Conjugation of tacrine with genipin derivative not only enhances effects on AChE but also leads to autophagy against Alzheimer's disease.

ABSTRACT

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 Aß 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).