by Zolfigol et al., were in fair agreement with the disciplines of green synthesis and their key benefits are ease of separation, cleaner reaction profile, reasonably high productivity, short times of reaction and recyclability of NIL.
4.1.8 Copper(II) IL for chemoselective green preparation of highly functionalized pyrazoles
A chemoselective, eco-friendly, novel and effective technique for the production of highly substituted pyrazoles 48 by the one-pot reaction of aldehydes 45, aryl-hydrazine 46 and dimethyl 2-butynedioate 47 in the presence of Lewis acidic IL [n-\(\hbox {Bu}_{4}\hbox {P}\)][\(\hbox {CuBr}_{3}\)] as a reusable catalyst has been described by Safaei et al.[46] This catalytic system is chemoselective and simple with excellent yields (Scheme 8). Short times of reaction, straightforward operation, eco-friendliness and elimination of the application of toxic reagents, as well as organic solvents, are remarkable benefits of the present technique.
4.1.9 Green formation of fluorinated pyrazolines by means of ultrasonic irradiation
A library of fluorinated pyrazoles 52 were constructed by Shelke et al.,[47] in reasonable yields (65–82%) from the respective fluorinated-chalcones 51 by using ultrasonic irradiation and the reaction took place in the presence of hydrazine monohydrate, ethanol and AcOH (Scheme 9). The fluorinated-chalcones 51 were obtained through the reaction of aldehydes 49 and aromatic ketones 50 in the existence of 40% KOH in ethanol under ultrasonic irradiation. Owing to higher yields, shorter reaction times, lower temperatures and ease of operation, the ultrasonic irradiation approach is an eco-friendly alternative process to the conventional formation of pyrazoline analogues.
4.1.10 Pyrazole-4-carbonitriles formation in aqueous bath with copper(II) oxide in zirconium dioxide
Maddila et al., reported an eco-friendly and well-organized one-pot three-component process for the formation of pyrazole-4-carbonitirile analogues 54 via reaction of malononitrile 23, aldehydes 24 and phenyl hydrazine 53 in the presence of copper(II) oxide in zirconium dioxide (\(\hbox {CuO/ZrO}_{2}\)) as a catalyst in water as reaction medium (Scheme 10). The catalyst is recyclable for over five runs, without affecting its outstanding potency. This recyclable and simple heterogeneous catalytic system, CuO in \(\hbox {ZrO}_{2}\), displayed an extraordinary catalytic affinity for MCR approach. The existing methodology deals with numerous benefits, for instance, short reaction times, good to high yields, purity of products, simple workup, cost-effectiveness, need of environmentally benign green solvents and a small amount of inexpensive catalysts. This technique reveals to be a favorable environmentally benign method for the preparation of a series of pyrazole analogues.[48]
4.1.11 A multi-component aqueous preparation of pyrido[2,3-d]pyrimidine-dione derivatives
A unique one-pot preparation of pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-diones 59 (pyrazole-based pyrido[2,3-d]pyrimidine-dione derivatives) via a five-component aqueous reaction has been disclosed by Heravi et al.[49] The aqueous reaction of acetoacetic ester 55 and hydrazine monohydrate 56 was rapidly and smoothly proceeded to furnish 3-methyl-5-hydrazolone 57, nearly in quantitative yield. Next, in the same flask, the synthesized 3-methyl-5-hydrazolone 57 was reacted with other three components (ammonium acetate, aryl aldehydes 24 and 1,3-dimethyl barbituric acid 58) to furnish a five-component reaction and affords pyrazole derivatives 59 (Scheme 11). The whole process was catalyzed by nano ZnO catalyst in water. The notable advantages of this method are short times of reaction, good yields, simple workup, and environmental benignancy.
4.1.12 Utilization of silica supported sodium bisulfate for pyrazoles synthesis
An effective and useful process for the preparation of library of pyrazole analogues 63 under solvent-free thermal conditionsvia heterocyclic–enaminones using \(\hbox {SiO}_{2}\)-\(\hbox {NaHSO}_{4}\) (sodium bisulfate supported on silica) as an efficient catalyst has been described by Siddiqui et al.[50] This approach demonstrates very striking features such as economic viability, simple work-up and reasonable yields of the pyrazoles (Scheme 12). The catalyst can be reused various times without important loss of its catalytic potency.
4.1.13 Four-component one-pot reaction in aqueous media for pyrazole cores formation
A green, four-component, catalyst-free and one-pot formation of methyl 6-amino-5-cyano-4-aryl-2,4-dihydropyrano[2,3-c]pyrazole-3-carboxylate derivatives 64 in aqueous media is described by Adeleh Moshtaghi Zonouz et al.[51] The four-component were aldehyde, malononitrile, hydrazine and dimethyl but-2-ynedioate (Scheme 13). The technique does not include any tedious purification or work-up and is atom-economical, catalyst-free and affords the target pyrazoles in reasonable yields.
