A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC₅₀ = 0.29 ± 0.01 μM and 0.46 ± 0.02 μM, respectively), MAO-A (IC₅₀ = 8.2 ± 0.08 μM and 7.9 ± 0.07 μM, respectively) and MAO-B (IC₅₀ = 20.1 ± 0.16 μM and 43.8 ± 2.0% at 10 μM, respectively) inhibitory activities, moderate self-induced Aβ_1–42 aggregation inhibitory potency (35.4 ± 0.42% and 48.0 ± 1.53% at 25 μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.

设计，合成和评估了一系列5,6-二甲氧基苯并[ d ]异噻唑-3（2 H）-N-烷基苄胺衍生物，作为治疗阿尔茨海默氏病（AD）的潜在多功能剂。在体外测定法表明，大部分这些衍生物的有选择性的AChE抑制剂具有良好的多功能性质。其中，化合物11b和11d具有综合优势，具有良好的AChE（IC ₅₀  = 0.29±0.01μM和0.46±0.02μM），MAO-A（IC ₅₀  = 8.2±0.08μM和7.9±0.07μM）和MAO-B（IC ₅₀ 分别为20.1±0.16μM和10μM时的43.8±2.0％）抑制活性，中度自我诱导的_Aβ1–42聚集抑制能力（25μM时分别为35.4±0.42％和48.0±1.53％）和潜在的抗氧化活性。另外，这两种代表性化合物在体外显示出高的BBB渗透性。综上所述，这些多功能特性使11b和11d成为开发抗AD高效药物的有希望的候选者。