Recent Advancement in Drug Design and Discovery of Pyrazole Biomolecules as Cancer and Inflammation Therapeutics

Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC50, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.


Introduction
The pyrazole moiety is a heterocyclic ring system (five membered) with 3 C and 2 N in adjacent sites. In the year 1959, 1-pyrazolyl-alanine (natural pyrazole) was obtained from watermelons seeds [1,2]. Pyrazole compounds have an extensive past of applications, being used as herbicides, agrochemicals, and as active pharmaceutical agents. The current scenario of pyrazole moiety (Scheme 1) as a selective COX-2 inhibitor and anticancer agents has additionally emphasized their significance in pharmaceutical chemistry [3].
An organized observation of these groups of heterocyclic molecules exhibited that pyrazole-bearing therapeutic agents play an essential part in pharmaceutical sciences. The dominance of the pyrazole moiety in therapeutically potential lead compounds has encouraged the necessity for sophisticated and well-organized methods to prepare these heterocyclic compounds. The pyrazole moiety is shown to possess a broad range of biological profiles in the literature, mainly anticancer, anti-inflammatory, analgesic, antioxidant, anti-convulsant, anti-microbial, anti-mycobacterial, anti-amoebic, anti-depressant, hypotensive, and ACE inhibitors [4]. Several pyrazole-containing moieties have previously found their therapeutic application clinically, as NSAIDs such as celecoxib, lonazolac, tepoxaline, antipyrine (analgesic and antipyretic), phenylbutazone (in rheumatoid arthritis, osteoarthritis), novalgine, deracoxib, difenamizole, mepirizole, SC-560, crizotinib, pyrazofurin, and many more are already in the market [5]. Such drugs are listed in Table 1. In this updated review, our chief intention is to accentuate the anti-inflammatory and anticancer profiles displayed by the pyrazole moiety ( Figure 1). The mechanism of action of anticancer activity are given in Figure 2. The different kinds of pharmacological activities of various compounds containing the pyrazole moiety are summarized in Figure 3.

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--   Table 11 for the structure of the compound). Baytas et al., prepared (E)-3-[3-(pyridin-4-yl)-1-phenyl-1H-pyrazole-4yl]acrylamides and tested them for anti-platelet and anti-inflammatory activity [165]. Compound 148 revealed significant activity. Ragab et al., reported 1,3,4-trisubstitutedpyrazole containing derivatives and evaluated them for their anti-inflammatory and analgesic potential and ulcerogenicity [166] (Refer to Table 11 for the structure of the compound). Compounds 149, 150, and 151 showed good inhibition of inflammation and analgesic potential. They showed less selectivity for COX (I/II) but displayed good tolerance to GIT in comparison to phenylbutazone. Derivatives of pyrazole carboxamides bearing naproxen were developed by El-Sehemi et al., and assessed for anti-inflammatory potential. Compound 152 appeared to be the best potential derivative [167] (Refer to Table 11 for the structure of the compound). Hassan et al., prepared celecoxib analogues with a benzofuran ring and assessed them for COX (I/II) inhibitory bioassay. Among all these compounds, compound 153 displayed noteworthy inhibition of inflammation. The outcome exposed the vital role of derivatives containing C-3-pyridine-3-yl to exhibit better anti-inflammatory potential [6]. Kumar et al., reported pyrazolyl pyrazoline-containing derivatives and tested them for anti-inflammatory potential. Compound 154 appeared to have the most potential as an anti-inflammatory compound [168]. Mohammed et al., prepared hydrazone linked pyrazole derivatives. These compounds were evaluated for anti-inflammatory activity, blocking PGE2 production in blood serum of adult wistar rats, COX-1/2 inhibition, and ulcerogenicity. Compound 155 displayed significant anti-inflammatory efficacy compared to diclofenac, with no or minimal ulcerogenicity observed in comparison with indomethacin as a standard drug. The pyrazole derivatives demonstrated SI of 11.1 for COX (I/II) inhibition [169] (Refer to Table 11 for the structure of the compound). Pyrazole derivatives were prepared by Tewari et al., and investigated for anti-inflammatory potential and COX-2 inhibition [170]. Among these, compound 156 with IC 50 = 0.44 µM and 157 with IC 50 = 0.51 µM showed the most significant results compared to celecoxib with IC 50 = 0.002 µM for COX-2 selectivity and paw volume of 1.46 and 1.11 compared to the reference drug nimesulide, which showed a paw volume of 1.26. Alegaon et al., prepared 1,3,4-trisubstituted pyrazole derivatives and assessed them for anti-inflammatory potential [171] (Refer to Table 11 for the structure of the compound). Compound 158 pre-sented 64.6% inhibition of inflammation in comparison to diclofenac with 86.72% inhibition. Bansal et al. [172] prepared 1,3,4-oxadiazole-linked diarylpyrazole derivatives, in which compound 159 exhibited potential COX-2 inhibition with maximum selectivity compared to aspirin. Wang et al., synthesized pyrazole-linked benzamide derivatives and evaluated them for inverse agonistic activity on retinoic acid receptor Y. Compound 160 was identified as a potential lead molecule [173]. Newer pyrazole derivatives were prepared and evaluated for anti-inflammatory activity by Li et al.; among these, compound 161 exhibited better potency in comparison to indomethacin and ibuprofen [174] (Refer to Table 11 for the structure of the compound).

