A Review of the Recent Development in the Synthesis and Biological Evaluations of Pyrazole Derivatives

Pyrazoles are five-membered heterocyclic compounds that contain nitrogen. They are an important class of compounds for drug development; thus, they have attracted much attention. In the meantime, pyrazole derivatives have been synthesized as target structures and have demonstrated numerous biological activities such as antituberculosis, antimicrobial, antifungal, and anti-inflammatory. This review summarizes the results of published research on pyrazole derivatives synthesis and biological activities. The published research works on pyrazole derivatives synthesis and biological activities between January 2018 and December 2021 were retrieved from the Scopus database and reviewed accordingly.


Introduction
Heterocycles are a fundamental and unique class of compounds; they account for over half of all known organic compounds and have a broad range of physical, chemical, and biological properties, covering a broad spectrum of reactivity and stability [1]. Furthermore, their synthetic usefulness as synthetic intermediates, the protective groups, the chiral auxiliaries, the organocatalysts, and the metallic ligands in the asymmetric catalysts in pharmaceutical agents have rendered them multiple units of interest. Among heterocyclic compounds, five-membered rings containing nitrogen atoms constitute a vast and differentiated group with a broad spectrum of biological activity [2][3][4]. The members of this group, such as pyrazole, imidazole, oxazole, triazole, tetrazole, oxadiazole, thiazole, and isoxazole, are particularly important antibacterial and antifungal agents [3][4][5]. The pyrazole ring is a five-membered heterocycle containing two adjacent nitrogen atoms. It is a moiety found in many molecules that possess many applications. Additionally, naturally occurring pyrazoles and their synthetic derivatives are well-known to have a broad spectrum of biological properties ( Figure 1). In recent years, some of the FDA-approved and commercialized drugs, including patented ones, have been developed from pyrazole derivatives (Figure 2), which implies ample usage of these groups in new-fangled bioactive molecules. This review focuses on a concise overview of the pyrazole pharmacophore synthesis and biological activities reported between 2018 and 2021. Thus, it will serve as a helpful reference guide for researchers interested in the field. This review is loosely categorized into chemical synthesis and biological applications. The first section includes the synthesis of pyrazole derivatives, and the second section describes the biological applications.  The tandem reactions between amine-functionalized enaminones 1 and aryl sulfonyl hydrazine or tosylhydrazone derivatives 2 and 3 in the absence of a metal catalyst have been reported [6]. The synthesis of the substituted pyrazoles 4 and 5 occurred in water, TBHP, and NaHCO 3 , respectively. In addition, when alkyl-based sulfonyl hydrazine such as methyl sulfonyl hydrazine was incorporated, the reaction was not successful. Additionally, when the reaction was carried out in EtOH and DMF, all the analogs were obtained with a good yield. The expected products with a lower yield were formed by introducing double-ethyl functionalized enaminone (R 1 = R 2 = ethyl). (see Scheme 1). Scheme 1. Synthesis of the substituted pyrazoles using hydrazine [6].
Wan et al. [7] reported a different synthetic route to forming-substituted pyrazole derivatives, including celecoxib (7a), mavacoxib (7b), and deracoxib (7c), respectively. The compounds were synthesized using enaminones and aryl hydrazines in ethanol with acetic acid. The reaction produced regioselective compounds with a high yield. Notably, compared to the other synthetic methods, using fluoroalkylated pyrazoles [8], β-diketones [9], and ynones [10], this method gives an excellent yield, a regioselective product. The synthetic route can be explored to synthesize pyrazole derivatives that are not easy to get from fluoroalkyl βdiketones. (see Scheme 2).

Pyrazoles from 1,3-Diketones
A silver-catalyzed synthesis of 5-aryl-3-trifluoromethyl pyrazoles using N'-benzylidene tolylsulfonohydrazides 8 with ethyl 4,4,4-trifluoro-3-oxobutanoate 9 as precursors has been reported [11]. The reaction involved consecutive nucleophilic addition, intramolecular cyclization, elimination, and finally, [1,5]-H shift. This led to trifluoromethylated pyrazole derivatives 10 with moderate to excellent yields (see Scheme 3). In optimizing the product, the yield improved by increasing the reaction temperature to 60 • C, but increasing the reaction temperature above 60 • C resulted in a lower yield. The Cu(OTf) 2 transition catalyst afforded 60% yield, while Fe(OTf) 3 was unproductive. THF or dioxane gave a poor yield of the product compared to toluene. Meanwhile, K 2 CO 3 was more effective than NaH, KOt-Bu, and NaOt-Bu. Additionally, the use of Me 2 phen as a ligand yielded the best performance (>99%), compared to using bpy or phen as a ligand (57% or 92%). Scheme 2. Synthetic route to the formation of celecoxib, deracoxib, and mavacoxib using hydrazine [7]. Scheme 3. Synthesis of 5-aryl-3-trifluoromethyl pyrazole derivatives in the presence of a silver catalyst [11].

Pyrazoles from Acetylenic Ketones
The merging of substrates with five electron-rich heteroaromatic nuclei interacts with arylhydrazines with the carbonyl group and triple carbon bond. The cyclo-condensation of cross-conjugated enynones 13 with hydrazines has produced pyrazole derivatives 14 and 15 in good yield [13] (see Scheme 5).
Chen et al. [15] reported a synthetic approach for synthesizing polysubstituted 4difluoromethyl 28 and perfluoroalkyl 31 pyrazole derivatives. The authors utilized a Lewis acid and base co-mediated reaction of perfluoroacetyl diazoester with ketones (see Scheme 7). Catalysts such as Cu(OTf) 2 , CuCN, Sc(OTf) 3 , NiCl 2 , FeC l3 , Fe(OTf) 3 , CoCl 2 , and ZnI 2 were explored for the optimization of the reaction. Particularly, the Sc(OTf) 3 catalyst displayed the best performance with 97% yield in the presence of DBU as the base. Meanwhile, the base, such as Et 3 N, t -BuOK, K 2 CO 3 , and K 3 PO 4 , did not give the expected product. Scheme 7. Synthetic route to 4-difluoromethyl pyrazole derivatives using Sc(OTf) 3 as the catalyst [15].

