Novel Pyridine‐Containing Sultones: Structure‐Activity Relationship and Biological Evaluation as Selective AChE Inhibitors for the Treatment of Alzheimer's disease

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.

Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4‐oxadiazole derivatives

“…[37][38][39] Furthermore, different moieties reported the development of new pyridine hybrids for the cholinesterase inhibitory activity. [40][41][42][43][44][45][46] Various pyridine-based drugs have been or are used in the treatment of AD, such as tacrine (AChEI) and umibecestat (BACE-1 inhibitor). [42,47] In addition, there has been a lot of interest in the development of pyridine scaffolds for the treatment of AD.…”

“…[40][41][42][43][44][45][46] Various pyridine-based drugs have been or are used in the treatment of AD, such as tacrine (AChEI) and umibecestat (BACE-1 inhibitor). [42,47] In addition, there has been a lot of interest in the development of pyridine scaffolds for the treatment of AD. [48,49] Thiazoles are another class of nitrogen heteroaromatics that are prominently studied.…”