Department of Pharmacy, Fuyang People's Hospital of AHMU, Anhui Medical University, Fuyang, 236000, China.
School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
ChemMedChem. 2021 Oct 15;16(20):3189-3200. doi: 10.1002/cmdc.202100272. Epub 2021 Jun 22.
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 =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 (K =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.
新型含吡啶的砜被合成并评估其对胆碱酯酶（ChE）的抑制活性。大多数化合物表现出对乙酰胆碱酯酶（AChE）的选择性抑制活性。构效关系（SAR）表明：（i）稠合的含吡啶的砜增加 AChE 抑制作用，B 系列＞A 系列；（ii）对于 A 系列，4-取代基对 AChE 活性的影响，p-＞m-或 o-；（iii）对于 B 系列，卤代苯基增加活性。化合物 B4（4-（4-氯苯基）-2,2-二氧化-3,4,5,6-四氢-1,2-氧杂噻嗪[5,6-h]喹啉）被鉴定为选择性 AChE 抑制剂（IC =8.93 μM），分子对接研究表明，δ-吡啶砜支架与 Asp72、Ser122、Phe288、Phe290 和 Trp84 之间通过氢键相互作用与 TcAChE 很好地契合。化合物 B4 表现出可逆和非竞争性（K =7.67 μM）的 AChE 抑制作用、非毒性和神经保护活性。体内研究证实，化合物 B4 可改善东莨菪碱处理的 C57BL/6 J 小鼠的认知性能，表明 AChE 抑制对 AD 疾病修饰治疗有显著益处。
