Work

Balsalazide-Derived Heterotriaryls as Sirtuin 5 Inhibitors: A Case Study of a Reversible Covalent Inhibition Strategy

Year: 2025

Type: article

Abstract: Sirtuin 5 is an NAD+-dependent lysine deacylase that is involved in various biological processes and has emerged as a promising target for pharmaceutical therapies. The development of highly potent and subtype-selective sirtuin 5 inhibitors for their application as chemical tools and drug candidates still poses a significant challenge. Based on our own optimized balsalazide-derived sirtuin 5 inhibitors, this work presents a systematic investigation of the inhibitory effects of derivatives with moieties that were guided by docking experiments to target the nicotinamide ribose vicinal hydroxy groups of the essential co-factor NAD+ via reversible covalent binding to potentially enhance their potency. Our results show that functionalizations with these moieties were tolerated to some extent and possessed a distinct stereo-selective preference. The (S)-configured cyanomethyl derivative 50 with an IC50 of 27 µM emerged from our synthesized library of compounds as the most potent functionalized inhibitor and lies in a similar potency range to other established sirtuin 5 inhibitors. Our findings offer a deeper insight into the structure–activity relationships of our balsalazide-derived heterotriaryl-based sirtuin 5 inhibitors and thus could provide an avenue for further optimizations in the future.

Source: Molecules

DOI: 10.3390/molecules30183821

Authors: Ricky Wirawan, Simon A. Huber, Thomas Wein, Franz Bracher

Institution: Ludwig-Maximilians-Universität München

Language: English

Topic: Sirtuins and Resveratrol in Medicine

Subfield: Geriatrics and Gerontology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,258