Assessment of novel azaanthraquinone derivatives as potent multi-target inhibitors of inflammation and amyloid-β aggregation in Alzheimer's disease.

Graphical abstract Highlights • The new derivatives showed strong anti-inflammatory activity. • Derivatives exhibited a significant inhibitory activity toward Aβ secretion levels. • Compound 7b could attenuate H 2 O 2 -induced neurotoxicity toward SH-SY5Y cells. • Half of the derivatives were predicted to be able to cross the blood-brain barrier. Abstract A series of 6-substituted azaanthraquinone derivatives have been designed, synthesized, and their anti-inflammatory activities, antiaggregation effects on β-amyloid proteins, anticholinesterase and neuroprotective activity were tested. The new derivatives strongly suppressed NO and iNOS production and modulate the production of cytokines by decreasing TNF-a, IL-1β and IL-6 formation in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Meanwhile, the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human b-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ42 secretion levels. Moreover, the derivatives exhibited moderate inhibitory potency toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Further investigations indicated that compound 7b could attenuate H 2 O 2 -induced neurotoxicity toward SH-SY5Y neuroblastoma cells and half of the synthetic compounds were predicted to be able to cross the blood–brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Taken together, azaanthraquinone derivatives targeting multiple pathogenetic factors deserves further investigation for prevention and treatment of AD. [ABSTRACT FROM AUTHOR]