4.1.14 One-pot eco-friendly solvent-less procedure for pyrano[2,3-c]-pyrazoles synthesis
Convenient multi-component synthesis of pyrazoles is disclosed by Al-Matar et al.[52] In this approach, synthesis of pyrano[2,3-c]pyrazole derivatives 69 were accomplished through the mixing of hydrazine monohydrate, malononitrile 23, ethyl acetoacetate 31, and ketones or aldehydes 65 in the solvent-free conditions (Scheme 14). Alternatively, the reaction of aminopyrazolones 66 with arylidene-malononitrile 67 afforded pyrano[2,3-c]pyrazoles 69. The yields in multi-component synthetic approach were observed to be nearly identical to those of previously reported synthetic methodologies in this book chapter but they are highly greener, avoiding the utilization of solvent, purification and separation steps. Chitosan could be employed as a catalyst for the reaction by replacing the use of homogeneous catalyst. The mild conditions applied as well as the high yields obtained are significant features of the reaction. This method avoids the use of tedious workup and column chromatographic purification of products, making the method expedient and superior.
4.1.15 Organo-nanocatalyst: magnetically retrievable iron oxide-anchored GSH for MW-mediated pyrazoles synthesis
Polshettiwar et al., developed a unique concept of organo-nanocatalyst, by supporting totally benign and environmentally abundant glutathione (GSH) on magnetic nanocatalyst.[53] Post-synthetic modification of magnetic NPs surface by GSH imparts required chemical functionality and allows the catalytic site’s formation on the exteriors of ensuing organocatalysts. The catalyst displayed an outstanding affinity for microwave (MW)-assisted pyrazoles synthesis. The reaction of 70 with 53 in the existence of organo-nanocatalyst in aqueous medium under MWI afforded pyrazoles 71 in 78–98% (Scheme 15). This innovative organo-nanocatalyst bridges the gap between heterogeneous and homogeneous catalysis; therefore, preserving the required attributes of both the synthetic systems. Their paramagnetic nature coupled with an insoluble character allows easy isolation of these nanoparticles from the reaction contents using bar magnet, which minimizes the prerequisite catalyst separation by filtration.
4.1.16 Scandium triflate-catalytic system for pyrazoles synthesis under MWI
An eco-friendly, rapid and effective formation of functionalized pyrazole derivatives 72 under solvent-less conditions by the treatment of aldehydes 24 with acetoacetic ester 31 and phenyl hydrazine 53 has been reported by Kumari et al.[54] This methodology exploits the synthetic potential of MWI and scandium(III) triflate \(\hbox {Sc}(\hbox {OT}_{\mathrm{f}})_{3}\) combination and illustrates numerous benefits such as easy isolation of products, shorter reaction times, eco-friendly reaction conditions and excellent product yields (Scheme 16).
4.1.17 Multi-component green media formation of 5-amino-1,3-aryl-1H-pyrazole-4-carbonitriles
Hasaninejad et al., disclosed a convenient and novel three-component one-pot approach for the preparation of poly-substituted amino-pyrazoles 73 via a tandem cyclo-Knoevengel condensation of malononitrile 23, aryl-aldehydes 24, and phenyl hydrazine 53 in \(\hbox {H}_{2}\hbox {O}\) and EtOH at r.t.[55] This multi-component catalyst-free methodology smoothly proceeded in reasonable yields and illustrates numerous other benefits i.e., no toxic by-products, simple work-up experimental procedures and short reaction times (Scheme 17). The method also eliminates the application of anhydrous conditions, toxic organic solvents and catalysts. This procedure signifies a promising eco-friendly pathway for the construction of poly-substituted amino-pyrazole systems 73.
4.1.18 Benzylpyrazolyl coumarins and pyrano[2,3-c]pyrazoles synthesis using zirconium dioxide NPs
A one-pot novel multi-component procedure for the development of bio-active benzylpyrazolyl coumarin derivatives 75 and pyrano[2,3-c]pyrazole derivatives 76 has been reported by Saha et al., using \(\hbox {ZrO}_{2}\) (zirconium dioxide) nanoparticles (NPs) as a nanocatalyst at r.t.[56] The reactions were high yielding and very fast (Scheme 18). The tetragonal plane of the zirconium dioxide NPs and catalytic potency remained unaffected after the tenth recycle. The process by Saha et al., is eco-friendly as the nanocatalyst is reusable and non-toxic, reactions were accomplished at 25 \(^{\circ }\hbox {C}\) in a green solvent (ethanol-water); pyrazoles were decontaminated through recrystallization from EtOH, and chromatographic purification was not desired by this scheme; hence, the application of hazardous and volatile solvents has also been circumvented.
