Reference Drug Celecoxib Research Articles

Metabolomic profiling of barley extracts obtained via different solvents and evaluation of their anti-inflammatory efficacy

Barley (Hordeum vulgare L.) stands out for its special nutritional value compared to other cereals, garnering significant attention in recent years. In this study, a comprehensive chemical and biological evaluation of different barley cultivars extracted with different solvents was performed. Ultra-high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-QTOF-MS/MS) was used in the phytochemical study. The molecular docking with absorption, distribution, metabolism, excretion, and toxicity (ADMET) study and multivariate analysis alongside the quantification of total phenolic contents (TPC) were performed. Furthermore, the anti-inflammatory action was in vitro assessed by measuring COX-1, COX-2, and 5-LOX inhibition. This study seeks to establish a suitable solvent for extracting anti-inflammatory properties from diverse barley cultivars. The methanol extract obtained from the G.131 cultivar, followed by the 80% methanol extract from the G.136 cultivar, exhibited the most favorable IC50 values in comparison to the reference drugs indomethacin and celecoxib. The phytochemical profile revealed more than 60 compounds that belonged to nitrogen-containing compounds, phenolic compounds, organic acids, flavonoids, and their glycosides, hordatines, and other classes. The TPC and COX-2 inhibition was positively correlated with isoscoparin, coumaroyle–OH–eagmatine, isoorientin, isovitexin 7-O-rhamnosylglucoside, isoscoparin 7-O-glucoside, and isoorientin-7-O-[6-feruloyl]-glucoside. These findings along with their pharmacodynamics study suggested a potential synergistic and significant contribution of these compounds with the anti-inflammatory activity.

Rhodanine Derivatives Containing 5-Aryloxypyrazole Moiety as Anti-inflammatory and Anticancer Agents.

In this study, a series of rhodanine derivatives containing 5-aryloxypyrazole moiety were identified as potential agents with anti-inflammatory and anticancer properties. Most of the synthesized compounds demonstrated anti-inflammatory and anticancer activity. Notably, compound 7 g (94.1 %) exhibited significant anti-inflammatory activity compared with the reference drugs celecoxib (52.5 %) and hydrocortisone (79.4 %). Compound 7 g, at various concentrations, effectively inhibited nitric oxide (NO) production in a dose-dependent manner. Western blot results showed that compound 7 g could prevents LPS-induced expression of inflammatory mediators in macrophages. Enzyme-linked immunosorbent assay (ELISA) assay suggested that 7 g is a promising compound capable of blocking the downstream signaling of COX-2. In summary, these findings indicate that compound 7 g could be a promising candidate for further investigation.

Methanesulfonamide derivatives as gastric safe anti-inflammatory agents: Design, synthesis, selective COX-2 inhibitory activity, histopathological and histochemical studies

Novel chalcone 3a-c, pyrazoline 4a-i and pyridine 5a-c, 6a&b derivatives bearing methanesulfonamide moiety were synthesized. Their construction was confirmed using spectral data and elemental analysis. The stereo-chemical configuration for compounds 3a-c was predicted by MM2 property and 1H NMR spectra. All the prepared compounds were screened for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity. The most active anti-inflammatory derivatives, 4f-4i, after 3, 5 & 7 h were further subjected to histopathological and histochemical studies showing safe effect on gastric mucosa, especially 4h derivative. To explore the mechanism of action of COX-2 inhibitory compounds 4f and 6b with the highest S.I. values, they were docked inside COX-2 active site. Physicochemical properties for 4f-i and 6b derivatives were predicted and compared to the reference drug celecoxib. They showed good oral bio-availability specially pyrazoline derivative 4f and pyridine containing compound 6b.

Exploring the potential of propanamide-sulfonamide based drug conjugates as dual inhibitors of urease and cyclooxygenase-2: biological and their in silico studies.

