Glycosylation of Reduced Chalcones as Antidiabetic Compounds: Design, Synthesis, Characterisation, and in Silico Evaluation

Background/Objectives: Diabetes is a chronic metabolic disorder that leads to elevated blood sugar levels and has become a global concern. Though there has been an increase and evolution of antidiabetic drugs and therapeutics, they fall short of the desired efficacy and are often associated with adverse effects. This study explores reduced chalcone as a scaffold to design and synthesize potential antidiabetic drugs with improved efficacy through glycosylation and supplemented by in silico evaluation. Methodology: The 3ʹ-hydroxychalcone was initially reduced to 1-phenyl-3-(3ʹ-hydroxyphenyl)propane (2), followed by direct C-glycosylation at C-4ʹ under temperature control from -78 ℃ to room temperature (RT) and afforded the C-4ʹ glucosylated 1,3-diaryl propane. The first step in the mechanism was 3ʹ-O-glycosylation, and the resultant 3ʹ-O-a,b-glucose isomer mixture was isolated at -40 ℃. NMR spectroscopy and mass spectrometry were used to characterise and validate compound structures. These compounds' antidiabetic potentials and drug-likeness were evaluated through integrated computational techniques. Results: The main compound (5) showed no inhibitory activity against α-glucosidase and α-amylase. However, all the compounds showed higher probable antidiabetic activities and improved drug-likeness relative to aspalathin. Their binding affinity assessment showed they are potential ‘pan-binders’ with high binding affinities to several proteins implicated in the advancement of diabetes, including AKT, AMPK, GLUT4, SGLT2, and SIRT6. Furthermore, they were observed to stabilise within the binding pocket of AKT, underscored by strong hydrogen and hydrophobic bonds resulting in protein conformational changes, thus highlighting their antidiabetic potential. Conclusion: The synthesised glucosyl chalcones could be potential lead compounds for developing novel antidiabetic compounds.