4.1.19 Polyfunctionalized pyrano[2,3-c]pyrazole systems synthesis through \(BMIMBF_{4}\) ILs
A rapid, eco-friendly and highly effective production of 4H-pyrano[2,3-c]pyrazoles 77 using multi-component cyclocondensation of phenyl hydrazine/hydrazine monohydrate, malononitrile 23, aryl-aldehydes 24 and acetoacetic ester 31 in the presence of IL 1-butyl-3-methylimidazolium tetrafluoroborate and L-proline at r.t. has been disclosed by Khurana et al.[57] Reusability of the IL without important loss of potency was a chief benefit (Scheme 19).
4.1.20 Grinding induced formation of highly substituted pyrazoles
Grinding induced formation of highly substituted pyrazoles 80 by application of malononitrile 23, phenylhydrazine 53 and functionalized aldehydes 78 has been disclosed by Madhulika Srivastava et al.[58] In this process, IL 79 is utilized as a catalyst with \(\hbox {H}_{2}\hbox {O}\) and no byproducts were formed (Scheme 20). Most importantly, simple handling and attainment of high yield up to 97% are the advantages of this methodology.
4.1.21 Synthesis of tert-butylpyrazoles by using ionic liquid
This approach is reported by Clarissa P. Frizzo et al. In his report, investigations on different ionic liquids, ([HMIM][\(\hbox {CF}_{3}\hbox {CO}_{2}\)], [HMIM][\(\hbox {HSO}_{4}\)], [BMIM][SCN], [BMIM][OH], [DBMIM][\(\hbox {BF}_{4}\)], [DBMIM][Br], [BMIM][\(\hbox {PF}_{6}\)], [OMIM][\(\hbox {BF}_{4}\)], [BMIM][Br] and [BMIM][\(\hbox {BF}_{4}\)]) were performed. The results of the investigation revealed that ionic liquid [BMIM][\(\hbox {BF}_{4}\)] provides the highest efficiency for cyclocondensation reactions. The cyclocondensation reaction between 4-dimethylamino-1-phenyl-3-alken-2-one derivatives 81 and tert-butylhydrazine 82 in the existence of ionic liquid [BMIM][\(\hbox {BF}_{4}\)] afforded tert-butylpyrazoles 83 in excellent yields.[59] [BMIM][\(\hbox {BF}_{4}\)] IL was also observed to be an efficient, fast and mild approach for the regioselective preparation of tert-butylpyrazoles 83 (Scheme 21). This technique permitted the formation of a series of new pyrazole derivatives that are problematic to prepare by other techniques.
4.2 Well-known classical approaches to construct important pyrazole derivatives
4.2.1 Synthesis of 5-amino-3-(cyanomethyl)-1H-pyrazol-4-yl cyanide
Using the \(1^{\mathrm{st}}\) attempt in 1894, Rothenburg suggested that malononitrile 23 can be treated with hydrazine monohydrate to afford 1H-pyrazole-3,5-diamines 84 (Scheme 22). Von Rothenburg failed to observe that the formation 1H-pyrazole-3,5-diamine 84 was completed through the release of ammonia.[60, 61]
After some years, co-workers have demonstrated that the product was already 87 produced through the process of malononitrile 23 dimerisation to furnish dimer of malononitrile (2-aminoprop-1-ene-1,1,3-tricarbonitrile) 86 (Scheme 23).[62] The mechanism of reaction proposed that the elimination of a \(\hbox {H}^{+}\) from the activated methylene moiety in malononitrile 23 and subsequent nucleophilic addition of this anion to the unsaturated carbon of a \(2^{\mathrm{nd}}\) malononitrile entity 23 affords a 2-iminopropane-1,1,3-tricarbonitrile 85 which would readily rearrange to the more stabilized form 86.[63] Compound 86 appears as one of the numerous zwitterionic structures stabilized by election delocalization (Scheme 23).
The reaction of malononitrile dimer 86 or malononitrile 23 with hydrazine hydrate provided 5-amino-3-(cyanomethyl)-1H-pyrazol-4-yl cyanide 87 (Scheme 24).[64, 65]
The product was synthesized from one mole of hydrazine monohydrate and two moles of malononitrile 23 with the elimination of one mole of \(\hbox {NH}_{3}\) to produce 87 in 40% yields. The best method was the reaction of a dimer of malononitrile 86 with hydrazine monohydrate to provide 87 in 71.5% (Scheme 24). The mechanism of the reaction for the synthesis of pyrazoles involves Michael addition in which hydrazine hydrate attacks the \(\alpha \),\(\beta \)-unsaturated system of malononitrile dimer as intermediate and cyclizes to give pyrazole 87.
