Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti-Alzheimer's agents: AChE inhibition, antioxidant activity and metal chelating capacity

Abstract

Three novel potentially site-activated multitarget tacrine-(hydroxybenzoyl-pyridone) (TAC-HBP) hybrids were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors, antioxidants and biometal chelators. All of them are dual-binding site AChE inhibitors with activity in sub-micromolar range (IC₅₀=0.57-0.78μM), which is comparable to the parent tacrine, and have good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (EC₅₀=204-249μM) conferred by the hydroxybenzoyl-pyridone (HBP) moiety. Their chelating capacity towards redox-active and/or amyloid-β-binding metal ions (Fe(III), Cu(II)), Zn(II)) was evaluated by using 2'-hydroxy-4'-methoxybenzoyl-2-pyridone derivative as a model compound in 30% w/w DMSO/water medium. It was proved that the HBP moiety acts as a moderate/good chelator of these biometals (pFe=13.9, pCu=6.0 and pZn=6.0 at pH6.0, C_L/C_M=10, C_M=10^-6M), being able to form complexes with β-phenol-keto coordination mode, and that this chelating ability is preserved in the TAC-HBP hybrids.

Keywords: Anti-AChE activity; Anti-neurodegeneratives; Anti-oxidant activity; Hydroxybenzoyl-pyridones; Metal chelation; Tacrine.