A series of quinazolin-4(3H)-one derivatives was designed through scaffold-hopping strategy and synthesized as novel multifunctional anti-AD agents demonstrating both cholinesterase inhibition and anti-inflammatory activities. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated, and the enzyme kinetics study as well as detailed binding mode via molecular docking were performed for selected compounds. MR2938 (B12) displayed promising AChE inhibitory activity with an IC₅₀ value of 5.04 μM and suppressed NO production obviously (IC₅₀ = 3.29 μM). Besides, it was able to decrease the mRNA levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CCL2 at 1.25 μM. Further mechanism study suggested that MR2938 suppressed the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. All these results indicate that MR2938 is a good starting point to develop multifunctional anti-AD lead compounds.

通过支架跳跃策略设计了一系列 quinazolin-4(3 H )-one 衍生物，并将其合成为新型多功能抗 AD 药物，展示了胆碱酯酶抑制和抗炎活性。评估了它们对乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 的抑制活性，并对所选化合物进行了酶动力学研究以及通过分子对接的详细结合模式。MR2938 ( B12 ) 显示出良好的 AChE 抑制活性，IC ₅₀值为 5.04 μM，并且明显抑制 NO 产生 (IC ₅₀ = 3.29 微米）。此外，它能够在 1.25 μM 时降低促炎细胞因子 IL-1β、TNF-α、IL-6 和 CCL2 的 mRNA 水平。进一步的机制研究表明，MR2938 通过阻断 MAPK/JNK 和 NF-κB 信号通路来抑制神经炎症。所有这些结果表明 MR2938 是开发多功能抗 AD 先导化合物的良好起点。