Novel chromanone-dithiocarbamate hybrids as multifunctional AChE inhibitors with β-amyloid anti-aggregation properties for the treatment of Alzheimer’s disease

Abstract

By connecting chromanone with dithiocarbamate moieties through flexible linkers, a series of hybrids as novel multifunctional AChE inhibitors have been designed and synthesized. Most of these compounds displayed strong and excellently selective inhibition to eeAChE as well as potent inhibition to self- and AChE-induced Aβ aggregation. Among them, compound 6c showed the best activity to inhibit eeAChE (IC50 = 0.10 μM) and AChE-induced Aβ aggregation (33.02% at 100 μM), and could effectively inhibit self-induced Aβ aggregation (38.25% at 25 μM). Kinetic analysis and docking study indicated that compound 6c could target both the CAS and PAS, suggesting that it was a dual binding site inhibitor for AChE. Besides, it exhibited good ability to penetrate the BBB and low neurotoxicity in SH-SY5Y cells. More importantly, compound 6c was well tolerated in mice (2500 mg/kg, po) and could attenuate the memory impairment in a scopolamine-induced mouse model. Overall, these results highlight 6c as a promising multifunctional agent for treating AD and also demonstrate that the dithiocarbamate is a valid scaffold for design of multifunctional AChE inhibitors.