4.2.2 Synthesis of azo dyes of pyrazole
Azo dyes are prepared through two-step reactions, i.e., diazotization and coupling reactions. Diazotization involves treatment of a primary aromatic amino group of pyrazole analogues with nitrous acid to afford an aromatic diazonium ion; the next step is the coupling of the diazonium salt of pyrazole analogues with a nucleophilic compound in baseline conditions. Active methylene compounds are very beneficial because they act as intermediates in organic synthesis; they show different reactions, for example, Knoevenagel condensation and synthesis of azo dyes, on account of the acidic hydrogens in the active methylene group that could copulate with a number of aminoaromatic compounds to configure numerous hydrazones. Diazonium salts of pyrazole analogues couple with active hydrogen-containing reagents mainly ethyl acetoacetate, ethyl cyanoacetate, malononitrile, acetylacetone, pyrazole derivatives and pyrazolones and yield the corresponding azo derivatives or lead to the development of the pyrazolo[1,5-c] as-triazines,[66, 67] through cyclocondensation reaction, that takes place by nucleophilic attack of nitrogen atom of pyrazole on the electrophilic group in active hydrogen reagents.
In 1989, triazine analogues were formed directly under the same reaction conditions by coupling 5-amino-3-phenyl-4-nitropyrazole 88 with malononitrile and benzoylacetonitrile reagents, the resulting compound was readily cyclized to yield pyrazolo[5,1-c]-1,2,4-triazines 90a-b, respectively (Scheme 25).[68]
Also, malononitrile and benzoylacetonitrile could easily be coupled with the amino compound 91, the resulting compound can readily be cyclized via stirring under the same conditions of coupling reaction to afford 92a–b, respectively (Scheme 26).[69] The coupling of Diazonium salt of arylazopyrazole 94 with malononitrile and ethyl acetoacetate yielded directly the pyrazolo[5,1-c]1,2,4-triazines 93 and 95 (Scheme 26).[70]
Diazotization of 4-(ethoxycarbonyl)-3-methyl-1H-pyrazole-5-diazonium chloride 97,[71] on reaction with mono and 1,3-disubstituted pyrazolones 98 produced three tautomeric forms of compound 99a–c, as well as cyclization possibilities in good yields of 85% (Scheme 27). Hydrazone derivative 101 was formed through the conversion of 3-aminopyrazole 100 into diazonium salts, followed by coupling with 3-amino-1H-pyrazol-5(4H)-one in pyridine as solvent (Scheme 27).[72]
Fati and Fikret[73] reported the ten unique dyes viz., pyrazolo[5,1-c][1,2,4]triazines 103a–b, prepared by refluxing ethyl pyrazolylazo cyanoacetate 102b and pyrazolylazo malononitrile 102a in glacial AcOH. Whereas, coupling reaction of 5-amino-3-methyl-4-heterylazo-1H-pyrazole 104 with 3-methyl-1H-pyrazole-5(4H)-one produced pyrazolone dye 105, without cyclization attempt/step (Scheme 28).[74] Pyrazolyl diazonium chloride 106 has been coupled with the active methylene group of cyanoacetanilide and affords the corresponding hydrazone derivative 107.[75]
Also, the cyclocondensation reaction was completed when compound 108 was refluxed with acetic acid. The reaction mechanism occurs via nucleophilic attack of the ring nitrogen atom on the electrophilic cyano group in the compound to yield 109 (Scheme 29).[76] Malononitrile dimer reacts with different aryldiazonium chlorides to give pyridazine derivatives that are found to be good intermediates for the formation of fused heterocycles.[55] The reaction of MND with diazonium chloride salts of aniline derivatives yields intermediate substituted arylhydrazones 110a–b, that readily cyclizes in basic medium providing pyridazinimine derivatives 111a–b (Scheme 29).[77]
5 Overview of biological potency of pyrazole containing compounds
Pyrazoles are known to be one of the most prominent types of N-containing heterocycles exhibiting large spectrum of biological potencies such as anti-inflammatory, anti-cancer, anti-bacterial, anti-microbial, anti-analgesic, anti-tubercular, anti-viral, anthelmintic, antifungal, hypotensive, anti-nociceptive, insecticidal, MAO inhibitory, anti-mycobacterial, antihelmintic, anti-HIV, antitumor, anti-oxidant, ACE-inhibitory, anticonvulsant and antidepressant activities.[78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118] The following section describes in brief, the biological activities elucidated by the presence of pyrazole moiety in various compounds.