Pyrazoles from Hydrazones
Zhu and colleagues [17] investigated the oxidative coupling reaction of phenylhydrazone 36 and maleimide 37 to synthesize pyrazoles derivatives. The reaction was carried out with CuCl as the catalyst, and dimethylformamide (DMF) was used as a solvent (see Schemes 9 and 10). In the reaction, it produced 12% yield in the presence of 20 mol% Cu(OAc) 2 in dimethylsulfoxide (DMSO) at 80 • C for 2 h. Additionally, other Cu(II) salts did not enhance the reaction. The reaction yielded 86% when CuCl as the catalyst in DMSO was utilized, while Cu(I) salts, mainly CuOAc, CuBr, CuI, and CuSCN, led to product reduction. Moreover, catalysts such as Mn(OAc) 3 , Ag 2 CO 3 , FeCl 3, and Pd(OAc) 2 were inefficient.
An effective protocol for synthesizing pyrazoles derivatives 46 and 49 via an iodinecatalyzed reaction of aldehyde hydrazones with electron-deficient olefins has been reported [18] (see Scheme 11). The transformation of the reaction produced a 35% yield in the presence of 20 mol% I 2 and 3.0 equiv of TBHP in DMF at 80 • C. The solvents, such as CH 3 CN, displayed a moderate yield. When different oxidants were utilized, BPO displayed a superior performance up to an 81% yield compared to TBHP, K 2 S 2 SO 8 , DTBP, BTI, H 2 O 2 , and m-CPBA. The product was reduced by replacing molecular iodine with other iodides, such as NaI, NIS, or TBAI. Scheme 9. Synthesis of pyrazole derivatives via copper-catalyzed an oxidative coupling reaction [17].
A facile one-pot, copper-catalyzed aerobic cyclization has been consecutively used to synthesize the pyrazole derivatives (51 and 54) by Fan and coworkers [19]. In this reaction, β and γ-unsaturated hydrazones were readily available substrates. While O 2 acted as the terminal oxidant and economic Cu(I) salt was used as the catalytic agent, CuOTf showed the best performance compared to other employed catalysts such as CuOAc, CuBr, Cu(acac) 2 , CuOTf, and Cu(OTf) 2 (see Schemes 12 and 13). Scheme 12. Synthesis of the pyrazole derivatives in the presence of terminal oxidant and copper salt [19]. Scheme 13. Synthesis of the pyrazole derivatives from β,γ-unsaturated hydrazones [19].

Pyrazoles from Vinyl Sulfone
Dihydro-pyrrolo-pyrazoles have been synthesized through a cascade reaction involving cinnamyl azides and vinyl sulfones with moderate to good yields [23]. The protecting group, ethylene sulfone, can be removed by heating the product in pyrrolidine (see Scheme 17). The reaction tolerated a range of solvents such as benzene, acetonitrile, methanol, 1,3-dichloroethene, isopropanol, and dioxane. However, dioxane with triethylamine as a base produced dihydro-pyrrolo-pyrazole excellently compared to dioxane and diisopropyethylamine (DIPEA) or diisopropanolamine (DIPA).

Pyrazoles from Alkynes
A visible light-promoted cascade of Glaser coupling/annulation alkynes and hydrazines has been utilized to synthesize polysubstituted pyrazoles 73 and 75 [25] (see Scheme 19). The replacement of CuI with CuCl, CuCl 2 , Cu(OTf) 2 , and Cu(OAc) 2 in the reaction using maintaining Ru(bpy) 3 Cl 2 as the photocatalyst did not improve the reaction product.  [26] (see Scheme 20). The substitution of tert-butyl (81g) with MBH carbonate was not reactive, probably due to its steric barrier. It is noteworthy that MBH carbonates derived from other aldehydes, namely benzaldehyde, did not function in this reaction.

Multicomponent Strategies
A one-pot multicomponent reaction for synthesizing bispyranopyrazole 86 derivatives using MMT K10 as a support heterogeneous catalytic system has been reported [27] (see Scheme 21). Notably, the economic and environmentally friendly catalyst was recycled and reused five times in the reaction, and no lack of activity was observed.

Scheme 21.
Synthesis of bispyranopyrazole under a support heterogeneous catalytic system [27].
Alizadeh-Kouzehrash et al. [28] reported new N-fused pyrazole derivatives 91 via an efficient one-pot multicomponent reaction. Using a cheap catalyst, namely 4-toluenesulfonic and ethanol, as a green organic solvent (see Scheme 22), the best yields were reached in ethanol as a solvent under the reflux temperature, and in the absence of a catalyst, the yields percentage of reactions were reduced. Scheme 22. Synthesis of fused pyrazole derivatives using 4-toluenesulfonic as the catalyst [28].

Miscellaneous
The synthetic route to JNJ-18038683 83 and other fused pyrazole derivatives were reported by Dvorak et al. [29]. Two synthetic routes were employed to construct the fused pyrazole-azepine heterocyclic core (see . In the reaction path to pyrazole triflate 107, a bi-phasic solvent system of toluene/water was optimal, and no triflate hydrolysis was identified. Meanwhile, the displacement of the BOC-protecting group was achieved by treating 107 with trifluoroacetic acid to give the free base of the amine. Subsequently, the free base was converted into citrate salt, and the salt formation was then performed with a free base and citric acid in methanol. The final recrystallization yielded clinical candidate 108 as a nonhygroscopic free-flow powder. Scheme 23. Synthetic route to the formation of fused pyrazole [29]. Scheme 24. Synthetic route to the formation of pyrazole triflate using N-phenyltriflamide in pyridine [29]. 1H-pyrazole-5-amines were obtained from the microwave reaction of arylhydrazines 108 with 3-aminocrotonitrile 109 in moderate to excellent yields after 10 min of irradiation [30]. In addition, the reaction of phenylhydrazine 110 with α-cyanoketones 110 under similar conditions produced many functionalized 1H-pyrazole-5-amines. Meanwhile, the m-nitrophenyl and p-nitrophenyl-3-oxopropanenitrile substituents did not react with phenylhydrazine, even at a longer heating time. However, the reaction conditions tolerated other functionalized aromatic groups such as trifluoromethyl and methyl sulfone (see Scheme 26).