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-- Wang et al., synthesized benzamide-containing pyrazole derivatives and investigated them for anti-inflammatory potential. Compound 162 showed potential anti-inflammatory results [173]. El-Fekyet al., carried out a series of quinoline-integrated pyrazole scaffolds and assessed them for anti-inflammatory property. Compound 163 revealed the maximum inhibition and more binding affinity for the COX-2 binding position [175] (Refer to Table 12 for the structure of the compound). Newer pyrazole-containing heterocycles were prepared by Kendre et al., and tested for analgesic potential. Scaffold 164 displayed good analgesic activity [176]. Kumar et al., synthesized novel pyrazole derivatives and identified anti-inflammatory activity. Compound 165 appeared to be the best potential inhibitor of inflammation [177]. Pelcman et al., prepared pyrazole carboxamide derivatives and screened them for inhibitory activity against 15-lipoxygenase. Scaffold 166 appeared to show significant anti-inflammatory potential with good % inhibition and analgesic activity [178] (Refer to Table 12 for the structure of the compound). Compound 167 was identified as the most potent and selective inhibitor of COX-2 with IC 50 = 1.33 µM. Newer pyrazole-linked analogues were prepared and tested for analgesic potential by Abdellatif et al.; among these synthesized compounds, compound 168 demonstrated the highest anti-inflammatory action post carrageenan after 3 h of inflammation initiation (89% inhibition) as compared to the standard drug celecoxib (80% inhibition) [179] (Refer to Table 12 for the structure of the compound). Abdel-Aziz et al., prepared newer pyrazole derivatives, of which compound 169 exhibited remarkable anti-inflammatory potential with ED 50 = 68 ± 2.2 mg/kg and 51 ± 0.7 mg/kg [180]. Doma et al., reported novel pyrazole analogues and evaluated them for anti-inflammatory activity using 0.1% carrageenan and injecting it into the subplantar region of the rat's right paw. Derivative 170 was found to be the most significant member of the class [181]. Newer benzophenones were reported by Bandgar et al., and assessed for analgesic potential. Compound 171 showed significant inhibition of inflammation and analgesic activity [149] (Refer to Table 12 for the structure of the compound). Jadhav et al., prepared pyrazole derivatives and tested them for inhibition of inflammation. Compound 172 demonstrated the highest anti-inflammatory results when compared to diclofenac [182]. Vijesh et al., synthesized newer pyrazole-bearing 1,2,4-triazole and benzoxazole derivatives and assessed their anti-inflammatory potential. Compound 173, containing dichlorothiophene and triazole, was confirmed to have good analgesic and anti-inflammatory potential [183]. Aggarwal et al., reported many pyrazole-containing derivatives and investigated their analgesic efficacy. Compound 174 revealed noteworthy inhibition of inflammation (62-76%) in comparison to indomethacin (78%) [184] (Refer to Table 12 for the structure of the compound). Among the leads established by Yewale et al., compound 175 appeared as the most potent molecule with superior anti-inflammatory potential compared to diclofenac sodium and equivalent results against the standard drug celecoxib (dose 25 mg/kg) [145] (Refer to Table 12 for the structure of the compound).   [188]. Abdellatif et al., synthesized 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives and assessed their inhibition of COX enzymes, anti-inflammatory potential, analgesic potential and ulcerogenicity. Compound 180 displayed significant anti-inflammatory potential with ED 50 = 53.99 µmol/kg in comparison to celecoxib with ED 50 = 82.15 µmol/kg, with lessen ulcer index (1.20 for compound 180 and 2.90 for celecoxib) [189]. Elshemya et al., prepared triazine-linked pyrazole derivatives and assessed them for inhibition of COX-2. Compound 181 displayed the best potential results with IC 50 = 0.74 µM compared