Design, synthesis and evaluation of bis-nicotine derivatives as inhibitors of cholinesterases and β-amyloid aggregation

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC₅₀, 2.28-117.86 μmol·L^-1 for AChE and 1.67-125 μmol·L^-1 for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Aβ aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 μmol·L^-1.