Derivative synthesis has been a crucial method for altering the effects of already-approved medications, especially to lessen adverse effects and enhance results. Making use of this multi-target approach, a series of naproxen-sulfa drug conjugates was designed and synthesized. The newly designed conjugates were confirmed by spectroscopic techniques like IR, 1HNMR, 13CNMR, and elemental analysis. The conjugates were screened for anti-inflammatory, urease, and cyclooxygenase-2 (COX-2) inhibition. Naproxen conjugated with sulfanilamide, sulfathiazole, and sulfaguanidine was found potent and showed a competitive mode of urease inhibition, with IC50 (µM) values 6.69 ± 0.11, 5.82 ± 0.28, 5.06 ± 0.29, respectively. When compared to other screened conjugates, the naproxen-sulfamethoxazole conjugation showed better anti-inflammatory action by inhibiting induced edema by 82.8%, which is comparable to the medication indomethacin (86.8% inhibition). Whereas it exhibited 75.4% inhibition of COX-2 at 10µM concentration which is comparable with the reference drug (celecoxib, 77.1% inhibition). Moreover, the binding modes of competitive inhibitors with the urease and COX-2 receptor were predicted through molecular docking studies and their stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and there were no conformational changes that occurred during simulation. The obtained results showed that the conjugates of approved therapeutic molecules may lead to the development of novel types of pharmacological agents in the treatment of several pathological disorders where urease and COX-2 enzymes are involved.

Synthesis and biological evaluation of resveratrol amide derivatives as selective COX-2 inhibitors

Selective COX-2 inhibitors have been considered to be reliable alternatives to tNSAIDs, but most of them were withdrawn from the market due to their risk of heart attack and stroke. Therefore, it is urgent to develop a new type of selective COX-2 inhibitor with high efficiency and low toxicity. Inspired by the cardiovascular protection, and anti-inflammatory activity of resveratrol, we synthesized 38 resveratrol amide derivatives and evaluated their COX-1/COX-2 inhibitory activities. Compounds 8a, 6a, 8c and 13c showed important inhibitory activity against COX-2 (IC50 = 0.42–2.54 μM) with definite selectivity (SI = 48–83). Molecular docking study demonstrated that these compounds partially entered the 2°-pocket of the COX-2 active site and interacted with the amino acid residues responsible for the COX-2 selectivity, which was in a similar orientation and binding interactions to rofecoxib. Further anti-inflammatory activity evaluation in vivo of these active compounds revealed that compound 8a showed no gastric ulcer toxicity, and displayed evident anti-inflammatory effect (45.95% inhibition of edema) with three oral doses of 50 mg/kg, which is worthy of further study. Moreover, compounds 6a and 8c also exhibited superior gastric safety profiles compared to the reference drugs celecoxib and indomethacin.

Synthesis of new multitarget-directed ligands containing thienopyrimidine nucleus for inhibition of 15-lipoxygenase, cyclooxygenases, and pro-inflammatory cytokines

A new series of thieno[2,3-d]pyrimidine derivatives 4, 5, 6a-o, and 11 was designed and synthesized starting from cyclohexanone under Gewald condition with the aim to develop multitarget-directed ligands (MTDLs) having anti-inflammatory properties against both 15-LOX and COX-2 enzymes. Moreover, the potential of the compounds against the proinflammatory mediators NO, ROS, TNF-α, and IL-6 were tested in LPS-activated RAW 264.7 macrophages. Compound 6o showed the greatest 15-LOX inhibitory effect (IC50 = 1.17 μM) which was superior to that of the reference nordihydroguaiaretic acid (NDGA, IC50 = 1.28 μM); meanwhile, compounds 6h, 6g, 11, and 4 exhibited potent activities (IC50 = 1.29–1.77 μM). The ester 4 (SI = 137.37) and the phenyl-substituted acetohydrazide 11 (SI = 132.26) showed the highest COX-2 selectivity, which was about 28 times more selective than the reference drug diclofenac (SI = 4.73), however, it was lower than that of celecoxib (SI = 219.25). Interestingly, compound 6o, which showed the highest 15-LOX inhibitory activity and 5 times higher COX-2 selectivity than diclofenac, showed a greater poteny in reducing NO (IC50 = 7.77 μM) than both celecoxib (IC50 = 22.89 μM) and diclofenac (IC50 = 25.34), but comparable activity in inhibiting TNF-α (IC50 = 11.27) to diclofenac (IC50 = 10.45 μM). Similarly, compounds 11 and 6h were more potent in reducing TNF-α and IL6 levels than diclofenac, meanwhile, compound 4 reduced ROS, NO, IL6, and TNF-α levels with comparable potency to the reference drugs celecoxib and diclofenac. Furthermore, docking studies for our compounds within 15-LOX and COX-2 active sites revealed good agreement with the biological evaluations. The proposed compounds could be promising multi-targeted anti-inflammatory candidates to treat resistant inflammatory conditions.

