Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, A beta(1-42) aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 mu M and 1.2 mu M, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 mu M and 3.7 mu M, respectively. In addition, compounds 5b and 5h could inhibit self-induced A beta(1-42) aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced A beta(1-42) aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.