Premium
Discovery of Potent Dual Binding Site Acetylcholinesterase Inhibitors via Homo‐ and Heterodimerization of Coumarin‐Based Moieties
Author(s) -
Pisani Leonardo,
Catto Marco,
De Palma Annalisa,
Farina Roberta,
Cellamare Saverio,
Altomare Cosimo D.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700282
Subject(s) - chemistry , acetylcholinesterase , coumarin , stereochemistry , fibrillogenesis , enzyme , active site , rational design , peptidomimetic , aché , binding site , biochemistry , fibril , peptide , nanotechnology , organic chemistry , materials science
Acetylcholinesterase (AChE) inhibitors still comprise the majority of the marketed drugs for Alzheimer's disease (AD). The structural arrangement of the enzyme, which features a narrow gorge that separates the catalytic and peripheral anionic subsites (CAS and PAS, respectively), inspired the development of bivalent ligands that are able to bind and block the catalytic activity of the CAS as well as the role of the PAS in beta amyloid (Aβ) fibrillogenesis. With the aim of discovering novel AChE dual binders with improved drug‐likeness, homo‐ and heterodimers containing 2 H ‐chromen‐2‐one building blocks were developed. By exploring diverse linkages of neutral and protonatable amino moieties through aliphatic spacers of different length, a nanomolar bivalent AChE inhibitor was identified (3‐[2‐({4‐[(dimethylamino)methyl]‐2‐oxo‐2 H ‐chromen‐7‐yl}oxy)ethoxy]‐6,7‐dimethoxy‐2 H ‐chromen‐2‐one ( 6 d ), IC 50 =59 n m ) from originally weakly active fragments. To assess the potential against AD, the disease‐related biological properties of 6 d were investigated. It performed mixed‐type AChE enzyme kinetics (inhibition constant K i =68 n m ) and inhibited Aβ self‐aggregation. Moreover, it displayed an outstanding ability to protect SH‐SY5Y cells from Aβ 1‐42 damage.