Anti-inflammatory efficacy and relevant SAR investigations of novel chiral pyrazolo isoquinoline derivatives: Design, synthesis, in-vitro, in-vivo, and computational studies targeting iNOS

Isoquinoline alkaloids are a rich source of multimodal agents with distinctive structural specificity and various pharmacological activities. In the present report, we propose a combination of design, synthesis, computational study, primary in-vitro screening using the lipopolysaccharide (LPS)-induced RAW 264.7 cell line, and in-vivo evaluation in mice models as a novel approach to speed up anti-inflammatory drugs discovery. The nitric oxide (NO) inhibitory effect of new compounds revealed that all of them displayed the potent NO inhibitory ability in a dose-dependent manner with no obvious cytotoxicity. A series of the model compounds 7a, 7b, 7d, 7f, and 7g have been identified as the most promising, with IC50 values of 47.76 μM, 33.8 μM, 20.76 μM, 26.74 μM, and 47.8 μM respectively in LPS-induced RAW 264.7 cell line. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. Western blotting data of 7d identified that our synthesized compounds can down-regulate and suppress the expression of the key inflammatory enzyme, inducible nitric oxide synthase (iNOS). These results suggested that synthesized compounds may be potent anti-inflammatory agents, inhibiting the NO-release, in turn, iNOS inflammatory pathways. Furthermore, in-vivo anti-inflammatory detection via xylene-induced ear edema in mice revealed that these compounds could also inhibit swelling in mice, with model compound 7h showing an inhibition activity (64.4%) at a concentration of 10 mg/kg comparable to the reference drug celecoxib. Molecular docking results showed that shortlisted compounds (7b, 7c, 7d, 7e, and 7h) had a potential binding affinity for iNOS with low energies, with S-Score to be −7.57, −8.22, −7.35, −8.95, −9.94 kcal/mol, respectively. All results demonstrated that the newly synthesized chiral pyrazolo isoquinoline derivatives are highly potential anti-inflammatory agents.

Novel thiadiazol derivatives; design, synthesis, biological activity, molecular docking and molecular dynamics

Currently, selective COX-2 inhibitors are used as a novel alternative approach in the course of pain management due to their reduced adverse that generally occur after COX-1 inhibition by non-selective COX inhibitors. In this work, 16 new thiadiazole derivatives (3a-3p) were designed, synthesized and biologically evaluated for their COX-1 and COX-2 inhibitory potential using the in vitro fluorometric method. The biological evaluation showed that compounds 3c and 3d displayed significant activity against COX-2 with IC50 values of 0.350±0.015 µM and 0.134±0.004 µM, respectively, making the compound 3d similar in its activity to the reference drug celecoxib (IC50=0.132±0.005 µM). Further docking simulation also revealed that the most active derivative (3d) interacted with the enzyme active site in a similar manner to celecoxib. The binding modes of the compound on COX-2 were fully elucidated by molecular dynamics studies.

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.

Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on celecoxib scaffold supported with in vivo anti-inflammatory activity, ulcerogenic liability, ADME profiling and docking study

Four new series of 1,2,4 triazole derivatives 4a,b 5a-d, 6a-f, and 7a,b possessing methylsulphonylphenyl moiety as COX-2 pharmacophore were designed and synthesized. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compounds 4a, 5b, 6a, and 7a showed the highest selectivity towards the COX-2 enzyme (S.I. = 8.64–14.58) in comparison to celecoxib (S.I. = . 6.44). Interestingly, compounds 4a, 6a, and 7a showed good anti-inflammatory activity with edema inhibition (54.17, 53.03, and 50.29 %, in order) relative to the reference drug celecoxib (49.60%) after 3 h. Additionally, these potent derivatives 4a, 5b, 6a and 7a were significantly less ulcerogenic (U.I. = 2.27–2.97) than both reference drugs celecoxib (U.I. = 2.99) and indomethacin (U.I. = 20.25). Besides, a histopathological study of the stomach was also included. Moreover, docking simulation for the most selective compounds 4a, 5b, 6a, and 7a inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the above findings reveal that newly developed compounds 4a, 6a, and 7a represent a potential selective COX-2 NSAID candidate with minimum gastrointestinal risks.