5.1 Anti-bacterial potency of pyrazole derivatives
Nada M. Abunada and co-workers prepared 1,3,4,5-tetraaryl-2-pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione and 1,3-diaryl-5-(cyanoaminocarbonyl and ethoxycarbonyl)-2-pyrazoline analogues of pyrazole.[78] The synthesized derivatives were subjected to investigation for anti-bacterial potency. The compound 112 viz., 1-((4R,5S)-1,3-bis(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-7-chlorohepta-2,4,6-triyn-1-one was observed to be active against S. aureus and E. coli. R. Antimicrobial screening results of the compound 112 shows that inhibition zones were 12 mm, 12 mm, 0.0 mm and 10 mm for E. coli, S. aureus, A. flavus and C. albicans, respectively. Chawla and co-workers prepared 3,5-diphenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives 113a–113f by making the use of MWI technology (Figure 7). All the prepared pyrazole derivatives were investigated for anti-microbial potency against two Grampositive strains (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative strains (Pseudomonas aeruginosa and Escherichia coli).[79] The investigation revealed that derivatives 113a–113f of synthesized compounds show reasonable anti-bacterial efficacy and noteworthy anti-fungal activity (Table 2). S. B. Jadhav and co-workers synthesized a new library of 5-(6-methoxynaphthalen-1-yl)-3-phenyl-4,5-dihydro-1H-pyrazole analogues 114a–114e (Figure 7).[80] All the constructed pyrazole derivatives were inspected for their anti-microbial power. All the derivatives demonstrated significant to modest anti-microbial capacity (Table 2). A. Kumar and co-workers synthesized a variety of pyrazole derivatives.[81] All the newly developed derivatives were evaluated for their anti-bacterial potency against B. sublitis, E. coli, S. aureus and K. pneumonia. All the results were compared with that of ciprofloxacin, which is a standard drug. The most potent anti-bacterial derivative of the series was 115 (Figure 7). In detail, zone of inhibition were 28, 24, 27 and 22 mm against K. pneumoniae, S. aureus, E. coli, and B. sublitis, respectively) than standard drug ciprofloxacin.
5.2 Role of pyrazole derivatives as anti-cancer agents
Faidallah and co-workers[82] synthesized some poly-substituted fused pyrazole-based ring systems viz., pyrazolo[4,3-c] pyridines and pyrano[4,3-c]pyrazoles 116 (Figure 8). All the prepared pyrazole derivatives were investigated for anti-microbial and anti-cancer potencies. All the derivatives demonstrated considerable to modest anti-cancer capacity. Dean et al.,[83] synthesized pyrazolo[1,5-a]pyrimidine derived compounds. Among all the derivatives, the compounds 117 and 118 were found to be potent. However, the best results were demonstrated by 117. It was selective CDK inhibitor and significantly inhibit the activities of CDK9, CDK7, CDK5, CDK1 and CDK2 (\(\hbox {IC}_{50}= 90\), 250, 30, 30 and 3 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and \(\hbox {G}_{2}/\hbox {M}\) phases. Consistent with these findings, 117 demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean \(\hbox {GI}_{50} = 280~\hbox {nmol/L}\)). Zask et al.,[84] reported the mammalian target of rapamycin pyrazolopyrimidine pyrazole derivatives 119 which were highly potent in anti-cancer activity (Table 3).[85, 86]
5.3 Application of pyrazoles in anti-inflammatory activity
V. H. Bhaskar and co-workers[87] prepared various derivatives of 5-phenyl-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4H-1,2,3-triazoles 120 through the reaction of hydrazine monohydrate with chalcones in presence of AcOH. All the prepared derivatives 120 were investigated for anti-inflammatory affinity (Figure 9). The detected increase in anti-inflammatory affinity was owing to the presence of 4-Cl, 4-OH and 4-\(\hbox {NO}_{2}\) in phenyl ring at five-position of pyrazoline ring of prepared derivatives. In some cases, their potencies were equal or more potent as compared to standard drugs (Table 4). Venkataraman and co-workers[88] designed and developed pyrazoline analogues. All the prepared derivatives were characterized by their anti-inflammatory potency. Some of the evaluated derivatives showed excellent anti-inflammatory potency. The 121 was found to be the most potent. Antibacterial screening results of the compound 121 show that inhibition zones were 8 mm, 6 mm, 0.0 mm and 2 mm for S. aureus, B. subtilis, E. coli and P. aeruginosa, respectively. Sridevi et al.,[89] disclosed a library of 1,3,5-trifunctionalized-2-pyrazolines. All the constructed products were screened for their anti-depressant potency. The examined pyrazoline-benzimidazole 122 and pyrazoline-benzoxazole 123 analogues in the library were shown to have important anti-depressant properties in improved forced swimming tests (Table 5).
