LAUSR

Novel pyridine‐containing sultones were synthesized and evaluated for their cholinesterase (ChE) inhibitory activity. Most of compounds showed selective acetylcholinesterase (AChE) inhibitory activity. The structure‐activity relationship (SAR) showed: (i) the fused pyridine‐containing sultones increase AChE inhibition, series B>series A; (ii) for series A, the effect of the 4‐substituent on AChE activity, p‐>m‐ or o‐; (iii) for series B, a halophenyl group increase activity. Compound B4 (4‐(4‐chlorophenyl)‐2,2‐dioxide‐3,4,5,6‐tetrahydro‐1,2‐oxathiino[5,6‐h]quinoline) was identified as a selective AChE inhibitor (IC50=8.93 μM), and molecular docking studies revealed a good fit into TcAChE via hydrogen interactions between the δ‐pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non‐competitive (Ki=7.67 μM) AChE inhibition, nontoxicity and neuroprotective activity. In vivo studies confirmed that compound B4 could ameliorate the cognitive performance of scopolamine‐treated C57BL/6 J mice, suggesting a significant benefit of AChE inhibition for a disease‐modifying treatment of AD.