title: 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, CL/CM=10, CM=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.
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: Karam
authors.initials: K
authors.lastname: Chand
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; South Valley University, Faculty of Science, Chemistry Department, 83523 Qena, Egypt.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Alsoghier
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: silvia.chaves@tecnico.ulisboa.pt.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Chaves
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: masantos@ist.utl.pt.
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D013619:Tacrine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D019476:Insect Proteins; D011728:Pyridones; D013619:Tacrine; D000110:Acetylcholinesterase
keywords: Anti-AChE activity; Anti-neurodegeneratives; Anti-oxidant activity; Hydroxybenzoyl-pyridones; Metal chelation; Tacrine