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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Nov 25

PMID 38005376

Authors

Teng Ai

Daniel J Wilson

Liqiang Chen

Affiliations

Soon will be listed here.

Abstract

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 ()-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.

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