In this study, we designed and synthesized a series of deoxyvasicinone-donepezil hybrids and determined whether they could be used as novel multitarget inhibitors for Alzheimer's disease. In vitro studies showed that most of the hybrids demonstrated moderate to potent inhibition of hAChE, BACE1, and Aß1-42 aggregation. In particular, the hybrids 10a, 10d, 11a, and 11j exhibited excellent inhibitory activities against hAChE (IC50 = 56.14, 5.91, 3.29, and 8.65 nM, respectively), BACE1 (IC50 = 0.834, 0.167, 0.129, and 0.085 µM, respectively), and Aß1-42 aggregation (IC50 = 13.26, 19.43, 9.26, and 5.41 µM, respectively). In addition, 10a and 11a exhibited very low cytotoxicity and showed remarkable neuroprotective activity against Aß1-42-induced damage in SH-SY5Y cells.
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Donepezil/chemical synthesis , Nootropic Agents/classification , Quinazolines/chemical synthesis , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Cell Line , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil/chemistry , Donepezil/therapeutic use , Drug Therapy, Combination , Humans , In Vitro Techniques , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Nootropic Agents/therapeutic use , Quinazolines/chemistry , Quinazolines/therapeutic use
