Design and Development of Multi-target Directed 1,2,3-rriazole-dimethylaminoacryloyl-chromenone Derivatives with Potential use in Alzheimer's Disease

Abstract

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities were evaluated including acetylcholinesterase (AChE), butylcholinesterase (BuChE), and Aβ1−42 aggregation inhibition as well as neuroprotective effects and metal-chelating properties. The results indicated highly selective BuChE inhibitory activity with IC50 values of 21.71 µM for compound 10 h as the most potent compound. Besides, compound 10 h could inhibit self-induced Aβ1−42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition value, respectively. A Lineweaver–Burk plot and molecular modeling study also showed that compound 10 h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10 h was potent as a selective Cu2+ chelator. Thus, the designed scaffold could be considered as multifunctional agents for AD drug discovery developments.