to celecoxib with IC 50 = 0.78 µM [190] (Refer to Table 13 for the structure of the compound). Levent et al., reported diarylpyrazole-bearing carboxamide derivatives as newer antiplatelet drugs that interfere with platelet aggregation and inflammation (in cardiovascular diseases). Compound 182 revealed potential results with IC 50 = 5.7-8.3 nM [191]. Unlu et al., prepared novel regioisomeric 1-(3-pyridazinyl)-5arylpyrazole derivatives and evaluated them for anti-inflammatory and analgesic potential. Compound 183 displayed inhibitory potency for COX-I/II and can be a lead for future investigations [192] (Refer to Table 13 for the structure of the compound). A novel class of 1-phenylpyrazolo [3,4-d]pyrimidine derivatives were prepared by Bakr et al., and assessed for inhibition of COX, anti-inflammatory activity, and ulcerogenicity. Compound 184 displayed a higher edema inhibition of 34-68%; however, the in vivo active compound showed flexible ulceration (ulcer index = 0.33-4.0) compared to celecoxib (ulcer index = 0.33) [193]. Chandak et al., synthesized new 2-amino-substituted 4-coumarinylthiazolesbearing benzenesulphonamide moieties and determined their anti-inflammatory potential. Compound 185 revealed promising anti-inflammatory activity (0.11 ± 0.16% IA) equivalent to the standard drug indomethacin (0.17 ± 0.03% IA) [194]. Faour et al., synthesized di-pyrazole comprising N-phenylpyrazole nucleus containing polysubstituted pyrazole moieties through different amide linkages and investigated them for inhibition of COX-2, LPS induced iNOS, and anti-inflammatory and analgesic activities. Compound 186 inhibited COX-2 with IC 50 = 11.2 µM with 78% inhibition of inflammation, compared to 53% inhibition by diclofenac, and 54% protection against pain compared to 52% protection by diclofenac [195]. Alam et al., prepared hybrid pyrazole analogues, among which compound 187 exhibited anti-inflammatory potential with 80.63% inhibition after 4 h in comparison to ibuprofen (with 81.32% inhibition after 4 h and inhibition against COX-1/2 and TNF-α). The same compound showed high COX-2 inhibition, with half maximal inhibitory concentration of 1.79 µM compared to celecoxib [196] (Refer to Table 13 for the structure of the compound). Compound 188 (AD732) was designed as a pyrazole derivative with anti-inflammatory and analgesic properties. Compound 188 (AD732) showed a strong inhibitory effect against COX-2 (IC 50 = 0.57 ± 0.04 µM) rather than COX-1. Compound 188 (AD732) was compared to the standard celecoxib (IC 50 = 0.26 ± 0.32 µM target on COX-1, IC 50 = 2.62 ± 0.02 µM target on COX-2) and indomethacin medications (IC 50 = >100.00 µM target on COX-1, IC 50 = <0.30 µM target on COX-2) for anti-inflammatory action. In comparison to celecoxib, the COX-2 inhibitory activity of compound 188 (AD732) was less effective in vitro, suggesting that it may have less cardiovascular toxic effects. To summarize, compound 188 (AD732) appears to be a better and more efficient compound with intriguing promise for pain and inflammatory control. When treated rats were assessed 24 h following a single higher dose treatment, neither celecoxib nor compound 188 (AD732) caused stomach ulcers. The superior gastrointestinal safety of AD732 is based on its favorable inhibitory efficacy against COX-2 over COX-1 [197] (Refer to Table 14 for the structure of the compound). A novel pyrazole derivative was prepared and evaluated for inhibition of COX-1/2. The pyrazole ring's bridging amide N generates a reasonably stable H-bond with Ser 530 .  