Design, synthesis and evaluation of benzo[cd]indol-2(1H)-one-donepezil hybrids as cholinesterase inhibitors and living cell imaging agents

A novel series of benzo[ cd ]indol-2(1 H )-one-donepezil (BIO-DPZ) hybrids (5a-m, 6a-k) was designed, synthesized and evaluated as cholinesterase inhibitors and living cell imaging agents. These compounds were potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compound 6a exhibited the strongest inhibitory activity against AChE with an IC 50 value of 0.16 μM. Compound 6i had the strongest inhibition of BuChE with an IC 50 value of 5.37 μM. Kinetic and molecular modeling studies showed that 6a bound both catalytic active site and peripheral anionic site of AChE. Compounds 6a and 6i both showed lower SH-SY5Y, HepG2 and HL-7702 cytotoxicity than the mitoxantrone. Promisingly, the most active compound, 6a, was successfully used in living SH-SY5Y cell imaging and had predictable lipophilicity and blood-brain-barrier permeation properties. These hybrids should undergo further systematic study in the treatment of Alzheimer's disease.