Design and Synthesis of N-Arylphthalimides as Inhibitors of Glucocorticoid-Induced TNF Receptor-Related Protein, Proinflammatory Mediators, and Cytokines in Carrageenan-Induced Lung Inflammation

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• 作者：Mashooq A. Bhat ; Mohamed A. Al-Omar ; Mushtaq A. Ansari ; Khairy M. A. Zoheir ; Faisal Imam ; Sabry M. Attia ; Saleh A. Bakheet ; Ahmed Nadeem ; Hesham M. Korashy ; Andrey Voronkov ; Vladimir Berishvili ; Sheikh F. Ahmad
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8850-8867
• 全文大小：1049K
• ISSN：1520-4804

文摘

N-Arylphthalimides (1鈥?b>10P) derived from thalidomide by insertion of hydrophobic groups were evaluated for anti-inflammatory activity, and (4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N鈥?[(4-ethoxyphenyl)methylidene]benzohydrazide 6P was identified as a promising anti-inflammatory agent. Further testing confirmed that compared with the control, 6P treatment resulted in a considerable decrease in CD4⁺, NF-魏B p65⁺, TNF-伪⁺, IL-6⁺, GITR⁺, and IL-17⁺ cell populations and an increase in the Foxp3⁺, CD4⁺Foxp3⁺, and I魏B伪⁺ populations in whole blood and pleural fluid of a mouse model of lung inflammation. Moreover, treatment with compound 6P decreased the proteins associated with inflammation including TNF-伪, IL-6, IL-17, GITR, NF-魏B, COX-2, STAT-3, and iNOS and increased the anti-inflammatory mediators such as IL-10 and IL-4. Further, histopathological examination confirmed the potent anti-inflammatory effects of compound 6P. Thus, the N-arylphthalimide derivative 6P acts as a potent anti-inflammatory agent in the carrageenan-induced lung inflammation model, suggesting that this compound may be useful for the treatment of inflammation in a clinical setting.