Design, synthesis, biological evaluation, and docking studies of some novel chalcones as selective COX‐2 inhibitors

Çavuşoğlu, Betül Kaya; Sağlık, Begüm Nurpelin; Çevik, Ulviye Acar; Osmaniye, Derya; Levent, Serkan; Özkay, Yusuf; Kaplancıklı, Zafer Asım

doi:10.1002/ardp.202000273

Cited by 11 publications

(13 citation statements)

References 29 publications

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“…The fluorometric COX enzyme inhibition assay was applied to determine the inhibition power of all synthesized N ‐acyl hydrazone‐methyl sulfonyl derivatives [19,21–23] . A two‐step enzyme activity protocol was applied according to the inhibition percentages and concentrations of the compounds.…”

Section: Resultsmentioning

confidence: 99%

“…The percentage inhibition rates and IC 50 values of the selected compounds and reference drugs at the tested concentrations are presented in Table 2. The IC 50 values of the compounds were calculated from the inhibition curves drawn using the sigmoid dose‐response model with nonlinear regression analysis in Microsoft Office Excel 2013 [19,23] …”

Section: Resultsmentioning

confidence: 99%

“…First, as can be seen from Figure 2, compound 3j occupies a very similar position to that of celecoxib. A specific side pocket of COX‐2, consisting of the amino acids Leu338, Ser339, Arg499, Phe504, and Val509, is crucial for the selective inhibition and binding of certain groups such as sulfone (−SO 2 ), sulfonamide (−SO 2 NH 2 ), or methyl sulfonyl (−SO 2 CH 3 ) [19,23] . The sulfonamide group, which is the substituent of the drug celecoxib, forms exactly four hydrogen bonds with this specific side pocket.…”

Section: Resultsmentioning

confidence: 99%

“…The assay was based on the fluorometric detection of PG G2, the intermediate product generated by the COX enzymes. The in vitro COX‐1 and COX‐2 inhibition assay procedure was carried out as formerly explained by our research group [19,23] …”

Section: Methodsmentioning

confidence: 99%

“…Among the newly published research on selective COX‐2 inhibitors, N ‐acyl hydrazones, as a new class of anti‐inflammatory compounds, have shown great promise in terms of selectivity in COX‐2 binding and anti‐inflammatory activity [9–12] . It is also known that the methyl sulfonyl group enhances selective COX‐2 inhibition [13–20] …”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

Osmaniye

Sağlık

Levent

et al. 2021

Chemistry & Biodiversity

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The mechanism of action of nonsteroidal anti‐inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60 % similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX‐1 enzyme. Therefore, the use of COX‐2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX‐2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX‐2 inhibitors remain necessary. It is important to develop new COX‐2 inhibitors in the field of medicinal chemistry. Accordingly, novel N‐acyl hydrazone derivatives were synthesized as new COX‐2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX‐2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds (3a–3j) was characterized by spectroscopic methods. Evaluation of in vitro COX‐1/COX‐2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX‐2 enzyme inhibition. Compound 3j showed important COX‐2 inhibition with a value of IC50=0.143 uM. Interaction modes between the COX‐2 enzyme and compound 3j were investigated by docking studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

Osmaniye

Sağlık

Levent

et al. 2021

Chemistry & Biodiversity

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Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

Ayman

Radwan

Elmetwally

et al. 2022

Archiv der Pharmazie

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Searching for effective and selective anti-inflammatory agents, our study involved designing and synthesizing new pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 4-11. The structures of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using in silico docking simulation inside the active sites of four proteins classified as two cyclooxygenases (COX)-1 (PDB: 3KK6 and 4OIZ) and two COX-2 (PBD: 1CX2 and 3LN1). Among them, six derivatives 4c, 5b, 6a, 7a, 7b, and 10b displayed the highest binding energy. These derivatives were evaluated for their in vitro COX-1 and COX-2 inhibitory activities and their selectivity indexes were calculated. Additionally, these derivatives displayed IC 50 values ranging between 4.909 ± 0.25 and 57.53 ± 2.91 µM, and 3.289 ± 0.14 and 124 ± 5.32 µM, against COX-1 and COX-2, respectively. Furthermore, the tested derivatives were found to have selective inhibitory activity on the COX-2 enzyme. Surprisingly, the two pyrazole derivatives 4c and 5b were found to be the most active, with IC 50 values of 9.835 ± 0.50 and 4.909 ± 0.25 µM and 4.597 ± 0.20 and 3.289 ± 0.14 µM compared with meloxicam (1.879 ± 0.1 and 5.409 ± 0.23 µM) and celecoxib (5.439 ± 0.28 and 2.164 ± 0.09 µM) against COX-1/-2, respectively. Besides, two pyrazole derivatives, 4c and 5b, displayed a COX-1/COX-2 SI of 2.14 and 1.49. Computational techniques such as molecular docking, density function theory (DFT) calculation, and chemical absorption, distribution, metabolism, excretion, and toxicity evaluation were applied to explain the molecules' binding mode, chemical nature, drug likeness, and toxicity prediction.

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Synthesis, molecular dynamics simulation, and evaluation of biological activity of novel flurbiprofen and ibuprofen‐like compounds

Yıldız,

Osmaniye,

Saglik

et al. 2024

J of Molecular Recognition

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The frequent use of anti‐inflammatory drugs and the side effects of existing drugs keep the need for new compounds constant. For this purpose, flurbiprofen and ibuprofen‐like compounds, which are frequently used anti‐inflammatory compounds in this study, were synthesized and their structures were elucidated. Like ibuprofen and flurbiprofen, the compounds contain a residue of phenylacetic acid. On the other hand, it contains a secondary amine residue. Thus, it is planned to reduce the acidity, which is the biggest side effect of NSAI drugs, even a little bit. The estimated ADME parameters of the compounds were evaluated. Apart from internal use, local use of anti‐inflammatory compounds is also very important. For this reason, the skin permeability values of the compounds were also calculated. And it has been found to be compatible with reference drugs. The COX enzyme inhibitory effects of the obtained compounds were tested by in vitro experiments. Compound 2a showed significant activity against COX‐1 enzyme with an IC50 = 0.123 + 0.005 μM. The interaction of the compound with the enzyme active site was clarified by molecular dynamics studies.

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Design, synthesis, biological evaluation, and docking studies of some novel chalcones as selective COX‐2 inhibitors

Cited by 11 publications

References 29 publications

Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

Design, Synthesis and Biological Evaluation of New N‐Acyl Hydrazones with a Methyl Sulfonyl Moiety as Selective COX‐2 Inhibitors

Discovery of novel pyrazole and pyrazolo[1,5‐a]pyrimidine derivatives as cyclooxygenase inhibitors (COX‐1 and COX‐2) using molecular modeling simulation

Synthesis, molecular dynamics simulation, and evaluation of biological activity of novel flurbiprofen and ibuprofen‐like compounds

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