Abstract
In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.
Highlights
Alzheimer disease (AD) is the most common neurodegenerative disorder spread worldwide and is estimated to affect around 90 million people by 2050 [1]
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
3 of uracil derivative, respectively, to obtain quinazoline-2,4-dione, as depicted for compounds 3 and 4a,b. We expanded this series ofthe inhibitors based on 1,3-bis[ω-(substituted
Summary
Alzheimer disease (AD) is the most common neurodegenerative disorder spread worldwide and is estimated to affect around 90 million people by 2050 [1]. 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]-6methyluracils. 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.
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