Flurbiprofen-chalcone hybrid Mannich base derivatives as balanced multifunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation.

The complex pathogenesis of Alzheimer's disease (AD) calls for multitarget approach for disease management. Herein, a series of novel flurbiprofen-chalcone hybrid Mannich base derivatives were designed and synthesized. The biological screening results indicated that most of the derivatives exhibited potent multi-target effects involved in AD. In particular, compound 6c bearing a pyrrolidine group showed the highest activities against self- and Cu2+-induced Aβ1-42 aggregation (70.65% and 54.89% at 25.0 µM, respectively), highly selective inhibition towards AChE and MAO-B (IC50 = 7.15 μM and 0.43 μM respectively), good antioxidant ability and metal-chelating property. Moreover, 6c displayed excellent anti-neuroinflammatory activity and appropriate BBB permeability in vitro. These outstanding results qualified compound 6c as a promising multifunctional agent for further development of disease-modifying treatment of AD.