title: 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.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mashooq A
authors.initials: MA
authors.lastname: Bhat
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Al-Omar
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Khairy M A
authors.initials: KM
authors.lastname: Zoheir
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Faisal
authors.initials: F
authors.lastname: Imam
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Leninskie Gory, 1/3, Moscow 119991, Russia.|Digital Bio Pharm Ltd. , 145-157 St. John Street, London, EC1V 4PW, U.K.|Moscow Institute of Physics and Technology (State University) , 9 Institutskiy Lane, Dolgoprudny, Moscow Oblast 141700, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Voronkov
authors.affiliation: Department of Chemistry, Lomonosov Moscow State University , Leninskie Gory, 1/3, Moscow 119991, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berishvili
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University , 2457 Riyadh, Kingdom of Saudi Arabia.
authors.forename: Sheikh F
authors.initials: SF
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D016207:Cytokines / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology; D010996:Pleural Effusion / Q000188:drug therapy / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D010797:Phthalimides; C478966:Tnfsf18 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D013792:Thalidomide; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II