Compounds 189(a), 189(b), 189(c), and 189(d) showed high activity and selectivity against COX-2 (IC 50 = 39.43, 61.24, 38.73, and 39.14 nM). All compounds reported selectivity indices of 22.21, 14.35, 17.47, and 13.10, for 189(a), 189(b), 189(c), and 189(d), correspondingly. With IC 50 = 34.21 nM, compound 189a replaced with acetamide morpholine appeared to be a potential COX-2 inhibitor. The IC 50 values for compounds 189c and 189d substituted with fluoro and methoxy groups were 38.73 and 39.14 nM, correspondingly. In vivo, these compounds were superior to or equivalent to celecoxib as anti-inflammatory drugs. In silico, the same molecules exhibited comparable interactions to SC-588. Surprisingly, these drugs preferentially reduced the synthesis of the triggered microsomal PGE2 synthase [198] (Refer to Table 14 for the structure of the compound). Pyrazole and triazole compounds were synthesized, docking studies were performed, and their biological activity towards selective COX-2 inhibitors was investigated. Compound 190a, when substituted with sulfonamide on one N-aromatic ring, exhibited the highest inhibitory action against COX-2 with IC 50 = 0.017 ± 0.001 µM and COX-1 with IC 50 = 0.263 ± 0.016 µM. Compound 190b, which was replaced with nitro on the N-aromatic ring, inhibited COX-1 more effectively, with COX-1 (IC 50 = 0.012 ± 0.001 µM). All compounds were compared with the other existing drug celecoxib, which demonstrated anti-inflammatory action towards COX-1 and COX-2 with IC 50 = 1.479 ± 0.089 µM and 0.004 ± 0.000 µM, correspondingly. Because of its lower volume and far more optimal arrangement of the NO 2 in same area, 190b was the most effective pyrazole-containing COX-1 inhibitor. The presence of a spacer in the inhibitor structure is important because it places the aromatic ring in a favorable location for hydrophobic interaction in COX-2. There are 2 aryl groups on the heterocyclic cores (pyrazole or triazole) that are not the same as those on most COX-2 inhibitors [199] (Refer to Table 14 for the structure of the compound). Novel pyrazolo [3,4-d]pyridazinone-containing derivatives were developed and assessed against the alterations of discoidin domain receptor1 (DDR1) as anti-inflammatory agents. Compound 191 demonstrated strong inhibition of discoidin domain receptor1 (DDR1) with an IC 50 value of 10.6 ± 1.9 nM and significant selectivity against 430 kinases. In a dextran sulphate sodium prompted animal colitis model, compound 191 potently reduced the production of pro-inflammatory cytokines and DDR1 auto phosphorylation in cells. The removal or relocation of the trifluoromethyl group in Compound 191 resulted in a significant loss of efficacy against the DDR1 outcome. The activity was significantly reduced when trifluoromethyl-substituted phenyl was replaced with n-butyl or cyclohexyl. To retain robust DDR1 inhibitory activity levels ranging from 27.4 to 60.4 nM, the acetylaminophenyl group at the R1 position might be substituted with phenyl or substituted phenyl. In mice's bone-marrow-derived macrophages and human THP-11 generated macrophages, compound 191 effectively reduced LPS-induced production of these pro-inflammatory cytokines at 10 µM. Compound 191 suppressed basal autophosphorylation of discoidin domain receptor1 (DDR1) with an EC 50 of 34.4 nM, which was more powerful than the positive control DDR1-IN-1, which had an EC 50 of 114.5 nM [200].

Authors Perspective
The main goal of this revised study is to highlight the anticancer and anti-inflammatory profiles of the pyrazole molecule. Cancer is an uncontrollable abnormal cell proliferation that is a severe life-threatening disorder worldwide. Pharmaceutical firms are now investing heavily in developing and enhancing viable and safe anticancer treatments with minimal side effects. Pyrazole derivatives exhibit anti-inflammatory properties and have been shown to target several cancer cell lines, such as COX (I/II). The description includes a library of powerful compounds against cancer cell lines and inflammation. Among them, certain effective compounds and their SAR structures are strongly associated with biological activity and predicted some additional derivatives that approach structural alterations. We addressed the anticancer therapeutic action of compounds; all derivatives showed strong inhibitory activity, but certain powerful compounds demonstrated good inhibitory activity against cancer cell lines.

