Design, synthesis and biological evaluation novel 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives as AChE/MAO-B dual inhibitors for the treatment of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is an irreversible degenerative disorder of the brain, and there is no effective drug for it to date. Given its complex pathogenesis, the multi-target-directed ligands (MTDLs) strategy is considered as the promising approach against AD. Herein, a series of 3,4-dihydro-2(1H)-quinoline-O-carbamate derivatives was design and synthesized based on the MTDLs strategy. The in vitro biological results indicated that 3c displayed potent AChE/MAO-B dual inhibitor with IC50 value of 0.81 μM and 0.17 μM, respectively. Molecular modeling and molecular dynamics (MD) simulations offered possible insights into the AChE/MAO-B inhibition of 3c. Moreover, 3c showed good stability and BBB permeability, as well as favorable neuroprotective effects. In vivo evaluation exhibited that 3c impressively improved AlCl3-induced zebrafish AD model by elevating ACh, decreasing APP and inflammatory factors. Further, 3c effectively alleviated scopolamine-induced cognitive impairment model. Therefore, 3c is a promising AChE/MAO-B dual inhibitor for treating AD.