Production, structural and biochemical characterization relevant to antitumor property of acidic exopolysaccharide produced from Bacillus sp. NRC5

This study targeted the production of exopolysaccharide from Bacillus sp. NRC5 grown in Egyptian seawater to use it as natural antitumor therapy. The biological activities of selected exopolysaccharide (BEPS) as an antioxidant, anti-inflammatory and anticancer have been studied. BEPS was evaluated as an anti-inflammatory in vitro against cyclooxygenase (COX-1 and COX-2) and evaluated as an anticancer on human breast and prostate cancer cell lines (MCF-7 and PC3). In addition, BEPS antitumor activity was tested against the Ehrlich Ascites Carcinoma (EAC) model. The BEPS presented potent antioxidant activities, consisted of glucose, mannose, and mannuronic acid in a molar ratio of 1.0:1.7:0.8 with a molecular weight of 3.59 × 105g/mol. BEPS showed a promising COX-2 inhibitory effect in comparison with the reference drug celecoxib. BEPS appeared efficient anticancer property, where it killed 64.20 and 70.20% of MCF-7 and PC3 cells at 100µg/ml, respectively (IC50, 76.70, and 70.40µg/ml, respectively). BEPS exhibited antitumor ability as it prolonged the lifespan of mice to reach 75days instead of 20days in the tumor control, reduced viable cancer cells count, tumor volume and weight, modulated blood components, and white blood cells differentiation. BEPS produced from Bacillus sp. NRC5 showed its antioxidant and anti-inflammatory abilities and antitumor abilities, which may all be attributed to its unique composition containing sulfated moieties and uronic acids.

Design, synthesis of new anti-inflammatory agents with a pyrazole core: COX-1/COX-2 inhibition assays, anti-inflammatory, ulcerogenic, histopathological, molecular Modeling, and ADME studies

Novel anti-inflammatory pyrazole derivatives (4a,b, 5a,b, 6a,b, 7a,b, 8a,b, 11a-c, 12a-c, 13a-c and 14a-c) were designed as coxib analogues, synthesized and evaluated for both in vitro and in vivo inhibitory activity. Compounds 4a, 4b, 5a, 6a, 6b, 13a-c and 14a-c were the most COX-2 selective compounds (Selectivity Index) = 242.52, 235.32, 234.50, 462.91 and 334.25, 277.18, 229.07, 243.83, 287.51, 237.03, 236.22 respectively) in comparison with the COX-2 selective reference drug celecoxib (Selectivity Index) = 313.12). Also, compounds 6a and 6b (possess SO2NH2 as selective COX-2 pharmacophore) presented the highest anti-inflammatory activity (ED50 = 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. Moreover, the different binding mode of interactions between the synthesized compounds and COX-2 active site were elucidated through molecular docking analysis.

Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies

Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041–0.081 μM, SI 139.74–321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3–48.3, 1 h; 58.4–60.5, 2 h; 70.8–83.2, 3 h; 78.9–89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.

Design, synthesis and molecular modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors

The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE2 and NO. A novel series of aryl carboximidamides 4a-g and their cyclized 3-aryl-1,2,4-oxadiazoles 5a-g counterparts derived from indomethacin 1 were synthesized. Most of the target compounds displayed lower LPS-induced NO production IC50 in RAW 264.7 cells and potent in vitro iNOS and PGE2 inhibitory activity than indomethacin. Moreover, in carrageenan-induced rat paw oedema method, most of them exhibited higher in vivo anti-inflammatory activity than the reference drug indomethacin. Notably, 4 hrs after carrageenan injection, compound 4a proved to be the most potent anti-inflammatory agent in this study, with almost two- and eight-fold more active than the reference drugs indomethacin (1) and celecoxib, respectively. Compound 4a proved to be inhibitor to LPS-induced NO production, iNOS activity and PGE2 with IC50 of 10.70 μM, 2.31 μM, and 29 nM; respectively. Compounds 4a and 5b possessed the lowest ulcerogenic liabilities (35% and 38%, respectively) compared to 1. Histopathological analysis revealed that compounds 4a and 5b demonstrated reduced degeneration and healing of ulcers. Molecular docking studies into the catalytic binding pocket of the iNOS protein receptor (PDB ID: 1r35) showed good correlation with the obtained biological results. Parameters of Lipinski’s rule of five and ADMET analysis were calculated where compound 4a had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed anti-inflammatory therapy and entitled to be used as future template for further investigations.

Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on bumetanide scaffold

Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and other diseases where COX-2 plays important role in their pathophysiology.

