Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease.

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 included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC value of 21.71 μM for compound as the most potent compound. Besides, compound could inhibit self-induced Aβ aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver-Burk plot and molecular modeling study showed that compound targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.