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

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

  • Eur J Med Chem. 2019 Oct 1:179:680-693. doi: 10.1016/j.ejmech.2019.06.088.
Divan G van Greunen 1,  C Johan van der Westhuizen 1,  Werner Cordier 2,  Margo Nell 2,  Andre Stander 3,  Vanessa Steenkamp 2,  Jenny-Lee Panayides 4,  Darren L Riley 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa.
  • 2 Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Bophelo Road, Pretoria, South Africa.
  • 3 Department of Physiology, Faculty of Health Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa.
  • 4 Pioneering Health Sciences, CSIR Biosciences, Meiring Naudé Road, Pretoria, South Africa. Electronic address: jpanayides@csir.co.za.
  • 5 Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Pretoria, South Africa. Electronic address: darren.riley@up.ac.za.
PMID: 31280020 DOI: 10.1016/j.ejmech.2019.06.088
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).

Keywords

Acetylcholinesterase; Alzheimer's disease; Benzylpiperidine; Butyrylcholinesterase; Carboxamide; Cytotoxicity; Donepezil.

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