Synthesis and biological evaluation of 2-(4-methylsulfonyl phenyl) indole derivatives: multi-target compounds with dual antimicrobial and anti-inflammatory activities

Three series of 2-(4-methylsulfonylphenyl) indole derivatives have been designed and synthesized. The synthesized compounds were assessed for their antimicrobial, COX inhibitory and anti-inflammatory activities. Compound 7g was identified to be the most potent antibacterial candidate against strains of MRSA, E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii, respectively, with safe therapeutic dose. Compounds 7a–k, 8a–c, and 9a–c showed good anti-inflammatory activity with excessive selectivity towards COX-2 in comparison with reference drugs indomethacin and celecoxib. Compounds 9a–c were found to release moderate amounts of NO to decrease the side effects associated with selective COX-2 inhibitors. A molecular modeling study for compounds 7b, 7h, and 7i into COX-2 active site was correlated with the results of in vitro COX-2 inhibition assays.

Further insight into the dual COX-2 and 15-LOX anti-inflammatory activity of 1,3,4-thiadiazole-thiazolidinone hybrids: The contribution of the substituents at 5th positions is size dependent.

Herin we report the design, synthesis, full characterization and biological investigation of new 15-LOX/COX dual inhibitors based on 1,3-thiazolidin-4-one (15-lipoxygenase pharmacophore) and 1,3,4-thiadiazole (COX pharmacophore) scaffolds. This series of molecular modifications is an extension of a previously reported series to further explore the structural activity relationship. Compounds 3a, 4e, 4n, 4q, 7 and 8 capable of inhibiting 15-LOX at (2.74, 4.2, 3.41, 10.21, 3.71 and 3.36µM, respectively) and COX-2 at (0.32, 0.28, 0.28, 0.1, 0.28 and 0.27µM, respectively). The results revealed that binding to 15-LOX and COX is sensitive to the bulkiness of the substituents at the 5 positions. 15-LOX bind better with small substituents, while COXs bind better with bulky substituents. Compounds 3a, 4r and 4q showed comparable in vivo anti-inflammatory activity to the reference drug (celecoxib). The ulcer liability test showed no sign of ulceration which ensures the safe gastric profile. Docking study was performed to explore the possible mode of interaction of the new compounds with the active site of human 15-LOX and COX-2. This study discloses some structural features for binding to 15-LOX and COX, thus pave the way to design anti-inflammatory agents with balanced dual inhibition of these enzymes.

Design, synthesis, and biological evaluation of new 1,4-diarylazetidin-2-one derivatives (β-lactams) as selective cyclooxygenase-2 inhibitors.

A new series of 1,4-diarylazetidin-2-one derivatives (β-lactams) were designed and synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the 0.05-0.11 µM range, and COX-2 selectivity indexes in the range of 170-703.7. Among the synthesized β-lactams, 3-methoxy-4-(4-(methylsulfonyl)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (4j) possessing trimethoxy groups at the N-1 phenyl ring exhibited the highest COX-2 inhibitory selectivity and potency, even more potent than the reference drug celecoxib. The analgesic activity of the synthesized compounds was also determined using the formalin test. Compound 4f displayed the best analgesic activity among the synthesized molecules. Molecular modeling studies indicated that the methylsulfonyl pharmacophore group can be inserted into the secondary pocket of the COX-2 active site for interactions with Arg513 . The structure-activity data acquired indicate that the β-lactam ring moiety constitutes a suitable scaffold to design new 1,4-diarylazetidin-2-ones with selective COX-2 inhibitory activity.

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3–14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13–17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC50=6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC50=0.68 μM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC50=1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

New pyrazole derivatives possessing amino/methanesulphonyl pharmacophore with good gastric safety profile: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory activity and histopathological studies

New series of pyrazole derivatives Va-c, VIa-c, VIIa-f, and VIII possessing amino/methanesulphonyl moiety as COX-2 pharmacophore were designed and synthesized. All compounds were evaluated for both in vitro COX inhibition and in vivo anti-inflammatory activities and all of them were more potent against COX-2 than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds Va, VIa, VIc and VIIa-c showed good COX-2 SI (246.8–353.8) in comparison with the COX-2 selective drug; celecoxib (326.7). Also, they showed good anti-inflammatory activity with edema inhibition (51–86 and 83–96%) relative to celecoxib (60.6 and 82.8%) after 3 and 5 h respectively. Additionally, these potent derivatives Va, VIa, VIc and VIIa-c were significantly less ulcerogenic (ulcer indexes = 0.7–2.0) than indomethacin (ulcer index = 21.3) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 1.3). The obtained ulcerogenic liability data revealed the gastric safety of these derivatives which was confirmed by the histopathological studies. Docking study was performed for all synthesized derivatives to explain their interaction with COX-2 receptor active site.