Synthesis and biological activity evaluation of phthalimide-donepezil hybrids / 药学学报

ABSTRACT

A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.