Anti-Inflammatory
Bhale et al. [31] reported synthesizing 1,3,4,5-tetrasubstituted pyrazole derivatives and their in vitro anti-inflammatory effect (see Figure 3). Compound 117a showed excellent inhibition (93.80%) compared to the standard diclofenac sodium (90.21%) at a 1 mM concentration. El-Karim et al. [32] reported compounds 118a-118f (edema inhibition% = 98.16%, 96.73%, 88.81%, 81.5%, 76.17%, and 76.68%, respectively) as potent candidates producing rapid onset and a long duration of anti-inflammatory activity, as well as a good safety GIT profile. Meanwhile, the analgesic evaluation revealed that 118b-118e produced potent and long-acting analgesia accompanied by a significant inhibition of the inflammatory cytokine TNF-α level compared to the standard drugs. The inhibition in the protein denaturation of bovine albumin with IC 50 of 34.1 µg/mL using diclofenac sodium as the standard drug (IC 50 = 31.4 µg/mL). Out of the 15 novel compounds synthesized by Akhtar et al. [33], 123a-123d demonstrated a significant in vitro anti-inflammatory activity, with IC 50 values of 71.11, 81.77, 76.58, and 73.35 µg/mL, respectively, compared with the standard diclofenac. The benzylidene substituent attached remarkably influenced the anti-inflammatory potency. Abdellatif et al. [34] synthesized a new series of pyrazole derivatives. The inhibition efficacy of the target compounds to ovine COX-1 and human recombinant COX-2 was analyzed using an immune enzyme assay (EIA) kit. Most of the tested compounds showed high COX-2 inhibitory activity with IC 50 values ranging from 0.02-0.04 µM. Meanwhile, 119a and 119b had the most suitable COX-2 selectivity index (SI = 462.91 and 334.25, respectively), superior to celecoxib (SI = 313.12) and indomethacin (SI = 1.37). Compounds 119a and 119b (SO 2 NH 2 as the selective COX-2 pharmacophore) also showed the highest anti-inflammatory activity (ED 50 = 136 and 126 µmol/kg, sequentially). In addition, they have the lowest ulcerogenic liability (Ulcer Index = 1.25 and 1.00, respectively), reflecting their expected safe GI profiles. Shi and coworkers [35] discovered 120 as the most potent anti-inflammatory agent (IC 50 = 3.17 µM), with low toxicity and strong inhibitory NO release (inhibitory rates (IR) = 90.4% at 10 µM). This compound also showed potent inhibition of iNOS with an IC 50 value of 1.12 µM. The treatment of compound 120 on acute inflammatory models in AA rats displayed a remarkable inhibitory effect on hind paw swelling and body weight loss, comparable to the effect identified in the aspirin-treated group. Of all the compounds investigated by Sivaramakarthikeyan et al. [36], the para-nitrophenyl moiety linked to a pyrazole conjugate 121 (93.53 ± 1.37%) displayed the highest anti-inflammatory activity in the anti-inflammatory assay using the protein denaturation method. This is superior to the standard, diclofenac sodium (90.13 ± 1.45%). Nayak et al. [37] revealed that compound 122a showed remarkable sodium and celecoxib, which showed IC 50 values of 55.65 and 44.81 µg/mL, respectively. The potent compounds were further evaluated for their in vitro COX-2 inhibitory activities using an enzyme immunoassay. Compound 123d demonstrated able selectivity toward COX-2 with a selectivity index (SI) of 80.03 compared with the standard celecoxib, with an SI of 95.84. Dimmito et al. [38] reported that compound 124a displayed a good analgesic effect after subcutaneous and intracerebroventricular management in vivo. Additionally, 124a showed an excellent anti-inflammatory effect after subcutaneous administration, indicating prospective activity at the periphery. Harras and colleagues [39] synthesized a series of pyrazole derivatives and evaluated their in vitro COX-1/COX-2 inhibition and in vivo anti-inflammatory activity using the carrageenan rat paw edema model. It was noted that the targeted compounds exhibited more potent inhibitory activity against COX-2 than COX-1. Meanwhile, all compounds' selectivity indexes (SI) were analyzed and compared to celecoxib (SI = 8.17). Compounds 125a and 125b displayed an outstanding COX-2 selectivity index of 8.22 and 9.31, respectively. Meanwhile, the histopathological investigation of the rats' stomach, liver, and kidneys revealed that 125a and 125b triggered minimal degenerative changes, suggesting these derivatives' safety. Sivaramakarthikeyan et al. [40] reported the anti-inflammatory activity of the pyrazole derivatives. The derivative, lacking substitution on the aryl entity 126, exhibited the highest anti-inflammatory profile. Ab-dellatif et al. [41] synthesized a series of substituted pyrazole derivatives. The targeted compounds were screened for their COX-1/COX-2 inhibitory activity. Additionally, the carrageenan-induced rat paw edema model and histopathological study were demonstrated to examine their anti-inflammatory effectiveness and gastric safety. Compound 127 was the most potent anti-inflammatory agent (ED 50 = 65.6 µmol/kg) compared to the reference drug, celecoxib (ED 50 = 78.8 µmol/kg). In addition, the potent compound possessed minimum ulcerogenic (Ulcer Index = 7.25) Figure 3. A new series of thiazolidindione 128 and thiazolidinone 129 containing a pyrazole core has been synthesized as hybrid structures [42]. The synthesized compounds were further evaluated for COX-1/COX-2 in vitro anti-inflammatory activity and ulcerogenic liability ( Figure 3). The most COX-2-selective derivatives 128a and 128b and 129a and 129b showed the highest anti-inflammatory activities and the lowest ulcerogenic. Among the potent compounds, the thiazolidindione with a methoxy substituent 129b displayed excellent activity against COX-2 (IC 50 = 0.88 µM) with the highest COX-2 selectivity index (SI = 9.26). While compound 128c with a methoxy substituent displayed the highest potent inhibitory against COX-2 (IC 50 = 0.62 µM) with the highest COX-2 selectivity index (SI = 8.85). The highest anti-inflammatory (AI) activities were observed in 129a and 128b (after 1 h, AI = 82.34 and 81.15%; after 3 h, AI = 79.00 and 97.68%; and after 5 h, AI = 80.15 and 97.68%, respectively). Additionally, 128a was slightly more potent (ED 50 = 79.12 µmol/kg) than celecoxib (ED 50 = 82.2 µmol/kg), while 128b showed a superior ED 50 value of 5.63 µmol/kg with a more than 14-fold effectiveness of celecoxib. Some pyrazolopyrimidine hybrids were prepared using Schiff base by Abdelall and coworkers [43]. All the synthesized compounds were evaluated in vivo against carrageenan-induced rat paw edema as anti-inflammatory agents. Regarding the anti-inflammatory activity compounds, 130 and 131 showed excellent activity compared to celecoxib. Thangarasu et al. [44] reported the anti-inflammatory effect of pyrazole moieties, and compound 132b was found to have dominated activity potentials with an IC 50 value of 3.5 nM in the COX-2 inhibition studies.
