Chand_2016_J.Inorg.Biochem_163_266

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=0.57-0.78muM), which is comparable to the parent tacrine, and have good 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity (EC50=204-249muM) conferred by the hydroxybenzoyl-pyridone (HBP) moiety. Their chelating capacity towards redox-active and/or amyloid-beta-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, CL/CM=10, CM=10-6M), being able to form complexes with beta-phenol-keto coordination mode, and that this chelating ability is preserved in the TAC-HBP hybrids.