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

  1. Yuvixza Lizarme-SalasORCID Logo,
  2. Alexandra Daryl Ariawan,
  3. Ranjala RatnayakeORCID Logo,
  4. Hendrik Luesch,
  5. Angela FinchORCID Logo and
  6. Luke HunterORCID Logo

Submitting author affiliation: University of New South Wales, Sydney, Australia

Beilstein Arch. 2020, 202093. https://doi.org/10.3762/bxiv.2020.93.v1

Published 12 Aug 2020

  • Preprint

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.

Keywords: bioisostere; stereoselective synthesis; conformational analysis; gauche effect; Alzheimer's disease

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When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information:

Lizarme-Salas, Y.; Ariawan, A. D.; Ratnayake, R.; Luesch, H.; Finch, A.; Hunter, L. Beilstein Arch. 2020, 202093. doi:10.3762/bxiv.2020.93.v1

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© 2020 Lizarme-Salas et al.; licensee Beilstein-Institut.
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