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

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 (<i>S</i>)-configured cyanomethyl derivative <b>50</b> 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.