Paper Report for: Lin_2012_Chem.Res.Toxicol_25_1462
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Title: Synthesis and evaluation of a new series of tri-, di-, and mono-N-alkylcarbamylphloroglucinols as bulky inhibitors of acetylcholinesterase Lin MC, Lin GZ, Shen YF, Jian SY, Hsieh DK, Lin J, Lin G Ref: Chemical Research in Toxicology, 25:1462, 2012 : PubMed
1,3,5-Tri-N-alkylcarbamylphloroglucinols (1-4) are synthesized as a new series of bulky inhibitors of acetylcholinesterase that may block the catalytic triad, the anionic substrate binding site, and the entrance of the enzyme simultaneously. Among three series of phloroglucinol-derived carbamates, tridentate inhibitors 1,3,5-tri-N-alkylcarbamylphloroglucinols (1-4), bidentate inhibitors 3,5-di-N-n-alkylcarbamyloxyphenols (5-8), and monodentate inhibitors 5-N-n-alkylcarbamyloxyresorcinols (9-12), tridentate inhibitors 1-4 are the most potent inhibitors of mouse acetylcholinesterase. When different n-alkylcarbamyl substituents in tridentate inhibitors 1-4 are compared, n-octylcarbamate 1 is the most potent inhibitor of the enzyme. All inhibitors 1-12 are characterized as the pseudo substrate inhibitors of acetylcholinesterase. Thus, tridentate inhibitors 1-4 are supposed to be hydrolyzed to bidentate inhibitors 5-8 after the enzyme catalysis. Subsequently, bidentate inhibitors 5-8 and monodentate inhibitors 9-12 are supposed to yield monodentate inhibitors 9-12 and phloroglucinol, respectively, after the enzyme catalysis. This means that tridentate inhibitors 1-4 may act as long period inhibitors of the enzyme. Therefore, inhibitors 1-4 may be considered as a new methodology to develop the long-acting drug for Alzheimer's disease. Automated dockings of inhibitor 1 into the X-ray crystal structure of acetylcholinesterase suggest that the most suitable configuration of inhibitor 1 to the enzyme binding is the (1,3,5)- (cis,trans,trans)-tricarbamate rotamer. The cis-carbamyl moiety of this rotamer does not bind into the acetyl group binding site of the enzyme but stretches out itself to the entrance. The other two trans-carbmayl moieties of this rotamer bulkily block the tryptophan 86 residue of the enzyme.
        
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Lin MC, Lin GZ, Shen YF, Jian SY, Hsieh DK, Lin J, Lin G (2012) Synthesis and evaluation of a new series of tri-, di-, and mono-N-alkylcarbamylphloroglucinols as bulky inhibitors of acetylcholinesterase Chemical Research in Toxicology25: 1462-71
Lin MC, Lin GZ, Shen YF, Jian SY, Hsieh DK, Lin J, Lin G (2012) Chemical Research in Toxicology25: 1462-71