6‐Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease

Citations Over TimeTop 10% of 2015 papers

Abstract

Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain.

Related Papers

• → Comparison of methods used for the determination of cholinesterase activity in whole blood(2008)20 cited
• → Blood markers in Alzheimer disease: Subnormal acetylcholinesterase and butyrylcholinesterase in lymphocytes and erythrocytes(1994)40 cited
• → The role of cholinesterases in chagas disease(2022)3 cited
• → In-vitro Evaluation of Acetylcholinesterase and Butyrylcholinesterase Inhibitory Activities of Antlion Larvae Extracts(2021)2 cited
• → The alterations in cholinesterase activity (AChE and BChE) among the frequent cellphone users and non users: A pilot study(2011)