Design, synthesis and evaluation of tacrine-methoxybenzene hybrids as cholinesterases inhibitors

A series of tacrine-methoxybenzene hybrids (5a−5i) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs).  All the compounds had better ChEs inhibitory activities than tacrine with IC₅₀ values at the nanomolar range.  Compound 5h exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC₅₀ value of 6.74 nmol·L⁻¹ and compound 5f showed the most potent inhibition on butyrylcholinesterase with IC₅₀ value of 3.83 nmol·L⁻¹.  Kinetic and molecular modeling studies showed that these hybrids targeted both the catalytic active site and the peripheral anionic site of AChE.