Novel Deoxyvasicinone-Donepezil Hybrids as Potential Multitarget Drug Candidates for Alzheimer's Disease

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 A beta(1-42) 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), BACEI (IC50 = 0.834, 0.167, 0.129, and 0.085 ktM, respectively), and A beta(1-42) aggregation (IC50 = 13.26, 19.43, 9.26, and 5.41 mu M, respectively). In addition, 10a and Ila exhibited very low cytotoxicity and showed remarkable neuroprotective activity against A beta(1-42)-induced damage in SH-SYSY cells.