5.4 Pyrazole derivatives of anti-microbial potential
Halogenated derivatives of pyrazole, 1,5-diphenyl-4-(phenyl(1H-pyrazol-1-yl)methyl)-1H-pyrazoles 124 were constructed by Menozzi and co-workers.[90] These compounds were screened for anti-microbial potential. Anti-microbial screening results of the compound 124 show that inhibition zones were 11 mm and 2 mm for Bacillus pumilus and Staphylococcus aureus, respectively (Figure 10). All the derivatives demonstrated significant anti-microbial capacity. Ayoob Bazgir and his colleagues[91] synthesized pyrazolo[\(4^{\prime }\),\(3^{\prime }\):5,6]pyrido[2,3-d]pyrimidine-diones 125. These compound were investigated in vitro for their anti-bacterial and anti-microbial properties (Table 6). Rakesh et al.,[92] synthesized new derivatives of pyrazole 126 by Hantzsch cyclization and modified Bignelli’s reaction and all the derivatives exhibited better to moderate activity (Figure 10).
5.5 Analgesic and anti-tubercular capability of pyrazoles
S. K. Sahu and co-workers[93] prepared a variety of pyrazole analogues and evaluated them for their analgesic affinity. Compounds 127 and 128 demonstrated highly potent analgesic activity against herpes simplex virus type-1 (HSV-1) and hepatitis-A virus (HAV) (Figure 11). K.K. Sivakumar and co-workers[94] constructed a library of coumarin-mediated pyrazole analogues. All the compounds were investigated for anti-inflammatory and analgesic activities. Compound 129 was observed to have the most powerful analgesic activity. Dias and Salvado[95] prepared and exposed (4-methylthiophen-3-yl)(1H-pyrazol-1-yl)methanone 130, which has an excellent analgesic affinity (Figure 11). A variety of unique 1-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-1H-pyrazole-4-carbaldehyde derivatives 131 were disclosed by Prathapa et al. Their anti-tubercular and anti-oxidant properties were also scrutinized. All the prepared derivatives revealed significant anti-tubercular affinity.[96]
5.6 Pyrazoles as anti-viral, anthelmintic and anti-fungal agents
Osama and co-workers[97] synthesized 1-(5-(4-(benzyloxy)phenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethanone analogues. The analogue having R=Cl, i.e., 132 displayed powerful anti-viral action against a broad panel of viruses in various cell cultures (HEL Cell cultures) (Table 7). Aymn and co-workers[98] prepared functionalized pyrazole analogues 133. These analogues displayed excellent anti-viral potency against Herpes Simplex virus type-1 and hepatitis A virus using plaque infective assay (Figure 12). El Badwi and co-workers[99] disclosed that pyrazole-based alkaloids screened from ashwagandha possess significant anthelmintic property. Priyadersini and co-workers[100] synthesized 2-(5-(4-chlorostyryl)-1-(penta-1,3-dien-2-yl)-1H-pyrazol-3-yl)phenol 134 and 2-(5-(4-chlorostyryl)-1H-pyrazol-3-yl)phenol 135 and observed them possessing moderate potency against black mold. Hassan[101] observed that compound 135 enclosed excellent efficacy against C. albicans (Figure 12).
5.7 Usefulness of pyrazole-based hypotensive and insecticidal agents
Kevser Erol and co-workers[102] constructed some analogues of 2-(2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4-yl)-5-methoxyphenol (137a and 137b) and evaluated their hypotensive capability by a tail-cuff approach using catapres as the reference standard (Figure 13). All the inspected analogues illustrated considerable hypotensive capacities (Table 8). Silver and Soderlund[103] prepared pyrazole-based insecticides (138 and 139) and studied the mechanism of action of prepared entities mediated on available toxicological, pharmacological and electrophysiological information and observed these entities to act at neuronal target sites (Figure 13).
5.8 Anti-nociceptive capacity of pyrazole derivatives
Carlos F. Mello and co-workers[104] examined the participation of spinal noradrenergic and serotonergic systems in anti-nociception prompted by potent pyrazolines PPCA 140 and MPCA 141 (Figure 14). The results revealed that spinal \({\upalpha }2\)-adrenoreceptors and 5-HT receptors are involved and prompted by PPCA 140 and MPCA 141, but not elicited by dipyrone.
