Design, synthesis and cholinesterase inhibitory activity of quinoline-polyamine conjugates

A series of quinoline-polyamine conjugates (8a−8n) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs).  Some of these compounds had potent ChEs inhibitory activity with IC₅₀ values at micromolar range.  Compound 8n exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC₅₀ value of 8.78 μmol·L⁻¹, and compound 8i showed the most potent inhibition on butyrylcholinesterase (BChE) with IC₅₀ value of 1.60 μmol·L⁻¹ which was slightly better than rivastigmine.  The structure-activity relationship revealed that the chain length of polyamine and linker played important roles for inhibitory activity.  Molecular modeling studies showed that 8i targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of cholinesterases.