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

Abstract

N-Arylphthalimides (1-10P) 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'-[(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-κB p65(+), TNF-α(+), IL-6(+), GITR(+), and IL-17(+) cell populations and an increase in the Foxp3(+), CD4(+)Foxp3(+), and IκBα(+) 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-α, IL-6, IL-17, GITR, NF-κB, 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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 22 Pg. 8850-67 (Nov 25 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26456029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Inflammation Mediators
• Phthalimides
• Tnfsf18 protein, mouse
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors
• Thalidomide
• Carrageenan
• Nitric Oxide Synthase Type II

Topics

• Animals
• Behavior, Animal (drug effects)
• Carrageenan
• Cytokines (antagonists & inhibitors)
• Drug Design
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Female
• Inflammation Mediators (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Phthalimides (chemical synthesis, pharmacology)
• Pleural Effusion (drug therapy, metabolism)
• Pneumonia (chemically induced, drug therapy, metabolism)
• Th1 Cells (drug effects, metabolism)
• Th2 Cells (drug effects, metabolism)
• Thalidomide (analogs & derivatives, chemical synthesis, pharmacology)
• Tumor Necrosis Factor Inhibitors
• Tumor Necrosis Factors