Design, synthesis and biological evaluation of novel coumarin- N -benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease

摘要

Abstract Combining N -benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and A β (1–42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for h MAO-B, and it was also a good and balanced inhibitor to ChEs and h MAO-B (0.0373?μM for ee AChE; 2.32?μM for eq BuChE; 1.57?μM for h MAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit A β (1–42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit. Graphical abstract Display Omitted Highlights ? Novel coumarin- N -benzyl pyridinium hybrids with ChE and MAO-B inhibitory activities were designed. ? The most interesting hybrids inhibited AChE, MAO-B and self-induced β -amyloid (A β ) aggregation. ? Compound 7f showed a low neurotoxicity and good ability to inhibit A β (1–42) self-aggregation and cross the BBB.