Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

Yuvixza Lizarme-Salas, Alexandra Daryl Ariawan, Ranjala Ratnayake, Hendrik Luesch, Angela Finch, Luke Hunter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

Original languageEnglish
Pages (from-to)2663-2670
Number of pages8
JournalBeilstein Journal of Organic Chemistry
Volume16
DOIs
Publication statusPublished - 28 Oct 2020
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Alzheimer's disease
  • Bioisostere
  • Conformational analysis
  • Gauche effect
  • Stereoselective synthesis

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