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

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.

Supercomputer Modeling of Dual-Site Acetylcholinesterase (AChE) Inhibition

“…4. We have previously reported significant differences in estimated binding energies for the same compounds with these targets [12]. Here, we show that the target X-ray structure determines whether or not ligand poses reflect mixed-type inhibition.…”

“…Five X-ray structures of human AChE (PDB IDs 4EY4-4EY8, [3]) were used for docking. Rigid docking was performed with AutoDock 4.2.6 [8] as described earlier [12]. For flexible docking, Schrödinger Glide Induced Fit [13] was used with AChE as a target.…”

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease

“…Recently, we developed a new class of selective mammalian dual binding site AChE inhibitors with an acyclic and macrocyclic structure based on 1,3-bis[ω-(substituted benzylethylamino) alkyl]-6-methyluracils. In particular, novel 6-methyl uracil derivatives with ω-(substituted benzylethylamino) alkyl chains at the N atoms of the pyrimidine ring ( Figure 1 ) were reported as selective AChE inhibitors [ 25 , 26 ]. In these compounds, the substituted electron-withdrawing nitro-, trifluoro-, and fluoro-group benzylethylamino moieties were bridged to N atoms of the 6-methyluracil moiety via various polymethylene chains.…”

“…Some of the compounds demonstrated inhibitory power in the nanomolar range, 10,000 or more times higher than for human butyrylcholinesterase (hBChE). In vivo experiments showed that the most potent AChE inhibitor 1b improved working memory and significantly reduced the number and area of Aβ plaques in the brain of double transgenic mice expressing a chimeric mouse/human amyloid precursor protein and a mutant human presenilin 1 (APP/PS1) [ 25 , 26 ].…”

“…For compounds 2a – c , the polymethylene chains were varied, including tetra-, penta-, and hexamethylene chains. The choice of these chain lengths was based on our previous studies of compounds of similar structure, in particular, compounds 1a – f and the X-ray structure of 1b /hAChE complex [ 25 , 26 ], which indicated these to be optimal. In addition, the tertiary amino moiety and 6-methyluracil ring were replaced by a secondary amino moiety and a condensed uracil derivative, respectively, to obtain quinazoline-2,4-dione, as depicted for compounds 3 and 4a , b ( Figure 1 ).…”