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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Sirtuin 5 (SIRT5) is an NAD+-dependent lysine deacylase with significant therapeutic potential.
• Developing potent and selective SIRT5 inhibitors remains a challenge for drug development.

Purpose of the Study:

• To systematically investigate SIRT5 inhibitors based on optimized balsalazide derivatives.
• To explore the impact of moieties targeting NAD+ co-factor binding sites on inhibitor potency.
• To enhance potency through reversible covalent binding strategies.

Main Methods:

• Utilized docking experiments to guide the design of novel inhibitor moieties.
• Synthesized a library of balsalazide-derived compounds with specific functionalizations.
• Evaluated inhibitory effects and determined IC50 values for synthesized compounds.
• Assessed structure-activity relationships and stereoselective preferences.

Main Results:

• Functionalization of balsalazide derivatives was generally tolerated and exhibited stereoselective preferences.
• The (S)-configured cyanomethyl derivative 50 demonstrated the highest potency with an IC50 of 27 µM.
• Compound 50's potency is comparable to existing established sirtuin 5 inhibitors.

Conclusions:

• The study provides valuable insights into the structure-activity relationships of heterotriaryl-based SIRT5 inhibitors.
• The findings support the potential of these derivatives as chemical tools and drug candidates.
• Further optimization of these SIRT5 inhibitors is feasible based on the presented structure-activity data.