5.9 MAO and ACE-inhibiting activity of pyrazoles
B. Bizzarri and co-workers[105] prepared a library of 1-(but-1-en-2-yl)-5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole analogues 142 and examined them as inhibitors of monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) isoforms (Figure 15). The synthesized compounds displayed inhibiting action with micromolar (\({\upmu }\hbox {M}\)) values against MAO-selectivity and observed to be beneficial as coadjuvants in the medication of Alzheimer’s disease and Parkinson’s disease (PD) (Table 9). U. Salgin-Goksen and co-workers[106] constructed a variety of pyrazole derivatives and these derivatives were observed to be inhibitors of human MAO-selectivity. M. Bonesi and co-workers disclosed a series of pyrazoles 143 and examined them as an angiotensin-I-converting enzyme (ACE)-inhibitory agents by carrying out different assays (Figure 15).[107] These analogues of pyrazole presented efficient ACE-inhibitory potency with an \(\hbox {IC}_{50}\) value of 0.123 mM. A new molecular series of COX-2 inhibitors have been recently disclosed by Qi-Huang Zheng and co-workers. The products were tested for their inhibitory property. The investigation revealed that 144a and 144b demonstrate powerful inhibitory efficiency in the MDA-MB-435 human cancer cell line as compared to stranded entity celecoxib.[108]
5.10 Anti-mycobacterial, anti-helmintic and anti-HIV activity of pyrazoles
Mamolo and co-workers[109] synthesized pyridine-based pyrazole analogues and screened them for their in vitro anti-mycobacterial potency. Compound 145 confirmed potent anti-mycobacterial capacity. Ozdemir and co-workers[110] reported novel thiophene-based pyrazole analogues and tested them for in vitro anti-mycobacterial capacity against Mycobacterium tuberculosis H37Rv (Figure 16). The activity of the 145 against M. tuberculosis \(\hbox {H}_{37}\hbox {Rv}\) and M. tuberculosis H4 clinical isolate was observed to be 8 and 8, respectively. Compound 146 possessed the potent anti-mycobacterial capacity. M. G. Mamolo and co-workers[111] disclosed several imidazole-based pyrazole analogues and screened them for their in vitro anti-mycobacterial and anti-fungal potencies. The pyrazole analogue 147 exhibited a remarkable anti-tubercular affinity against Mycobacterium tuberculosis strain H37Rv and an outstanding anti-fungal capacity against the clinical strain of Candida albicans.[112] Sreenivara and co-workers[113] prepared a library of pyrazole derivatives 148 and estimated their anti-helminitic efficacy against earthworms. All the derivatives demonstrated significant to modest anti-helminitic capacity (Figure 16). Charles and co-workers[114,115,116] constructed 3-cyanophenoxypyrazoles 149 and investigated it in vitro against HIV. The compounds illustrated excellent anti-HIV affinity (Table 10).
5.11 Role of pyrazoles as anti-tumor and anti-oxidant
A variety of 5-(1H-indol-3-yl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives 150 were prepared by Nassar and his colleagues and the derivatives were also screened against tumors[117] and microbes (Figure 17).[118] Activity of the 150 against a human breast carcinoma cell line (MCF7) and a liver carcinoma cell line (HEPG2) was observed to be 2.62 and 2.48, respectively. C.F. Mello and co-workers[119] prepared a library of pyrazoles 151 and tested them for anti-oxidant activity. All pyrazoles displayed reasonable potency.
5.12 Pyrazole-mediated anti-convulsants and anti-depressants
Adriana Bolasco and co-workers synthesized a new variety of pyrazole analogues and examined their selectively inhibiting capability against monoamine (MAO) oxidase A and B. The synthesized compounds 152a and 152b were shown to be more potent (Figure 18), reversible and selective inhibitors of MAO-A as compared to MAO-B (Table 11).[120] Abdel-Aziz and co-workers disclosed a novel variety of pyrazole analogues (153a, 153b and 153c).[121] These compounds showed anti-depressant potency using tail suspension behavioral despair test and anti-convulsant potency against pentylenetetrazol (PTZ)-induced seizures in mice (Figure 18). Analogues 153a, 153b and 153c showed a protective effect against tonic-clonic seizure induced by intraperitoneal (I.P) injection of PTZ at a dose amount of 20 mg/kg (Table 12).[122]
5.13 Angiogenic and nematocidal activities of functionalized pyrazoles
Kumar et al., synthesized functionalized pyrazoles 54 and screened them for their antiangiogenic activity by the chorioallantoic membrane (CAM) assay (Figure 19).[123] Investigation reveals that functionalized pyrazoles 54 exhibit excellent cytotoxic and angiogenic properties (Table 13). Cheng et al., developed novel pyrazole carboxamides and investigated their nematocidal activity.[124] The preliminary insecticidal activity showed that some of them possessed good insecticidal activities against Meloidogyne incognita. Avermectin was used as control. The nematocidal activity decreased when the methyl group was replaced by ethyl group on the N-position of the amide group (Table 14). Likewise, Fei et al., synthesized a series of novel thioether bridged N-phenylpyrazole derivatives and insecticidal activities (Figure 19).[125] 56a, 56b and 56c with sulfur-containing heterocycle substituents possessing good insecticidal activity against Musca domestica L. among the series (\(\hbox {LC}_{50} = 0.67{-}1.30~ {\upmu }\hbox {g/g}\)).
