A series of 3-amino-6,7-dimethoxycoumarins conjugated with the N-benzylpyridinium moiety through an amide-bond linkage was synthesized and evaluated for their acetylcholinesterase inhibitory activity. A number of the benzylpyridinium derivatives exhibited potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3-difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 +/- 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme.
Khunnawutmanotham N, Laongthipparos C, Saparpakorn P, Chimnoi N, Techasakul S (2018) Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase Beilstein J Org Chem14: 2545-2552
Khunnawutmanotham N, Laongthipparos C, Saparpakorn P, Chimnoi N, Techasakul S (2018) Beilstein J Org Chem14: 2545-2552