Pyranotacrines as prospective multi-target compounds against Alzheimer's disease

Abstract

A series of tacrine-based 4-H-pyran derivatives were synthesized and biologically estimated as multifactorial ligands against Alzheimer's disease. Pyranotacrines were characterized by having the main core tacrine (ChE inhibition) and tetrahydro-4H-pyran (calcium channel blockers and β-amyloid activity). Among the series, compound 6c displayed a well-balanced multi-targeted activity against Alzheimer's disease and it was a potent AChE inhibitor with IC₅₀ = 0.06 ± 0.005 μM, approximately 3-folds more active than tacrine as a reference drug. Kinetic analysis and molecular docking displayed that 6c targeted both key binding regions of AChE. Moreover, its inhibitory activity against BuChE was 8-folds more active than rivastigmine with IC₅₀ = 0.09 ± 0.016 μM. Compound 6c showed blockade power of 46 % as a Ca²⁺ blockade agent and strong inhibition activity against β-amyloid with IC₅₀ = 1.09 ± 0.05 μM (71 % aggregation inhibition). Additionally, it showed higher anti-oxidative activity with 10.36 TE and chelating anchors activity for metal ions. The safety of 6c towards SH-SY5Y normal cells and HepG2 cancer cells was interesting with safety index ratio (Si = 2273), in addition to its BBB permeability and pharmacokinetic profile.