Taher and colleagues [48] reported the synthesis and pharmacologic evaluation of novel pyrazole and pyrazoline derivatives. The study presents the effect of lengthening the carbon chain in different pyrazole derivatives bearing various amine moieties. Their results showed that lengthening of the aliphatic chain in 137a-137c (26.19%, 30.95%, and 28.57%, respectively) led to higher activity. Meanwhile, the cyclization of chalcones into pyrazolines were more potently anti-inflammatory in compounds 138, 139a and 139b (21.43%, 26.19%, and 28.57%. Compounds 138 and 140 exhibited the highest analgesic activity among all the examined compounds (75.9% and 84.5%, respectively). Mustafa et al.
[49] presented a novel series of celecoxib derivatives. The in vivo anti-inflammatory activity of the synthesized compounds was evaluated using celecoxib as a reference standard by the paw oedema model on albino Wistars. Most of the compounds showed higher in vivo anti-inflammatory activity compared to celecoxib. Different substituents on the triazole moiety played a crucial role in the percentage inhibition of anti-inflammatory effects at 1h. Derivatives with chlorine atoms 141a-141d and the nitro derivative 141e showed good anti-inflammatory potency ( Figure 4). A series of novel benzophenones conjugated with an oxadiazole sulfur bridge pyrazole has been designed, synthesized, and characterized [50]. It was afterward evaluated for anti-inflammatory and analgesic effects. Among the series, compound 142 (65.38% edema inhibition) with an electron-withdrawing group (fluoro) at the para position of the benzoyl ring of benzophenone was characterized by great activity compared to the standard drug. The analgesics activity data also revealed that compound 142 was the highest potent compound among the compounds evaluated for an analgesic effect on the acetic acid-induced writhing response and thermal pain (see Figure 4). A novel series of pyrazole hybrids, such as pyrazole-thiohydantoin and pyrazolemethylsulfonyl, was synthesized by Abdellatif et al. [51]. The hybrids were evaluated in vivo for their anti-inflammatory activity ( Figure 5). Compounds 143a-143d were found to have the most active anti-inflammation. The unsubstituted 143b and 143d showed comparable ED50 (78.90 and 88.28 µmol/kg) with celecoxib (ED 50 = 78.53 µmol/kg), while the methoxy-substituted compounds 143a, 143c, and 143e (ED 50 = 62.61, 55.83, and 58.49 µmol/kg, respectively) showed superior activity to celecoxib. Thirteen pyrazole derivatives were synthesized and evaluated for their anti-inflammatory activity (in vitro and in vivo) and ulcerogenic liability [52]. Nine compounds 144-146 exhibited a moderate to high edema inhibition percentage (78.9-96%) than celecoxib (82.8%). Additionally, they were found to have potent COX-2 inhibitory activity, with the IC 50 values ranging from 0.034 to 0.052 µM. Compound 145a was the benign pyrazole with respect to the ulcerogenic effect (UI = 0.7) on the stomach, which may be ascribed to its high COX-2 enzyme selectivity (SI = 353.8), while compounds 144a, 145b, and 146a-c exhibited ulcer index values (UI = 0.8-2) comparable to celecoxib. Sulphonyl derivatives 147 and 148 have been reported to be selective for the COX-2 isozyme with COX-2 selectivity indexes of 9. The benzothiophen-2-yl pyrazole carboxylic acid derivative 149 showed the most potent analgesic and anti-inflammatory activity superior to celecoxib and indomethacin. It showed potent COX-1, COX-2, and 5-LOX inhibitory activities, with IC 50 of 5.40, 0.01, and 1.78 µM, respectively, showing a selectivity index of 344.56 superior to the reference standards (see Figure 5).
Thiazolyl pyrazole carbaldehyde hybrids have been synthesized and screened for their in vitro anticancer activity by Mamidala and colleagues [74]. Compound 181 exhibited the highest antiproliferative activity against the HeLa, MCF-7, and A549 cancer cell lines, with IC 50 values of 9.05 ± 0.04, 7.12 ± 0.04, and 6.34 ± 0.06 µM, respectively. Raghu et al. [75] designed and synthesized a new series of 1,3,5-triazine-based pyrazole hybrids with anticancer activity targeting the epidermal growth factor (EGFR) tyrosine kinase.  (BBB4-G4K NPs, 187), achieved from BBB4 in a nonbioactive, polyester-based, lysine-containing fourth-generation cationic dendrimer (G4K) has been reported to have an excellent antibacterial profile and highly selective toward the Staphylococcus genus [80]. The synthesis and biological screening of 5-pyrazolyl urea as potential antiangiogenic compounds were investigated by Morretta et al. [81]. Among the targeted compounds, compound 188a displayed 100% inhibition on leukemia cancer cell lines, while 188b and 188c impeded non-small cell lung cancer cell lines. Compound 188d, similar to the STIRUR-41 pharmacophore, exhibited 40% inhibition in the non-small cell lung cancer cell lines. Additionally, compounds 188e and 188f, containing a trifluoromethyl substituent on the urea moiety, displayed excellent inhibitory activity. Meanwhile, the mechanism of action detailed that 188e may likely exert its antiproliferative activity by targeting different signaling pathways, including ERK/MAPK and phosphatases, or the crosstalk between these two associated intracellular mechanisms. Compound 188e can regulate ERK1/2 phosphorylation and PP1g action.
A series of novel pyrazole-thiazole carboxamides were designed, synthesized, and investigated for their antifungal activity [93]. The outcomes showed that compounds 206, 207, and 208 have promising in vitro activities against Rhizoctonia cerealis, with EC 50 values from 1.1 to 4.9 mg/L, superior to thifluzamide (EC 50 = 23.1 mg/L). The antifungal activity of 207 (EC 50 value = 1.1 mg/L was~21-fold more active than thifluzamide and~2-fold more active than compound 206 (EC 50 = 2.0 mg/L). Meanwhile, 208 exhibited excellent antifungal activity towards S. sclerotiorum, with an EC 50 value of 0.8 mg/L, which was~6fold higher than thifluzamide (EC 50 = 4.9 mg/L). The conjugates bearing an aniline moiety with a single substituent at the orthoor meta-position exhibited promising antifungal activity. Additionally, the in vivo antifungal assay showed that 206 (90% at 10 mg/L) exhibited higher antifungal activity than thifluzamide against R. solani (90% at 10 mg/L). The synthetic route to pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether fragment was reported by Wang et al. [94]. The synthesized compounds were evaluated for their antifungal activity by targeting a succinate dehydrogenase. Among the tested compounds, 209a against Rhizoctonia solani, 209b against Fusarium graminearum, and 209c against Botrytis cinerea, exhibited