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Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies

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2023

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Shaker, Mohamed E.
Goma, Hesham A. M.
Alsalahat, Izzeddin
Elkanzi, Nadia A. A.
Azouz, Amany A.
Abdel-Bakky, Mohamed Sadek
Ghoneim, Mohammed M.
Hazem, Sara H.
Abdelgawad, Mohamed A.
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Journal of Biomolecular Structure and Dynamics. Taylor & Francis. ISSN 0739-1102. eISSN 1538-0254. Available under: doi: 10.1080/07391102.2023.2293257

Zusammenfassung

NSAIDs represent a mainstay in pain and inflammation suppression, and their actions are mainly based on inhibiting COX-1 and COX-2 enzymes. Due to the adverse effects of these drugs, especially on the stomach and heart, scientists efforts have been directed to manufacture selective COX-2 without cardiovascular side effects and with minimal effects on the stomach. The cardiovascular side effects are thought to be related to the chemical composition rather than mechanism of action of these drugs. Novel pyridopyrimidines, 9a-j, were prepared and their chemical structures were confirmed by NMR, mass and IR Spectra, and elemental analysis. The effect of the 9a-j compounds on COX-1 and COX-2 was assessed and it was found that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) was the most potent COX-2 inhibitor (IC50 ¼ 0.54 uM) compared to celecoxib (IC50 ¼1.11 uM) with selectivity indices of 6.56 and 5.12, respectively. The in vivo inhibition of paw edema of novel compounds 9a-j was measured using carrageenan-induced paw edema method, and that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-)pyrimidin-4-one (9d) showed the best inhibitory activity in comparison with the other compounds and celecoxib. The gastroprotective effect of the potent derivatives 9d, 9e, 9f, 9g and 9h was investigated. 2- Hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) and 7-(chlorophenyl)-hydrazino-5-(4-methoxyphenyl)-3H-pyrido[2,3-d)pyrimidin-4-one (9e) showed ulcer indices comparable to celecoxib (1 and 0.5 vs 0.5, respectively). Docking studies were carried out and they confirmed the mechanistic action of the designed compounds.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie

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COXs inhibitors, antiinflammatory, celecoxib, NSAIDs, pyridopyrimidines

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ISO 690SHAKER, Mohamed E., Hesham A. M. GOMA, Izzeddin ALSALAHAT, Nadia A. A. ELKANZI, Amany A. AZOUZ, Mohamed Sadek ABDEL-BAKKY, Mohammed M. GHONEIM, Sara H. HAZEM, Mohamed ELMESERY, Mohamed A. ABDELGAWAD, 2023. Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies. In: Journal of Biomolecular Structure and Dynamics. Taylor & Francis. ISSN 0739-1102. eISSN 1538-0254. Available under: doi: 10.1080/07391102.2023.2293257
BibTex
@article{Shaker2023-12-28Desig-69214,
  year={2023},
  doi={10.1080/07391102.2023.2293257},
  title={Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies},
  issn={0739-1102},
  journal={Journal of Biomolecular Structure and Dynamics},
  author={Shaker, Mohamed E. and Goma, Hesham A. M. and Alsalahat, Izzeddin and Elkanzi, Nadia A. A. and Azouz, Amany A. and Abdel-Bakky, Mohamed Sadek and Ghoneim, Mohammed M. and Hazem, Sara H. and Elmesery, Mohamed and Abdelgawad, Mohamed A.}
}
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