5.14 Anti-metastatic activities of hybrids based on coumarin/pyrazole oximes
A series of hybrids based on coumarin/pyrazole oxime have been synthesized by Dai et al. The formed compounds were screened for their metastatic activities (Figure 20).[126] Metastatic activities reveal that 157 displays significant anti-metastasis effects through inhibiting cell migration and invasion in highly metastatic SMMC-7721 cell line, and dose-dependently reverses TGF-\(\beta 1\)-induced epithelial-mesenchymal transition (EMT) procedure
6 Conclusions
Numerous biological activities of pyrazoles and various synthetic protocols to construct pyrazoles have been highlighted in this review article. In the recent past, a lot of research has been carried out for the development of pyrazole scaffolds. In the case of green approaches, \(\hbox {BMIMBF}_{4}\) IL, zirconium dioxide NPs, organo-nanocatalyst, ultrasonic irradiation, copper(II) IL and [bmim]OH IL are the most novel approaches; while, in the case of classical approaches, synthesis of pyrazoles from methylene ketones, alkanyl bromides and propargylic alcohols are some novel approaches. However, currently, there are some important challenges that need to be dealt with in order to further develop the chemistry of pyrazoles. These challenges deal with proficiency for quantitative chemical yields in the formation of pyrazoles, precisely characterizing the inhibiting affinity of the pyrazoles and generating novel pyrazoles with a biological profile in the submicromolar range. It is expected that this review will be helpful in future research and for new and novel ideas in the quest of rational designs for syntheses of more promising pyrazoles.
7 Future prospective
The aim of this review is to summarize recent synthetic developments and biological activities of pyrazole derivatives. This review will inspire the scientists to plan and construct a new and potent series of bioactive pyrazole derivatives using highly efficient synthetic protocols. Further, the review will be cooperative to achieve structural-modifications intended to understand and enhance the inhibitory efficiency of pyrazoles. For future research, authors have listed a number of recommendations. Following are these recommendations: (i) it is suggested to couple other molecular frameworks, such as isatin, carbazole, benzothiophene, thiophene and terpyridine derivatives, with pyrazoles in order to enhance the bioactivity of pyrazole-based drugs; (ii) to replace current commercial bioactive drugs or to construct commercial-level pyrazoles-based drugs; it is important to produce drugs that contain inexpensive and commercially available starting chemicals, milder reaction conditions and one-pot synthetic approach. Further, construction must include properties of quantitative yield and eco-friendly procedures, i.e., MW- assisted approaches and IL-mediated methods; (iii) in order to further enhance the yield of pyrazoles, it is recommended to investigate nano-catalytic systems and sono-mediated approaches; (iv) nowadays, cytotoxicity is the main issue of drugs; therefore, the researcher should focus on cytotoxic properties of pyrazoles. Further, solubility of pyrazoles is also required to be improved; (iv) dimer, trimer, tetramer and star-type polymeric pyrazoles should also be synthesized and investigated for anti-cancer activity; (v) to design and develop extremely bio-operative pyrazole derivatives for the selective and sensitive inhibiting the target cells it is important to understand the structure-activity relationship and develop computational models; and (vi) in order to make pyrazoles highly soluble in \(\hbox {H}_{2}\hbox {O}\), pyrazoles must be containing in the association of a hydrophobic region. It is hoped that this review will assist to increase knowledge and will be supportive of new thoughts in scheming more operative synthetic protocols for pyrazoles and in developing more potent drugs.
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Faisal, M., Saeed, A., Hussain, S. et al. Recent developments in synthetic chemistry and biological activities of pyrazole derivatives. J Chem Sci 131, 70 (2019). https://doi.org/10.1007/s12039-019-1646-1
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DOI: https://doi.org/10.1007/s12039-019-1646-1