superior antifungal activity. The compounds displayed EC 50 values of 0.14, 0.27, and 0.52 µg/mL higher than carbendazim against R. solani (0.34 µg/mL) and F. graminearum (0.57 µg/mL), along with penthiopyrad against B. cinerea (0.83 µg/mL). Compound 209a was~2-and 15-fold higher than the marketed fungicides carbendazim (0.34 µg/mL) and boscalid (2.21 µg/mL) towards R. solani. The results from the determination of the inhibitory effects of 209a against the SDH collected from the mycelia of R. solani showed IC 50 values of 3.99 µM (1.58 µg/mL). The in vivo anti-R. solani control effectiveness of the most potent compound, 209a (73.25% at 200 µg/mL), was significantly superior to carbendazim under the same conditions (59.81%). Compound 210 has been reported as an excellent antifungal agent with equivalent activity to the marketed fungicide drug thifluzamide, and its EC 50 value was 0.022 mg/L against R. solani [95] (see Figure 10). A synthetic route to substituted 3-(trifluoromethyl)-4,5-dihydro-1H-furo [2,3-c] pyrazole conjugates using the [3 + 2] Michael/Alkylation approach was developed by Tan et al. [96]. The antifungal activity of the synthesized compounds was further examined, and 211a exhibited excellent antifungal activity against A. solani with IC 50 values of 5.44 µM. Compounds 211b and 212 also displayed good antifungal effects, with corresponding IC 50 values of 9.00 and 31.45 µM, respectively. The antifungal effects of the most active compounds 211a and 211b and 212 were relatively superior to the standard compound cycloheximide (IC 50 = 71.00 µM). The conjugates bearing the electron-deficient group on the aromatic ring displayed higher inhibitory effects. At the same time, the compound bearing an electron-donating substituent on the aromatic ring showed reduced inhibitory effects. Compounds 213, 214a and 214b, and 215 have been unveiled to exhibit good antifungal activity toward Fusarium Oxysporum f. sp. and Albedinis (FOA) fungus with IC 50 values ranging from 25.6 to 33.2 µg/mL [97]. Compound 216 has been reported to have superior antifungal inhibitory activity against C. albicans (MIC= ≤146 µg/mL) compared to 217, which displayed a MIC= ≤183 µg/mL. Meanwhile, 218a and 218b exhibited significant antifungal effectiveness concentrations against C. albicans compared to the reference compound cycloheximide with the corresponding MIC values ≥ 168 µg/mL and ≥165 µg/mL, respectively [98]. Piperazine-pyrazole-4-carboxylic acids have shown good antifungal inhibitory effects. Compounds 219a-219e showed equipotent antifungal activity with the reference miconazole against C. albicans (MIC value = 78.1 µg/mL) [99] (see Figure 10). Dong and coworkers [100] synthesized a series of novel pyrazole-4-carboxamides hybrids and further evaluated their antifungal activity (see Figure 10). Compound 220 was the most potent compound against A. solani in vitro, with an EC 50 value of 3.06 µg/mL. It displayed 100% (10 µg/mL) inhibitory activity against A. solani in vivo compared to the standard drug boscalid. Makhanya et al. [101] revealed compounds 221a and 221b as promising antifungal agents. The antifungal assay showed that 221a and 221b exhibited significant inhibitory activity against Saccharomyces cerevisiae (zone inhibition (ZI) = 23 and 20 mm, respectively), with a MIC value of 0.18 µM. Comparable with the standard drug amphotericin, B. Bayazeed et al. [102] detected four chromen-3-yl-pyrazole derivatives: 222a, 222b, 223a, and 223b to have superior antifungal activity. Compared to the standard drug ketoconazole against Aspergillus fumigatus with the corresponding % ZI values of 164%, 147.1%, 158.8%, and 147.1%, respectively. In addition, compounds 222b (% ZI value = 150%) and 223b (% ZI value = 150%) have 1.5-fold superior activity against C. albicans compared to the reference ketoconazole (% ZI value = 150%). Notably, the insertion of two ester groups in compound 222a improved its antifungal activity. Meanwhile, incorporating electron-donating groups (OCH 3 and CH 3 ) at the para-position of the aromatic ring in 222b, 223a, and 223b enhanced their antifungal activity. Wang et al. [103] reported a novel series of pyrazole-4-acetohydrazide derivatives targeting fungal SDH, further evaluating their antifungal properties towards R. solani, F. graminearum, and B. cinerea. Among the evaluated compounds, the antifungal activity of 224a against R. solani, 224b against F. graminearum, and 224c against B. cinerea had EC 50 values of 0.27, 1.94, and 1.93 µg/mL, respectively. These values were superior to the standard reference boscalid against R. solani (0.94 µg/mL) and fluopyram against F. graminearum (9.37 µg/mL) and B. cinerea (1.94 µg/mL). Additionally, the compounds with hydroxyl group substituents at the R 1 position displayed higher anti-R. solani activity than the corresponding conjugates bearing an ethoxy group substituent. The in vivo studies detailed that compound 224a was effective toward R. solani (79.83% at 200 µg/mL), comparable to validamycin (86.56%) and thifluzamide (83.49%). Compound 224a was predicted as an SDH inhibitor (see Figure 11). A series of new pyrazole-4-carboxamide conjugates were designed and synthesized by Wu et al. [104]. The synthesized compounds were evaluated for their antifungal activity using four phytopathogenic fungi (G. zeae, F. oxysporum, C. mandshurica, and P. infestans). The EC 50 values were 1.8 µg/mL for 225a against G. zeae, 1.5 and 3.6 µg/mL for 225b against F. oxysporium and C. mandshurica, respectively, and 6.8 µg/mL for 225c against P. infestans. Meanwhile, the SDH enzymatic effectiveness unveiled corresponding IC 50 values of 6.9, 12.5, 135.3, and 223.9 µg/mL, for 225c, 222d, 225e, and penthiopyrad, respectively. Incorporating substituents (CH 3 , F, or Cl) into the 2-phenyl and methyl into 2-pyridinyl positions enhanced the antifungal activity. While the introduction substituent into the 3-phenyl and 3-pyridinyl positions decreased the antifungal properties. Xia et al. [105] reported novel pyrazole carboxylate derivatives bearing thiazole as potent fungicides. The antifungal studies revealed compound 226 displayed superior activities against Botrytis cinerea and Sclerotinia sclerotiorum, with EC 50 values of 0.40 and 3.54 mg/L, respectively. Compound 227 displayed superb antifungal activity against Valsa mali, with an EC 50 value of 0.32 mg/L. The in vivo fungicide control studies against B. cinerea and V. mali revealed that compounds 226 and 228 at 25 mg/L, respectively, were influential on cherry tomatoes and apple branches. Compound 227 displayed an inhibitory activity toward SDH, with an IC 50 value of 82.26 µM. Nevertheless, compounds 226 and 228 lack inhibitory activity toward SDH in the in vivo studies (see Figure 11).

