Design, synthesis and evaluation of novel tacrine–coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease

A series of tacrine–coumarin hybrids (8a–t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced β-amyloid (Aβ) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 μM) and Aβ aggregation (67.8%, 20 μM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 μM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment. [Display omitted] A series of novel tacrine–coumarin hybrids were designed and synthesized as multifunctional cholinesterase inhibitors. 8f was found to be a promising compound for further study. •A series of tacrine–coumarin hybrids were designed and synthesized.•All compounds showed better ChE inhibitory activity than galanthamine.•All compounds could inhibit Aβ aggregation and chelate metal ions.•Compound 8f was identified as the most promising candidate for further study.