Pyrazole Biomolecules as Cancer Therapeutics
Compound 21 exhibited the most strong biological activity against HCT116, MCF-7, and Aurora-A kinase inhibitory activity cell lines, with IC 50 values of 0.39 ± 0.06 µM, 0.46 ± 0.04 µM, and 0.16 ± 0.03 µM, which were equivalent to the positive control. The scaffolds of the known inhibitors of Aurora-A kinase can be categorized into four main groups, A-D. The scaffold in A contains 1,4,5,6-tetrahydropyrrolo [3,4-c]pyrazole; the scaffold in B contains pyrrolo [2,3-b]pyrimidine; the scaffold in C contains quinoline; and the scaffold in D contains 2-anilino-diaminopyrimidine. Benzamide is a significant pharmacophore of natural compounds as well as a synthetic precursor for a variety of medications. Benzamide has been shown to have several pharmacological effects, including anti-inflammatory, anticancer, and anti-fungal properties. To create a more potent reaction with the Aurora-A kinase domains, a benzamide moiety was transferred to the pyrazole moiety to create the N phenyl-1H-pyrazole-4-carboxamide template. The highest activity was found for 21 compounds with a para-NO2 group on the A-rings and a para-OEt group on the Brings [44] (refer to Figure 4 for Structure and SAR). In a separate investigation, compound 30 demonstrated a significant inhibitory effect against WM266.4 and A375 with IC 50 values ranging from 1.50 to 1.32 µM. It makes use of a common scaffold comprised of a terminal aromatic group (phenyl or pyrazole) that occupies the allosteric pocket generated by the displacement of the DFG loop and an amide linker that links an aryl group in the hydrophobic pocket to a hinge-binding heterocycle. The use of an amide bond would allow for the quick and efficient screening of several candidate hinge-binding groups. The original molecule was modified to see how the substituents affected the BRAFV600E inhibitory effects. Urea derivatives have higher inhibitory effects than Schiff base compounds and related intermediate amines. Changes in substituents on the benzene rings had a minor impact on the activity of the compounds. In contrast, differences in the skeleton had a greater impact, which may explain why substituents on the benzene rings had a minor impact on the ability for molecular bonding between BRAFV600E and the compounds. According to the findings, the pyrazolyl core and the phenyl urea motif are critical in the inhibition of BRAFV600E [51] (refer to Figure 4 for Structure and SAR).
Compounds with the OH and Me groups on the B-ring, compound 33, resulted in notable activity. Compound 33 displayed the most powerful effect, inhibiting the growth of MCF-7 and B16-F10 cells with IC50 values of 0.57 ± 0.03 and 0.49 ± 0.07 µM, respectively, and inhibiting the activity of telomerase with an IC 50 of 1.9 ± 0.43 µM. More than one way to achieve powerful coordination may be achieved by using hydrazone derivatives and, specifically, acyl hydrazones. Acylhydrazone derivatives have the potential to form complexes with metal ions, such as Fe 3+ and Ni 2+ , resulting in the inhibition of a physiologic reaction catalyzed by ions or the promotion of the absorption, transportation, distribution, and metabolism of drugs in the body, respectively. The F group outperformed the Cl group in antiproliferative action on the A ring, which might be attributable to the fluorine substituent's greater lipophilicity and metabolic stability. The presence of fluorine often increases the solubility of lipids, which increases the rates of absorption and transport of drugs. Compound 33, based on its data structure, may be useful in designing and manufacturing stronger telomerase inhibitors [54] (refer to Figure 4 for Structure and SAR). Changes in substituents on the benzene thiazole rings had only a small effect on the compounds' activity. As a consequence, compound 42 and the other pyrazole derivatives with effective thiazole and thiophene pharmacophores are promising candidates for further research as anticancer medicines [62](refer to Figure 4 for Structure and SAR).As shown in the figure below, compound 49 acts as a potent inhibitor of HER-2/EGFR, possessing a half-life of 0.26 m/0.51 m compared to the positive controls erlotinib (IC 50 = 0.41 µM for HER-2 and IC 50 = 0.20 µM for EGFR) and lapatinib (IC 50 = 0.54 µM for HER-2 and IC 50 = 0.28 µM for EGFR). On the mechanistic level, nitroimidazole derivatives drew much attention because of their ability to enter and accumulate in tumor areas. To boost the antiproliferation activity of pyrazolyl-nitroimidazole derivatives against Hela or HepG2 cell lines, electron-withdrawing groups were shown to be preferred to electron-donating groups. This indicates that the synthesized chemicals' significant inhibitory effects on cell growth were directly connected to their kinase inhibitory actions [68] (refer to Figure 4 for Structure and SAR).
