Discovery of Novel SIRT1 Activators Based on 2,3-Dihydro-1,5-benzodiazepines and a Study of Their Antidiabetic Properties

Abstract The sirtuin 1 (SIRT1) enzyme plays a pivotal role in regulating cellular homeostasis, making it a high-priority target for treating abolic and age-related diseases. We report the synthesis and biological evaluation of a novel series of 1,5-benzodiazepine derivatives designed as potential SIRT1 activators. High-throughput screening using recombinant SIRT1 protein in a luminescent assay was employed, identifying 2,4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepines as superior activators, whereas coumarin chalcones inhibit SIRT1 activity. Using molecular docking against hSIRT1, we found that the activators fit perfectly within a hydrophobic pocket of the allosteric site, being anchored by a conventional hydrogen bond to Asn226 and stabilized by π-alkyl interactions with Ile227. Beyond these structural studies, we evaluated the antidiabetic potential of one of the derivatives, known as pyrabentin. The effectiveness of pyrabentin under 8-week oral administration at 100 mg/kg per os in reducing glucose intolerance, insulin resistance, and obesity in animals with the metabolic memory model at the level of action of the comparator drug metformin has been proven. Finally, our findings demonstrate that the heterocyclic substitutions of the 1,5-benzodiazepine moiety are critical determinants of their interaction with the STAC-binding domain, providing a structure-based rationale for more efficient SIRT1 activators for the treatment of type 2 diabetes.