Synthesis of novel N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazine derivatives as cyclooxygenase‐2 inhibitors

Khan, Abida; Diwan, Anupama; Thabet, Hamdy Khamees; Imran, Mohd

doi:10.1002/ddr.21655

Cited by 9 publications

(32 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As per the published reports, incorporation of the thiazole moiety and the 4-thiazolidinone moiety in a compound imparts selectivity towards COX-2 inhibition and also improves its gastric safety profile [22][23][24][25][26][27][28]. Accordingly, as an extension of our work to develop superior anti-inflammatory compounds [29][30][31][32], we report herein novel pyridazine-based thiazole and 4-thiazolidinone derivatives as cyclooxygenase-2 inhibitors with an improved gastric safety profile.…”

Section: Introductionmentioning

confidence: 55%

“…The intermediates 2, 3, 4b, and 4c were reported in our previous publication [30]. The intermediates 1, 5a, 5b, and 13 are available commercially.…”

Section: Chemistrymentioning

confidence: 97%

“…The compounds 4a, 6a, 6b, 8, 9a, 9b, 10, 11, 12, 16a, 16b, 17, and 18 were examined as COX-1 and COX-2 inhibitors along with indomethacin and celecoxib. It was performed by the 10-fold dilution technique utilizing test packs of the human COX-1/COX-2 (Cayman Chemicals, 560131, Ann Arbor, MI, USA) [30]. Indomethacin and celecoxib were used as standard drugs.…”

Section: In Vitro Cox Inhibitory Actionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile

et al. 2020

Self Cite

View full text Add to dashboard Cite

Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde 3 and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds 9a (IC50 = 15.50 nM, 114.77%), 9b (IC50 = 17.50 nM, 101.65%), 12 (IC50 = 17.10 nM, 104.03%), 16b (IC50 = 16.90 nM, 105.26%), and 17 (IC50 = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC50 = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of 9a, 9b, 12, 16b, and 17. These compounds also displayed comparable onset and the duration of action concerning celecoxib and indomethacin in the in vivo studies. No ulcerogenic effects were observed for 9a and 12, whereas 9b, 16b, and 17 showed an insignificant ulcerogenic effect compared to celecoxib. The compounds 9a, 9b, 12, 16b, and 17 displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds 9a (%ABS = 84.09), 9b (%ABS = 84.09), 12 (%ABS = 66.87), 16b (%ABS = 75.02), and 17 (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds 9a, 9b, 11, 16b, and 17 have been recognized and postulated as non-ulcerogenic COX-2 inhibitors with promising physicochemical parameters and gastric safety profile. These compounds may be useful candidates to combat diseases caused by higher levels of COX-2.

show abstract

Section: Introductionmentioning

confidence: 55%

“…The intermediates 2, 3, 4b, and 4c were reported in our previous publication [30]. The intermediates 1, 5a, 5b, and 13 are available commercially.…”

Section: Chemistrymentioning

confidence: 97%

Section: In Vitro Cox Inhibitory Actionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, more investigations in the role of COX-2 inhibitors in cancer chemotherapy [ 6 , 7 ] and neurological diseases such as Parkinson [ 8 ] and Alzheimer's diseases are still needed [ 9 , 10 ]. Many valuable studies on COX-2 inhibitors have still published until now, as, these inhibitors are still subject to the interest of researchers worldwide [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore model, docking, QSAR, and molecular dynamics simulation studies of substituted cyclic imides and herbal medicines as COX-2 inhibitors

Moussa

Hassan

Gharaghani

2021

Heliyon

View full text Add to dashboard Cite

Cyclooxygenase-2 (COX-2) enzyme inhibitors have not eliminated the necessity for developed drugs not only in the nonsteroidal anti-inflammatory drug (NSAIDs) area, but also in other therapeutic applications including prevention of cancer and Alzheimer's disease. A series of novel substituted cyclic imides have been reported as selective COX-2 inhibitors. To understand the structural features responsible for their activity, a 3D validated pharmacophore and quantitative structure−activity relationship (QSAR) model have been developed. The values of enrichment factor (EF), goodness of hit score (GH), area under the ROC curve (AUC), sensitivity, and specificity refer to the good ability of the pharmacophore model to identify active compounds. Multiple linear regression (MLR) produced statistically significant QSAR model with (R 2 training = 0.763, R 2 test = 0.96) and predictability (Q 2 training = 0.66, Q 2 test = 0.84). Then, using the pharmacophore and QSAR models, eight authenticated botanicals in two herbal medicines and the ZINC compounds database, were virtually screened for ligands to COX-2. The retrieved hits which also obey lipinski's rule of five (RO5) were docked in the COX-2 3D structure to investigate their binding mode and affinity. Finally, based on the docking results, nine molecules were prioritized as promising hits that could be used as leads to discover novel COX-2 inhibitors. COX-2 inhibition of most of these hits has not been reported previously. Ten-nanosecond molecular dynamics simulation (10-ns MD) was performed on the initial structure COX-2 complex with ZINC000113253375 and ZINC000043170560 resulted from the docking. Our utilization of the 3D pharmacophore model, QSAR, molecular docking, and molecular dynamics simulation trials can be a potent strategy to successfully predict activity, efficiently design drugs, and screen large numbers of new compounds as active drug candidates.

show abstract

“…Their antimicrobial [5][6][7][8][9], antiviral [10], anti-inflammatory [11], antitumor [12,13] [properties] have been reported. These compounds are also the inhibitors of various enzymes [14][15][16]. At the same time, the less conformational restrictions of 5-benzyl-4-thiazolidinone derivatives are practically unexplored.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial activity of 5-R-benzyl-2-(arylidenehydrazono)thiazolidin-4-ones

et al. 2020

View full text Add to dashboard Cite

Synthesis of novel N‐substitutedphenyl‐6‐oxo‐3‐phenylpyridazine derivatives as cyclooxygenase‐2 inhibitors

Cited by 9 publications

References 33 publications

Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile

Discovery of Novel Pyridazine-Based Cyclooxygenase-2 Inhibitors with a Promising Gastric Safety Profile

Pharmacophore model, docking, QSAR, and molecular dynamics simulation studies of substituted cyclic imides and herbal medicines as COX-2 inhibitors

Synthesis and antimicrobial activity of 5-R-benzyl-2-(arylidenehydrazono)thiazolidin-4-ones

Contact Info

Product

Resources

About