These molecules are intriguing novel frameworks for the case of cancer therapies due to their simplicity of synthesis and extraordinary biological activity. Compound 50 inhibited MCF-7, A549, and HeLa cells significantly, with IC 50 values ranging from 0.83-1.81 µM. Furthermore, the compounds induced G1 phase cell cycle arrest in MCF-7 cells by inhibiting cyclin D1 and CDK2. It was observed that structural alterations and modifications on the B ring of pyrazolobenzimidazole derivatives resulted in distinct cytotoxic effects by studying the difference in selectivity of the three cell lines to the compounds. As a result, pyrazole-benzimidazole hybrids may lower cell cycle regulators, including cyclin D1 and CDK2 in MCF-7 cells, causing cell cycle arrest and growth suppression [69] (refer to Figure 5 for Structure and SAR). Because the pyrazolo [3,4-d]pyrimidine nucleus is an isostere of the purine nucleus, it has an anticancer effect via serving as an ATP competitive inhibitor for several kinase enzymes. It has been reported that hydrazinyl derivatives have anticancer properties, particularly in breast cancer cell lines. There is evidence that a methyl sulphonyl ring at position 3 enhances the antitumor activity of pyrazolo [3,4-d]pyrimidine nucleic. This study showed that compound 6d (X = H, R = 4-F) showed the highest IC 50 at 7.5 nM. More research is needed to understand the precise mechanism of antitumor activity and investigate the SAR of various nucleus locations [94] (refer to Figure 5 for Structure and SAR). A high-throughput screening method identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent Jak2 inhibitor. Increased polarity and the elimination or inhibition of metabolic hotspots such as N-methyl groups are two often used approaches for increasing stability against CYP-mediated metabolism. The H-bond accepting properties of oxygen atoms in heteroaromatic ring systems are weak; on the other hand, sp2 nitrogens of heteroaromatics tend to be strong H-bond acceptors. Compound 84 was found to be the most promising derivative, with an IC 50 of 7.4 nM. Compound 84 offers a good combination of cell potency, oral exposure, and in vivo pSTAT5 knockdown, making it a feasible tool for initial Jak2-dependent efficacy studies. Any alteration at the para-position of the N-aryl group reduces the inhibitory potency of all Jak family members considerably. The pyrazolo[1,5-a]pyrimidine scaffold was shown to be a strong inhibitor of Jak2 in a high-throughput screening study [98] (refer to Figure 5 for Structure and SAR). Several of the pyridyl-substituted five-membered heterocyclic rings were boosted in their inhibitory activity and selectivity by adding methylene, methylene amino, or amino methylene linkages between their core rings and their phenyl rings. The most active compound 87 inhibited ALK5 phosphorylation with a IC 50 value of 0.57 nM and demonstrated 94 percent inhibition at 100 nM in a luciferase reporter test using HaCaT cells irreversibly transfected with a p3TP-Luc construct. There was a significant increase in both the inhibitory activity and selectivity of compound 87 against p38a MAP kinase upon the incorporation of the [1,2,4]triazolo[1,5-a]pyridin-6-yl and phenycarbothioamide moiety at positions 4 and 1 of the pyrazole ring, respectively [101] (refer to Figure 5 for Structure and SAR).This work demonstrated the strong immunosuppressive actions of a variety of new pyrazole derivatives having an O-benzyl oxime moiety. Compound 104 had the greatest inhibitory efficacy (IC 50 = 1.18 µM for lymph node cells and IC 50 = 0.28 µM for PI3K). In particular, a variety of synthesized pyrazole oxime ether analogs were shown to have significant immunosuppressive effects in the low micromolar range. A study of the A-ring para substituents revealed that an electron-withdrawing group had increased immunosuppressive action, and the potency order is F > Cl > OMe > H > Me. The molecules with a potent inhibition effect towards IL-6 produced in ConA-stimulated murine lymph node cells were investigated [117] (refer to Figure 5 for Structure and SAR). The synthesis of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-carboxamides was reported well as their biological evaluation. Nocodazole (8.01-0.95 µM) exhibited significant inhibition against MIAPaCa-2, MCF-7, and HeLa cell lines with compound 105 (GI 50 ) in the range of 0.13-0.7 µM (GI 50 ). Using the pyrazole moiety with two aryl ring systems, A and B, this study investigated the compounds with electron-withdrawing and electron-donating groups, i.e., chloro, fluoro, and fluoro trifluoromethyl groups on the ring systems (A and B). This compound 105 resulted in cell cycle arrest in MCF-7 cells and downregulation of CDK1 expression in MCF-7 cells when it was treated with it. As a result, they can be regarded as promising lead molecules for creating more effective anticancer medicines against breast cancer cells [118] (refer to Figure 5 for Structure and SAR).