Antileishmanial
The incorporation of a heteroaromatic ring coupled with a 1,3,4-oxadiazole moiety improved the antileishmanial activity. Compounds 245, 246, and 247 ( Figure 13) proved the dose-dependent killing of the promastigotes with corresponding IC 50 values of 33.3 ± 1.68, 40.1± 1.0, and 19.0 ± 1.47µg/mL, respectively [118]. Additionally, the compounds (245, 246, and 247) displayed IC 50 values of 44.2 ± 2.72, 66.8 ± 2.05, and 73.1 ± 1.69 µg/mL, respectively, on amastigote infectivity. These compounds depicted a comparable point in dosedependent parasite killing with the standard drug, pentamidine (IC 50 = 2.6 ± 0.32 µg/mL). Camargo et al. synthesized a series of novel pyrazole hybrids [119]. The hybrids were investigated in vitro against the promastigote of Leishmania amazonensis. At the same time, the hybrids were examined against the epimastigote of Trypanosoma cruzi (T. cruzi). The S-methyl thiosemicarbazones 248a-248c and 2-amino-1,3,4-thiadiazole pyrazole hybrids 249a-249c displayed significant antileishmanial and antitrypanosomal properties. The substitution of Br, OCH 3 , or NO 2 at the para position of the aryl ring attached at position five of pyrazole favored their activity. The substituent attached to position three of the pyrazole ring also influenced the activity of the evaluated compounds. Silva et al. synthesized and screened a series of 1,5-biaryl 3-arylaminomethyl 4-carboxyethyl pyrazoles and screened against L. amazonensis and T. cruzi [120]. The most active compounds 249, 250, and 251 demonstrated similar profiles against both L. amazonensis and T. cruzi parasites, describing their dual activity. Meanwhile, compound 249 induced morphological and ultrastructural alterations in the promastigote of L. amazonensis (see Figure 13).

