Synthesis, Anti-Inflammatory, and Molecular Docking Studies of New Heterocyclic Derivatives Comprising Pyrazole, Pyridine, and/or Pyran Moieties
Bibliographic Information
Authors: Reheim M.A.M.A.; Rady H.S.A.; Mohamed O.A.; Hassan A.; Hafiz I.S.A.; Reffat H.M.; Elsaid F.G.; Eldesoqui M.; Alshaya D.S.; Badawy A.A.; Fayad E.; Abdelmonsef A.H.
Journal: Pharmaceuticals
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Publication Date: 26 February 2025
Volume / Issue: Volume 18 / Issue 3
Article No.: 335
ISSN: 14248247
DOI: 10.3390/ph18030335
Scopus: View on Scopus
Document Type: Article
Access: All Open Access; Gold Open Access; Green Open Access
Authors and Affiliations
Reheim M.A.M.A., Department of Chemistry, Faculty of Science, Arish University, Arish, 45511, Egypt; Rady H.S.A., Department of Chemistry, Faculty of Science, Arish University, Arish, 45511, Egypt; Mohamed O.A., Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Hassan A., Department of Medicinal Chemistry, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt; Hafiz I.S.A., Department of Chemistry, Faculty of Science, Arish University, Arish, 45511, Egypt; Reffat H.M., Department of Chemistry, Faculty of Science, Arish University, Arish, 45511, Egypt; Elsaid F.G., Department of Biology, College of Science, King Khalid University, P.O. Box 960, Abha, 61421, Saudi Arabia; Eldesoqui M., Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Alshaya D.S., Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia; Badawy A.A., Department of Biochemistry, Faculty of Medicine, Northern Border University, P.O. Box 1321, Arar, 91431, Saudi Arabia; Fayad E., Department of Biotechnology, College of Sciences, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia; Abdelmonsef A.H., Department of Chemistry, Faculty of Science, South Valley University, Qena, 83523, Egypt
Abstract
Introduction: Inhibiting cyclooxygenase-2 (COX-2) is a potential strategy in inflammation therapy. Thus, developing COX-2 inhibitors plays a pivotal role in efficient inflammation treatment. This study discloses the synthesis of new heterocyclic compounds incorporating pyridine, pyran, and/or pyrazole moieties as COX-2 inhibitors. Methods: In this study, the Claisen–Schmidt reaction of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)ethan-1-one 1 and p-methoxybenzaldehyde in ethanol containing aqueous sodium hydroxide (10%) led to the formation of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one) 2. The latter compound was allowed to react as a key precursor with various nucleophiles such as ethyl cyanoacetate, malononitrile, cyclohexanone, ethyl acetoacetate, hydrazine, cyano acid hydrazide, hydrazide, and/or thiosemicarbazide to yield new heterocyclic derivatives comprising pyridine, pyran, and/or pyrazole moieties 3–15, according to the Michael addition reaction. The newly synthesized compounds were depicted using spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and MS. Moreover, their anti-inflammatory efficiency was in vitro evaluated by means of protein denaturation inhibition and cell membrane protection assay. Results: The results of 2−ΔΔct values of COX-2 expression for compounds 6, 11, 12, and 13 were 6.6, 2.9, 25.8, and 10.1, respectively. Therefore, compound 12, followed by 13, 11, and 6, showed potent anti-inflammatory properties by in vitro evaluation. Further, an in silico molecular docking study was performed on the best-docked compounds and reference drug (Diclofenac) to investigate their binding affinities against the active site of the target enzyme. The obtained results from the in silico study aligned with the biological evaluation. Conclusions: The studies open new doors for designing new heterocycles containing pyridine, pyran, and/or pyrazole moieties as potent anti-inflammatory agents. © 2025 by the authors.
Keywords
anti-inflammatory; Claisen–Schmidt reaction; Michael addition; molecular docking; pyran; pyrazole; pyridine; 1 2 hydroxy 6 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl 4h pyran 3 yl ethanone; 1 3 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 5 4 methoxyphenyl 4 5 dihydro 1h pyrazol 1 yl ethanone; 1 5 hydroxy 1 3 dipheny 1h pyrazol 4 yl 3 4 methoxyphenyl prop 2 en 1 one; 2 3 5 hydroxy 1 3 diphenyl 1h-pyrazol 4 yl 1 4 methoxyphenyl 3 oxopropyl malononitrile; 2 amino 6 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl 4h pyran 3 carbonitrile; 2 amino 6 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl nicotine hydrazide; 2 amino 6 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl)nicotine nitrile; 2 amino 6 5 hydroxy 1 3 diphenyl 1H pyrazol 4 yl 4 4 methoxyphenyl)nicotinohydrazide 1; 2 hydroxy 6 5 hydroxy-1 3-diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl 4h pyran 3 carbonitrile; 3 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 5 4 methoxyphenyl 4 5 dihydro 1h pyrazole 1 carbothioamide; 3 acetyl 6 5 hydroxy 1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl)pyridin 2 1h one; 4 4 4 methoxyphenyl 1 4 5 6 7 8 hexahydroquinolin 2 yl 1 3 diphenyl 1h pyrazol 5 ol; 4 4 4 methoxyphenyl 1 4 5 6 7 8 hexahydroquinolin 2 yl 1 3 diphenyl 1h pyrazol 5 ol; 4 5 4 methoxyphenyl 4 5 dihydro 1h pyrazol 3 yl 1 3 diphenyl 1h pyrazol 5 o; 5 amino 1 3 diphenyl 1h thieno 3 2 c]pyrazol 6 yl 5 hydroxy 5 4 methoxyphenyl 1 3 diphenyl 1h 1h 3 4 bipyrazol 1 yl methanone; 6 5 hydroxy-1 3 diphenyl 1h pyrazol 4 yl 4 4 methoxyphenyl 2 oxo 1 2 dihydropyridine 3 carbonitrile; acetic acid; anisaldehyde; antiinflammatory agent; cyclooxygenase 2; diclofenac; heterocyclic compound; malononitrile; pyran derivative; thiosemicarbazide; unclassified drug; antiinflammatory activity; antioxidant activity; Article; binding affinity; bioavailability; carbon nuclear magnetic resonance; cell membrane; cell viability; chemical interaction; chemical structure; Claisen condensation; crystal structure; cyclization; electrospray mass spectrometry; enzyme inhibition; Fourier transform infrared spectroscopy; gene expression; gene expression level; hemolysis; hydrogen bond; in vitro study; mass fragmentography; molecular dynamics; pharmacokinetics; physical chemistry; protein denaturation; proton nuclear magnetic resonance; real time polymerase chain reaction; thin layer chromatography
Citation Information
Scopus Citations: 18
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