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  • Title: Novel Pyridine-Containing Sultones: Structure-Activity Relationship and Biological Evaluation as Selective AChE Inhibitors for the Treatment of Alzheimer's disease.
    Author: Zhang H, Wu C, Chen X, Zhang Z, Jiang X, Qin HL, Tang W.
    Journal: ChemMedChem; 2021 Oct 15; 16(20):3189-3200. PubMed ID: 34036731.
    Abstract:
    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.
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