Discovery of novel 2,6-disubstituted pyridazinone derivatives as acetylcholinesterase inhibitors

2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BuChE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.

A series of pyridazinones was evaluated and optimized for their AChE inhibitory activity in an enzyme assay. High AChE/BuChE selectivity of the lead compound was achieved.Figure optionsDownload as PowerPoint slideHighlights
► Pyridazinone derivatives as novel AChE inhibitors were synthesized.
► High AChE/BuChE selectivity of the lead compound was achieved.
► Novel 6-ortho-tolylamino substitution which involved in π–π stacking and hydrophobic ‘Magic Methyl’ effect was investigated.
► Novel 4-substituted piperidine motif for CAS binding was reported.
► Docking study revealed that these pyridazinone derivatives might function as dual binding site inhibitors.