J Med Chem. 2015 Nov 25;58(22):8850-67. doi: 10.1021/acs.jmedchem.5b00934. Epub 2015 Nov 5.

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

Bhat MA¹, Al-Omar MA¹, Ansari MA², Zoheir KM², Imam F², Attia SM², Bakheet SA², Nadeem A², Korashy HM², Voronkov A^3,^4,⁵, Berishvili V³, Ahmad SF².

Author information

1: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
2: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
3: Department of Chemistry, Lomonosov Moscow State University , Leninskie Gory, 1/3, Moscow 119991, Russia.
4: Digital Bio Pharm Ltd. , 145-157 St. John Street, London, EC1V 4PW, U.K.
5: Moscow Institute of Physics and Technology (State University) , 9 Institutskiy Lane, Dolgoprudny, Moscow Oblast 141700, Russia.

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.