Design, synthesis, and biological evaluation of compounds with a new scaffold as anti-neuroinflammatory agents for the treatment of Alzheimer's disease

• Published in: European journal of medicinal chemistry 2018-04, Vol.149, p.129-138
• Main Authors: Fang, Yuying, Xia, Wenjuan, Cheng, Bao, Hua, Pei, Zhou, Huihao, Gu, Qiong, Xu, Jun
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Anti-neuroinflammation; Blood-Brain Barrier - metabolism; Cell Line; Central Nervous System - pathology; Drug Design; Fragment-based drug design; Humans; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - biosynthesis; MAP Kinase Signaling System - drug effects; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Phosphorylation - drug effects; Pyrimidines - chemical synthesis; Stilbenes - chemical synthesis; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.02.063

Twenty-eight compounds with a new scaffold were designed and synthesized by assembling fragments derived from known agents such as stilbenes and piperazinyl pyrimidines. Many strategies have been explored to improve the druggability of these series of compounds, such as increasing the distance between two benzene rings in the scaffold and introducing functional groups at designated positions. These compounds were validated for their anti-neuroinflammatory activity in BV2 cells. Experimental results reveal that the most active compound 8b can inhibit nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) production with IC50 values of 1.0, 2.6, and 0.5 μM, respectively. The compound can also significantly modulate the MAPK pathways through inhibiting the phosphorylation of JNK, ERK1/2, and p38 MAPK without disturbing NF-κB pathway. Parallel artificial membrane permeation assay demonstrated that the most active compound can overcome the blood-brain barrier (BBB). Therefore, this compound can be a promising lead for the treatment of Alzheimer's disease. [Display omitted] •Compounds with a novel scaffold as anti-neuroinflammatory agents were discovered with fragment-based drug discovery approach.•The most active compound reaches anti-neuroinflammatory activity at single digit μM.•The new class of compounds can penetrate BBB, and are promising as CNS drug leads.