In:
ChemMedChem, Wiley, Vol. 16, No. 20 ( 2021-10-15), p. 3189-3200
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 (IC 50 =8.93 μM), and molecular docking studies revealed a good fit into Tc AChE via hydrogen interactions between the 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 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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.202100272
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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