Novel deoxyvasicinone derivatives as potent multitarget-directed ligands for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation

摘要

Abstract A series of multitarget ligands was designed by introducing several structurally diverse aminoacetamide groups at position 6 of the deoxyvasicinone group, with the aim of obtaining novel multifunctional anti-Alzheimer's disease agents using deoxyvasicinone as the substrate. In?vitro studies showed that almost all of the derivatives were potent inhibitors of human recombinant acetylcholinesterase ( h AChE) and human serum butyrylcholinesterase ( h BChE), with IC 50 values in the low nanomolar range, and exhibited moderate to high inhibition of A β 1?42 self-aggregation. In particular, compounds 12h , 12n , and 12q showed promising inhibitory activity for h AChE, with IC 50 values of 5.31?±?2.8, 4.09?±?0.23, and 7.61?±?0.53?nM, respectively. Compounds 12h and 12q also exhibited the greatest ability to inhibit h BChE, with IC 50 values of 4.35?±?0.32 and 2.35?±?0.14?nM, respectively. Moreover, enzyme kinetics confirmed that compound 12q caused a mixed type of AChE inhibition, by binding to both the active sites (PAS and CAS) of AChE. Remarkably, compound 12q also demonstrated the highest potential inhibitory activity for A β 1?42 self-aggregation (63.9?±?4.9%, 10?μM), and it was also an excellent metal chelator. Graphical abstract Display Omitted Highlights ? A series of novel deoxyvasicinone derivatives was synthesized. ? All derivatives showed excellent AChE and BChE inhibition activity. ? 12q had strong inhibition on AChE and BChE with IC 50 of 7.6 and 2.5?nM respectively. ? 12q had the greatest ability to inhibit A β 1?42 self-aggregation. ? 12q was also an excellent metal chelator.