Synthesis and evaluation of heterobivalent tacrine derivatives as potential multi-functional anti-Alzheimer agents

A new series of heterobivalent tacrine derivatives were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents for their inhibitory activity on cholinesterases, antioxidant activity and self-induced beta-amyloid (A beta) aggregation. All these synthesized compounds had potent inhibition activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) at nanomolar range. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The compounds containing hydroxyl group showed potent peroxyl radical absorbance activity. In addition, compound 5j exhibited higher self-induced A beta aggregation inhibitory activity than curcumin, which could become a multifunctional agent for further development for the treatment of AD. (C) 2011 Elsevier Masson SAS. All rights reserved.