对人丁酰胆碱酯酶 (hBChE) 抑制剂作为阿尔茨海默病 (AD) 治疗药物的研究具有重大前景，可以解决症状缓解和疾病进展问题。在寻找具有选择性 BChE 抑制模式的新候选药物时，我们专注于天然存在的模板结构，特别是石蒜科生物碱的 carltonine 型。在此，我们探索了一系列基于 3- 和 4-苄氧基-苄氨基化学型构建创新化学支架的化合物。值得注意的是，化合物 28 (hBChE IC50 = 0.171 ± 0.063 μM) 和 33 (hBChE IC50 = 0.167 ± 0.018 μM) 成为顶级 hBChE 抑制剂。计算机模拟阐明了这些化合物在 hBChE 中的结合模式。 CNS 可用性是使用 BBB 评分算法预测的，并通过最有效的衍生物的体外渗透性评估得到证实。还检查了化合物 33 的水溶性、微粒体和血浆稳定性。化学信息学分析验证了这些 hBChE 抑制剂可口服给药，表明胃肠道吸收良好，符合 Lipinski 和 Veber 的规则。通过对人神经母细胞瘤 (SH-SY5Y) 和肝细胞癌 (HepG2) 细胞系进行细胞毒性测试，进行了安全性评估，这对于 AD 治疗中典型的长期给药至关重要。本期刊版权所有 © 英国皇家化学学会。

The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds 28 (hBChE IC50 = 0.171 ± 0.063 μM) and 33 (hBChE IC50 = 0.167 ± 0.018 μM) emerged as top-ranked hBChE inhibitors. In silico simulations elucidated the binding modes of these compounds within hBChE. CNS availability was predicted using the BBB score algorithm, corroborated by in vitro permeability assessments with the most potent derivatives. Compound 33 was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these hBChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines.This journal is © The Royal Society of Chemistry.