APN inhibition was best with compound 109, which had an IC 50 value of 0.16 ± 0.02 µM, a value over one order of magnitude less than that of bestatin (IC 50 = 9.4 ± 0.5 µM). Depending on where R was substituted on the pyrazoline ring, these compounds could have significantly different APN inhibitory potencies. B series compounds have higher inhibitory activity when compared to APN equivalents. As determined by the structure-activity relationships (SARs) of A series compounds, only orthoor meta-substituted hydroxamates can be synthesized from B series compounds, while para-substituted hydroxamates are inactive. Compound 109 might be a starting point for developing more powerful APN inhibitors. To test human APN against the ES-2 and PLC/PRF/5 cell surfaces, compounds with significant porcine kidney APN inhibitory properties were selected. APN is abundantly expressed on both cell lines' membranes [122] (refer to Figure 6 for Structure and SAR). The strongest inhibitory effect was achieved by compound 111 with N-(3-methoxy-2-hydroxybenzal)-3-substituted(p-chlorophenyl)-4cyano-5-oxopyrazol-1-thiocarboxamide against HL-60, with an IC 50 of 1.35 µM compared to Dox's IC 50 of 2.02 µM. Compound 111 improved the G2/M phase from 11.05 percent to 39.22 percent compared to the untreated control. The highest intense cytotoxic action was demonstrated by compound 111. In a study that included activity assays of apoptosis detection and Topoisomerase II inhibition, compound 111 was found to be an effective inhibitor of Topo II [124] (refer to Figure 6 for Structure and SAR).

Pyrazole Biomolecules as Inflammation Therapeutics
The efficacy of new pyrazole and pyrazoline compounds to inhibit ovine COX-1 and COX-2 isozymes was assessed utilizing an in vitro cyclooxygenase (COX) inhibition test. Among the molecules examined, 129 exhibited excellent COX-2 inhibitory efficacy (IC 50 = 0.26 µM) and selectivity (SI) = >192.3, which is equivalent to the reference medication celecoxib (IC 50 = 0.28 µM and selectivity index = 178.57). Compound 129 is overly lipophilic due to the presence of trifluoromethyl fragments; therefore, it should serve as a lead molecule for further optimization of certain biological properties and ADME characteristics [127] (refer to Figure 7 for Structure and SAR). Novel 1-(4-methane(amino)sulfonylphen yl) derivatives 5th (4-substituted-aminomethyl-phenyl)-3-trifluoromethyl-1H-pyrazoles were developed, synthesized, and tested for biological activity. Compound 168, derived from the library, exhibited significant anti-inflammatory action. Compared with the standard celecoxib drug (80% inhibition), compound 168 demonstrated the greatest antiinflammatory effect post carrageenan, 3 h after inflammation onset (89% inhibition) [179]. A total of fifteen pyrazolyl urea derivatives were produced and tested for their ability to inhibit p38 MAPK and act as antioxidants. Among the tested compounds, derivative 178 was discovered to be the most powerful, and its binding mechanism inside the p38 MAPK was also documented. Compound 178, which has a 4-chloro group and has significant p38 MAPK activity, also had the greatest anti-inflammatory efficacy (80.93 percent inhibition). The substitution of 2-chloro and 3-chloro groups for the 4-chloro groups resulted in a modest reduction in inactivity (76.19 percent and 78.06 percent inhibition, respectively). In both the in vitro and in vivo models, the monosubstituted electron-withdrawing group in the phenyl ring linked to the pyrazole nucleus showed strong anti-inflammatory efficacy. Compound 178 was found to be a strong anti-inflammatory agent, equivalent to the standard reference medication diclofenac sodium. In addition, compared to conventional medicine, this molecule had a lower ulcerogenic potential and the least activity in causing oxidative stress in tissues. In contrast, pyrazole compounds with a urea pharmacophore exhibited comparable anti-inflammatory effects and better TNF-inhibitory characteristics in the investigations. Moreover, pyrazolyl urea derivatives were investigated for p38 MAPK inhibition and demonstrated substantial efficacy [187] (refer to Figure 7 for Structure and SAR).
