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Chemical structures of Pyrazolyl and pyrazoline bearing benzene sulphonamides with their IC50 values.
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Pyrazole moiety is considered as the most important therapeutic agent for the treatment of inflammation and inflammation associated cancers. Celecoxib, Ramifenazone, Rimonabant and Lonazolac are some of the commercially available pyrazole moieties which are potent COX‐2 inhibitors and also acts in inhibiting various cancers. Recently there are nume...
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Heterocyclic pyrazole compounds have cytotoxic, anticancer, antimicrobial, anti‐inflammatory properties, as well as their derivatives containing sulfonamide moiety, show superior effects on inhibiting various enzymes. Pre‐synthesized celecoxib‐derived compounds were studied for their inhibitory effects on human carbonic anhydrase (hCA I and hCA II)...
Citations
... Celecoxib, Ramifenazone, Rimonabant, and Lonazolac are some of the commercially available pyrazole moieties that are potent COX-2 inhibitors as anticancer agents. We have reported the significance of diversified pyrazoles as COX inhibitors and anti-inflammatories, and against related disorders like cancer in our recent review [18]. Further, we have also reported a thorough quantitative structure-activity relationship (QSAR) study on a series of benzene sulphonamide-substituted 1,5-diaryl pyrazole derivatives, resulting in the identification of the 3D-MoRSEC-6 (atomic charges) and GATSe3 (Sanderson electronegativities) descriptor necessary for selective COX-2 inhibitory activity [19]. ...
A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC50) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC50 of 4.655μM and T5 with IC50 of 5.596 μM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.
... In this current study, we used PTZ-induced kindling to develop the epilepsy-like condition in the zebrafish model. Furthermore, we investigated the protective effect of T1 derived from pyrazole benzenesulfonamide, which are best known for its anti-inflammatory potential [27]. PTZ instigates seizures by targeting GABA A receptors associated with chloride ion channels. ...
... Specifically, it was found from the survey, pyrazole moiety displays potent anti-inflammatory activity (Arunkumar et al. 2009;Zabiulla et al. 2019;Priya et al. 2022). The commercially available drugs bearing the pyrazole group like celecoxib, ramifenazone, lonazolac, and rimonabant are reported to demonstrate good anti-inflammatory activity (Mantzanidou et al. 2021). ...
The thiophene bearing pyrazole derivatives (7a-j) were synthesized and examined for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities followed by the in vivo analgesic, anti-inflammatory, and ulcerogenic evaluations. The synthesized series (7a-j) were characterized using ¹H NMR, ¹³C NMR, FT-IR, and mass spectral analysis. Initially, the compounds (7a-j) were evaluated for their in vitro cyclooxygenase, 5-lipoxygenase, and tumour inducing factor-α inhibitory activities and the compound (7f) with two phenyl substituents in the pyrazole ring and chloro substituent in the thiophene ring and the compound (7g) with two phenyl substituents in the pyrazole ring and bromo substituent in the thiophene ring were observed as potent compounds among the series. The compounds (7f and 7g) with effective in vitro potentials were further analyzed for analgesic, anti-inflammatory, and ulcerogenic evaluations. Also, to ascertain the binding affinities of compounds (7a-j), docking assessments were carried out and the ligand (7f) with the highest binding affinity was docked to know the interactions of the ligand with amino acids of target proteins.
Graphical abstract
... Several review articles have been published recently explaining the importance of the pyrazole nucleus in drug discovery. These compounds have α-glucosidase [85], carbonic anhydrase inhibitor [86], antineoplastic [87] and anti-inflammatory [88] properties, as well as several other therapeutic uses [89][90][91]. In our quest to find azole derivatives to be used as therapeutic agents [92][93][94][95], we have reported the various classes of pyrazole derivatives that can act as potent antibacterial agents [96][97][98][99][100][101][102][103][104], also summarized in our recent mini-review article [2]. ...
Pyrazole or 1 H-pyrazole, a five-membered 1,2-diazole, is found in several approved drugs and some bioactive natural products. A myriad number of derivatives of this small molecule have been reported in clinical and preclinical studies for the potential treatment of several diseases. The number of drugs containing pyrazole nucleus has gone up significantly in the last 10 years. Some of the best-selling drugs in this class are ibrutinib, ruxolitinib, axitinib, niraparib and baricitinib, and are used to treat different types of cancers; lenacapavir to treat HIV; riociguat to treat pulmonary hypertension; and sildenafil to treat erectile dysfunction. Several aniline-derived pyrazole compounds have been reported as potent antibacterial agents with selective activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Here, we discuss the pyrazole-derived drugs reported up to September 2023.
... Among others, Pzs present significant antibacterial [11], antimicrobic, anticancer, anti-inflammatory, anti-diabetic, and anti-degenerative activity [12]. In Figure 1, Betazole [13], CDPPB [14], Difenamizole [15], Fezolamine [16], Rimonabant [17], and Ruxolitinib [18,19] are examples of Pz-containing drugs already available on the market (Figure 1). Especially, their potential bioactive properties have made this class of heterocycles attractive targets for organic synthesis and in particular, in the past decade, many methods to synthesize tetrasubstituted Pzs have been developed [20]. ...
An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives’ titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki’) in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs’ inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation.
... In the last decade, an extensive series of pyrazole derivatives have shown promising anti-inflammatory and anticancer activities [27][28][29][30][31], indicating the use of the pyrazole motif as a robust nucleus for novel medicines. Among the reported studies, the pyrazole framework and the mono and di hetero five-membered rings are recognized to be essential components of several prominent selective COX-2 inhibitors, including Celecoxib I, Valdecoxib II, Rofecoxib III, and SC-558 IV. ...
Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.
