Rivastigmine and metabolite analogues with putative Alzheimer’s disease-modifying properties in a Caenorhabditis elegans model

Satish N. Dighe, Eugenio De la Mora, Stephen Chan, Srinivas Kantham, Gawain McColl, Jared A. Miles, Suresh Kumar Veliyath, B. Yogi Sreenivas, Zeyad D. Nassar, Israel Silman, Joel L. Sussman, Martin Weik, Ross P. McGeary, Marie Odile Parat, Xavier Brazzolotto, Benjamin P. Ross

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

The development of polyphenols as drugs for Alzheimer’s disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Aβ) fibrillation, protect against Aβ42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Aβ42, with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.

Original languageEnglish
Article number35
JournalCommunications Chemistry
Volume2
Issue number1
DOIs
Publication statusPublished or Issued - 1 Dec 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)
  • Environmental Chemistry
  • Materials Chemistry

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