An inhibitor of COX-2 with a five-membered pharmacophore, such as pyrazole, and isoxazole, which is polysubstituted 1,3,5-triazines. Compound 181 from synthesized derivatives showed promising findings with an IC 50 of 0.74 µM vs. celecoxib's IC 50 of 0.78 µM. When a methanesulphonylphenyl pyrazole moiety was added, the selectivity increased significantly. To summarize, when the triazine core was replaced with pyrazoline, isoxazole, or unsubstituted pyrazole moieties, a considerable COX-2 selectivity was observed. Thus, scaffolds derived from Compound 181 might be further developed, and their biological activity tested [190] (refer to Figure 7 for Structure and SAR). The pyridazine 6-position was substituted with phenyl, and the carboxyl arm in the central pyrazole was extended by adding polar substituents. In addition, pyrazole compounds without either the 1pyridazine or the 5-phenyl groups were synthesized. These derivatives were designed to explore how a side chain of different sizes and basicity at three positions of the pyrazole could affect the antiplatelet activity and to learn about the effects of exposure to vicinal diaries about the central heterocycle, as well as the necessary presence of central pyrazoles on their biological profiles. Various compounds of this class had different inhibitory effects on platelet aggregation induced by AA and collagen, mainly depending on the shape and size of the carboxamide molecules at the 3-position of the pyrazole ring. However, only small carboxamide molecules specifically inhibited collagen-induced platelet aggregation. Finally, we describe compound 182 as a new potent antiplatelet agent with an IC 50 in the two-to one-digit nanomolar range (IC 50 values of 5.7 nM). Because of their great efficacy in the cellular milieu, these simple pyrazole derivatives may hold promise for developing more effective molecules for cardiovascular disease intervention [191] (refer to Figure 7 for Structure and SAR). The primary pyrazole core of selective COX2 inhibitors (celecoxib and SC558) was engaged, and structural alterations led to the identification of additional pyrazole analogs. In comparison to ibuprofen (which inhibited COX-1/2 and TNF-after 4 h and exhibited 81.32 percent inhibition), compound 187 exhibited 80.63 percent inhibition at 4 h. We, therefore, found that methylamine pyrazole derivatives provided the requisite geometry to effectively and selectively inhibit the COX2 enzyme and provide good anti-inflammatory properties when substituted for sulfonamide pyrazole derivatives. As a result, the hydrophobic benzyloxyphenyl group was introduced in the same way as the celecoxib trifluoromethyl group to boost the affinity for COX2 [196] (refer to Figure 8 for Structure and SAR). A novel pyrazole derivative was created and evaluated for its potential to inhibit COX-1/2 activity. There was good selectivity towards COX-2 inhibition in many pyrazoles bearing the benzenesulfonamide moiety, and consequently, these compounds had powerful antiinflammatory activity . Compounds 189(a), 189(b), 189(c), and 189(d) showed high activity and selectivity against COX-2 (IC50 = 39.43, 61.24, 38.73, and 39.14 nM). All compounds reported selectivity indices of 22.21, 14.35, 17.47, and 13.10 for 189(a), 189(b), 189(c), and 189(d), correspondingly. In vivo, these compounds were superior to or equivalent to celecoxib as anti-inflammatory drugs. Interestingly, these molecules specifically reduced the induced microsomal PGE2 synthase synthesis, indicating that additional research into these derivatives is needed [198] (refer to Figure 8 for Structure and SAR). In an easy synthetic procedure, a series of diaryl pyrazole and triazole derivatives to produce selective COX-2 inhibitors were designed and synthesized. Among the synthesized derivatives, compound 190a with a sulfonamide substitution on one N-aromatic ring had the strongest inhibitory action against COX-2 with IC 50 = 0.017 ± 0.001 µM and COX-1 with IC 50 = 0.263 ± 0.016 µM. In contrast, compound 190b, which has nitro on its N-aromatic ring, inhibited COX-1 more effectively (IC 50 = 0.012 ± 0.001 µM). The best COX-2 selectivity was obtained with sulfonamide and sulfone substituted on the Naromatic ring. More interestingly, the heterocyclic cores (pyrazole or triazole) contain two not vicinal aryls in contrast with the most commonly known COX-2 inhibitors. Additional work is needed to synthesize diverse pyrazoles and triazoles with different spacer lengths and substitutions in order to assess their role in COX-2 inhibitory activity and selectivity [199] (refer to Figure 8 for Structure and SAR). Researchers developed and tested new compounds known as pyrazolo[3,4-d]pyridazinones as anti-inflammatory drugs against discoidin domain receptor 1 (DDR1) modifications. Mouse bone-marrow-derived and human THP-11 macrophages were effectively decreased by compound 191 at ten micromolar concentrations when exposed to LPS. Compound 191 inhibited pro-inflammatory cytokines and autophosphorylation of DDR1 in cells in a mouse colitis model induced by dextran sulfate sodium (DSS). DDR1-IN-1, a positive control compound, had an EC 50 of 114.5 nM, whereas compound 191 suppressed basal autophosphorylation at 34.4 nM, more powerful than the positive control compound. As the N-phenyl group of DC-1 was exposed above the solvent-exposed area of DDR1, further modifications can be made to this group in DDR1 [200] (refer to Figure 8 for Structure and SAR).

Conclusions
This literature survey focused on merging different pharmacophoric subunits of a large number of pyrazolic analogues to create potential lead compounds showing anticancer and anti-inflammatory activities. It also highlighted the prestige of these biomolecules in the design, discovery, and advancement of novel drug molecules.