Antioxidant
Antioxidant activities of pyrazoline derivatives were screened using the 2,2,-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method. All the tested compounds showed antioxidant activity [88]. Compound 197c bearing 4-fluoro and 4-methyl substituents was the most potent antioxidant agent among all the tested compounds at all the concentrations. Compound 234 has been reported as a promising antioxidant agent [109]. Compounds 237d and 237c have been revealed as having effective antioxidant activity (IC 50 values = 4.25 µM and 5.40 µM, respectively) [112]. The results of an evaluation of synthesized thiazolidine-2,4-dione-pyrazole conjugates as antioxidant agents showed the efficacy of all the examined compounds [107]. Compounds 259a and 259b and 260 (see Figure 14) showed the most potent results, with IC 50 values of 110.88, 127.18, and 128.55 µg/mL, respectively. The standard drug ascorbic acid showed an IC 50 value of 81.12 µg/mL. The synthesis of functionalized pyrano [2,3-c]pyrazoles and pyrazolopyrano [2,3-d]pyrimidines containing a bioactive chromone moiety has been achieved, along with their antioxidant activity [124]. The in vitro antioxidant activity was determined using DPPH radical scavenging methods. Among the tested hybrids, 261-264 displayed promising activity with all the concentrations in the evaluation with the reference drug. The hybridization of pyranopyrazole with the pyrimidine moiety with substituted NH and OH groups improved the antioxidant properties. Ali et al. [125] reported the synthesis of a novel series of pyrazoline 269a-269e, phenylpyrazoline 270a-270e, isoxazoline 271a-271e, and pyrazoline carbothioamide derivatives 272a-272e using chalcones as a precursor 268a-268e. The hybrid compounds were vetted for in vitro antioxidant activity using DPPH, nitric oxide (NO), and the superoxide radical scavenging (RSA) assay, along with 15-lipoxygenase (15-LOX) inhibition activity. Pyrazoline carbothioamide derivatives 272a and 272e were the most potent anti-LOX compounds, 2.2-and 2.1-fold superior to quercetin, while compounds 269a, 270e, 271b, 271c, 272a, 272c, and 272e exhibited substantial RSA in all the three in vitro assays relative to the ascorbic acid, along with 15-LOX inhibition potency. The presence of electron-donating groups (CH 3 and OCH 3 ) or halogens (di-Cl) on the benzene ring enhanced the inhibition activity. The potential antioxidant activity of 272a and 272e were comparable in all three assays. Compounds 271b, 271c, and 271e ( Figure 15) showed significant in vivo antioxidant potential compared to the standard group at a dose of 100 mg/kg B.W. Meanwhile, there was an increase in CAT activity, the GSH level, and a decrease in lipid peroxidation in the treated rat liver compared to the control treatment. The in vitro antioxidant effectiveness of 4-(arylchalcogenyl)-1H-pyrazoles bearing sulfur or 1H-pyrazole groups has been investigated in different assays by Oliveira et al. [126], along with their oxidative stress impacts in biological systems. Compounds 273 and 274 showed significant inhibition in the ABTS assay, revealing that the mechanisms of the antioxidant action of compounds 273 and 274 were connected to their ability to donate electrons. Additionally, compounds 273 and 275 are more potent in the NO scavenging assay, while 274 reduced the lipid peroxidation levels in the brain and the liver after 72 h of treatment remarking on the compound efficacy in oxidative stress. A new series of pyrazole-containing heterocyclic skeletons-namely, pyrimidine, triazole, triazepine, pyrrolone, and thiadiazolopyrimidine-along with acylthiourea derivatives, were synthesized from 2-cyano-3-pyrazolylpropenoyl isothiocyanate by Badawy et al. [127]. The antioxidant screening of all the synthesized compounds showed that pyrimidinethione derivatives 276 and 277 were the most potent antioxidant agents. El-Borai et al. [128] achieved a biological evaluation of the cytotoxicity, antihemolytic and antioxidant activities of some thienopyrazole compounds. The antioxidant activity of the examined compounds was achieved by utilizing the DPPH radical scavenging assay with ascorbic acid as the reference. Compound 278 exhibited excellent radical scavenging activity, with an IC 50 value of 4.49 µg/mL comparable to an IC 50 of 4.76 µg/mL. The excellent antioxidant result was obtained due to the existence of the two amino groups on the pyrimidine ring. Additionally, 279 exhibited strong antihemolytic and antioxidants, justifying that the antioxidant activity may protect red blood cells from hemolysis. The insertion of chlorine atoms, hydroxyl, and cyanide with a pyrimidine ring in a single moiety enhanced the activity of 279. In addition, 280 was noxious to all the tested cancerous cell lines; however, a lower cytotoxicity activity against the normal fibroblast cell line was observed. Elnagdy and colleagues [129] described a synthetic route to pyrazole analogs by using copper oxide nanoparticles (CuO-NPs) as catalyzed. The compounds were evaluated for their antioxidant activity using the DPPH radical scavenging assay. Most of the compounds tested demonstrated a greater interaction with the DPPH radical relative to the standard compound Trolox (IC 50 = 11.48 mM). The compounds 281, 282, and 283 showed maximum antioxidant activity in the order of 282 > 281 > 283, with IC 50 values of 3.06, 3.53, and 5.42 mM, respectively. The ability of 281 and 282 to recover the DPPH radical assay resulted from the prolonged conjugation in compounds, while that of compound 283 was due to a phenolic hydroxyl group at the ortho-position and a fluorine group. The condensation reaction between 1,3-thiazole or aminopyridine derivatives and 1H-pyrazole,3,5-dimethyl-1H-pyrazole or 1,2,4-triazole was described by Kaddouri and colleagues [130]. The reaction produced novel heterocyclic compounds containing pyrazole, thiazole, and pyridine. Additionally, the DPPH scavenging assay was utilized to investigate their antioxidant activity. Ligand 284 showed the best antioxidant activity, with an IC 50 value of 4.67 µg/mL, while the IC 50 value for the reference compound was 2 µg/mL (ascorbic acid). The applicable route for the direct synthesis of (E)-ethyl 2-benzylidene-3-oxobutanoate through the 3 + 2 annulation method, including the investigated in vitro antioxidant vulnerabilities through the DPPH and hydroxyl radical scavenging methods of this compound, have been reported [131]. The assays showed that compound 285 has a strong antioxidant power (see Figure 16).
The multicomponent reaction of some heterocyclic compounds with activated acetylenic, alkyl bromides, triphenylphosphine, and hydrazine in water under ultrasonic irradiation yielded pyrazole derivatives in better yields [132]. Additionally, the antioxidant activities of the compounds were examined using DPPH radical scavenging and the ferric-reducing power assay. Compound 286 ( Figure 16) exhibited exceptional DPPH radical scavenging activity and greater reducing power compared to the standard reference butylated hydroxytoluene (BHT) and 2-tertbutylhydroquinone (TBHQ). Compounds 287 and 288 have been reported as more potent antioxidant inhibitors than ascorbic acid and butylated hydroxyanisole (BHA) [133]. The corresponding IC 50 values for 287 and 288 from the DPPH radical assay were 0.245 ± 0.01 and 0.284 ± 0.02 µM, respectively. These compounds have more potent RSA than ascorbic acid (IC 50 = 0.483 ± 0.01 µM). In the hydroxyl radical scavenging assay, compounds 287 and 288 showed IC 50 values of 0.905 ± 0.01 µM and 0.892 ± 0.01 µM, respectively. They displayed greater RSA than BHA (IC 50 = 1.739 ± 0.01 µM).
Patil et al. [134] prepared sulfonic acid functionalized 1,4-diazabicyclo [2.2.2]octane assisted on Merrifield resin, [MerDABCO-SO 3 H]Cl as a catalyst to synthesized pyrazolopyranopyrimidines in one-pot four-component reactions in an excellent yield. The antioxidant effect of the synthesized compounds was determined using the 1,1-diphenyl-2-DPPH radicals scavenging assay, and ascorbic acid was used as a standard control. Among the evaluated compounds, 289-292 showed excellent antioxidant activity compared to the standard ascorbic acid due to the incorporation of an electron-withdrawing substituent (nitro group) on the phenyl ring, enhancing the resonance impact stabilizing the consistently formed radical. Compounds 293 and 294 have been reported as promising antioxidant agents [135] (see Figure 16).

