5-((3-Amidobenzyl)oxy)nicotinamides as SIRT2 Inhibitors: A Study of Constrained Analogs

Teng Ai, Daniel Wilson, Liqiang Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


SIRT2 is a member of NAD+-dependent sirtuins and its inhibition has been proposed as a promising therapeutic approach for treating human diseases, including neurodegenerative diseases, cancer, and infections. Expanding SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide core structure, we have synthesized and evaluated constrained analogs and selected stereoisomers. Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications.

Original languageEnglish (US)
Article number7655
Issue number22
StatePublished - Nov 2023

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© 2023 by the authors.


  • constrained inhibitors
  • SIRT1
  • SIRT2
  • SIRT3
  • sirtuin inhibitors
  • sirtuins

PubMed: MeSH publication types

  • Journal Article

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