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Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease.

Abstract：

:A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ± 0.07 μM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ± 1.25 and 5.94 ± 1.08 μM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

van Greunen DG,Johan van der Westhuizen C,Cordier W,Nell M,Stander A,Steenkamp V,Panayides JL,Riley DL

doi

10.1016/j.ejmech.2019.06.088

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

680-693

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30615-4

journal_volume

179

pub_type

杂志文章

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