Design synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2 6-dioxopiperidines and 3-substituted 2 6-dioxopiperidines for TNF-α inhibitory activity

摘要

Eight novel 2-(2, 6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates >9 and >10, N-substituted 3-(phthalimidin-2-yl)-2, 6-dioxopiperidines >11–14 and 3-substituted 2, 6-dioxopiperidines >16 and >18 were synthesized as tumor necrosis factor-α (TNF-β) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds >9–14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-β in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds >9, >14 and >16 exhibited potent TNF-α lowering activity, reducing TNF-α by up to 48% at 30 μM, compounds >12, >17 and >18 presented moderate TNF-α inhibitory action. The TNF-α lowering properties of these analogues proved more potent than that of revlimid (>3) and thalidomide (>1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2, 6-dioxopiperidine >14 not only possessed the greatest potency of the analogues to reduce TNF-α synthesis, but achieved this with minor cellular toxicity at 30 μM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation that is commonly associated with neurodegenerative disorders, epitomized by Alzheimer’s disease and Parkinson’s disease.