N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

Citations Over TimeTop 10% of 2010 papers

Abstract

Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimer's disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimer's brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.

Related Papers

• → One-Pot Synthesis of Symmetrical and Unsymmetrical Aryl Sulfides by Pd-Catalyzed Couplings of Aryl Halides and Thioacetates(2011)150 cited
• → Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction(2021)3 cited
• → ChemInform Abstract: Iron‐Catalyzed Coupling of Aryl Sulfamates and Aryl/Vinyl Tosylates with Aryl Grignards.(2015)
• → ChemInform Abstract: SYNTHESIS OF ARYL THIOCYANATES FROM ARYL ALKYL SULFIDES. CONVERSION OF UNACTIVATED ARYL HALIDES INTO ARYL THIOCYANATES(1983)
• → Aryl-Aryl and Aryl-Alkyl Coupling via N-Heterocycle C-H Activation(2005)