Agrochemical
Series of novel pyrazole−isoindoline-1,3-dione hybrids as favorable 4hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors were designed by combining 2-benzoylethen-1-ol and isoindoline-1,3-dione into a single moiety [153]. Among the evaluated compounds against Arabidopsis thaliana HPPD in vitro, using mesotrione and pyrasulfotole as the positive control, the IC 50 of 316 ( Figure 18) was extended to 90 nM. In addition, 316 was identified as the most promising inhibitor, with a K i value of 3.92 nM, which was~10 times superior to pyrasulfotole (K i = 44 nM) and 300 times marginally superior to mesotrione (K i = 4.56 nM). Jiang et al. [154] designed and synthesized novel heptacyclic pyrazolamide conjugates using the scaffold hopping approach. The insecticidal activities of all synthesized compounds were examined against P. xylostella in vivo at 500 mg/L. Meanwhile, the marketed insecticide-namely, tebufenozide-was used as the reference drug. Compounds 317 and 318 flaunted excellent insecticidal activities (>90%) against P. xylostella. Additionally, compound 317 displayed 100% insecticidal activity at the dose of 200 mg/L. The lower dose and LC 50 value of 317 (64.13 mg/L) was akin to tebufenozide (LC 50 = 33.83 mg/L). Zhao et al. [155] reported a novel series of fluoro-substituted compounds bearing altered pyrazole and their anti-larvicidal effects. The larvicidal activity unveiled fluoro-substituted compounds to have good to excellent activities against M. separata and P. xylostella. The corresponding LC 50 values for 320a and 320b against P. xylostella were 2.9 × 10 −6 mg/L and 3.1 × 10 −6 mg/L, respectively, superior to the LC 50 of chlorantraniliprole (4.6 × 10 −5 mg/L). In addition, fluoro-substituted compounds 320a-320c bearing ether groups at position three of the pyrazole showed better inhibitory effects than compounds with halogen, amide, or ester groups substituents. The insertion of fluorine atoms on the ethoxy group enhanced the larvicidal activity. Compound 320a exhibited the 50% larvicidal mortality against M. separata to 0.1 mg/L. Moreover, 320a displayed 90% larvicidal activity against P. xylostella at 10 −5 mg/L, higher than that of chlorantraniliprole. Judge and colleagues [156] revealed substituted 3-hydroxyprozole derivative 321 as a promising herbicidal agent. Pyridylpyrazole-4-carboxamides bearing 1,3,4-oxadiazole rings were designed and synthesized by dehydration of aromatic hydrazine derivatives and formanilides [157]. The synthesized compounds were further evaluated for their insecticidal activities (Plutella xylostella). Among the examined compounds, 322 displayed promising activity as follows, 67%, 50%, 34%, 20%, and 17% activity at the concentrations of 100, 50, 10, 5, and 1 µg/mL, respectively (see Figure 18).

Conclusions
Pyrazoles are five-membered heterocyclic compounds containing nitrogen. They are an important class of compounds for drug development; they constitute an essential class of hit compounds to develop new pharmacological agents to treat various infections of clinical primacy. With such a diverse range of biological activities, they have attracted much attention from researchers focusing on synthesizing different pyrazole analogs to developing novel and more effective drugs. This literature review documented various synthetic pathways to pyrazole derivatives and the biological potential of some pyrazole derivatives in recent years. Their biological activity properties, such as antibacterial, analgesic, antiinflammatory, anticancer, antibacterial, antidiabetic, antioxidant, and agrochemical, were detailed in this review. The information presented in this review will assist prospective researchers in further investigating pyrazole derivatives and update scientists with promising biological activities of recently developed derivatives. Additionally, this will allow them to identify other derivatizations that can be explored. However, where the pyrazole unit itself plays a significant role in the compound's mode of action, including cases where the pyrazole is more of a structural element, still needs to be explored. Additionally, the molecular hybridization of pyrazole with other bioactive compounds will be explored in our future work.