Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease

ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100272. Online ahead of print.ABSTRACTNovel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B > series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 μM), which was nicely fallen into Tc AChE via hydrogen interactions between δ-pyridylsultone scaffold with Asp72, Ser122, Phe288, Phe290 and Trp84. Compound B4 showed reversible and non-competitive ( K i = 7.67 µM) AChE inhibition, nontoxicity and remarkable neuro-protective activity. In vivo studies confirmed that compound B4 significantly ameliorates performances of scopolamine-treated C57BL/6J mice, suggesting a significant benefit of AChE inhibition for a disease-modifying treatment of AD.PMID:34036731 | DOI:10.1002/cmdc.202100272
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research