Seven tacrine/CHR21 conjugates have been designed and synthesized. Compound 8-7 was confirmed as the most active AChE inhibitor with IC₅₀ value of 5.8 ± 1.4 nM, which was 7.72-fold stronger than tacrine. It was also shown as a strong BuChE inhibitor (IC₅₀ value of 3.7 ± 1.3 nM). 8-7 was clearly highlighted not only as an excellent ChEs inhibitor, but also as a good modulator on protein expression of AChE, p53, Bax, Bcl-2, LC3, p62, and ULK, indicating its functions against programmed cell apoptosis and decrease of autophagy. 8-7 significantly reversed the glutamate-induced dysfunctions including excessive calcium influx and release from internal organelles, overproduction of nitric oxide (NO) and Aβ high molecular weight oligomer. This compound can penetrate blood−brain barrier (BBB). The in vivo hepatotoxicity assay indicated that 8-7 was much less toxic than tacrine. Altogether, these data strongly support that 8-7 is a potential multitarget-directed ligand (MTDL) for treating Alzheimer’s disease (AD).

已经设计并合成了七种他克林/ CHR21共轭物。确认化合物8-7是最具活性的AChE抑制剂，IC ₅₀值为5.8±1.4 nM，比他克林强7.72倍。它还显示为强BuChE抑制剂（IC ₅₀值为3.7±1.3 nM）。明确强调了8-7不仅是出色的ChEs抑制剂，而且还是AChE，p53，Bax，Bcl-2，LC3，p62和ULK蛋白质表达的良好调节剂，表明其对程序性细胞凋亡和减少的功能自噬。8-7显着逆转了谷氨酸诱导的功能障碍，包括过多的钙流入和从内部细胞器释放，一氧化氮（NO）和Aβ高分子量低聚物的过量生产。该化合物可以穿透血脑屏障（BBB）。在体内的肝毒性试验表明，8-7比他克林毒性更小。总体而言，这些数据强烈支持8-7是治疗阿尔茨海默氏病（AD）的潜在多靶标配体（MTDL）。