Synthesis and biological evaluation of diastereomeric natural products: Discovery of a novel synergistic combination for α-glucosidase inhibition.

Cabraleahydroxylactone (1a) and 3-epi-cabraleahydroxylactone (1b) are naturally diastereomers found in Aglaia abbreviata, known for their biological potential. While 1b has been synthesized and studied as an anti-diabetic agent, the activity of 1a remained unexplored. This study successfully enhanced 1a in the reaction mixture through the reduction of cabralealactone (2), increasing its ratio from trace levels to 9.5:1 (1b:1a). Molecular docking revealed distinct binding interactions of these diastereomers with α-glucosidase allosteric sites, suggesting a drug synergy mechanism. Kinetic studies confirmed non-competitive inhibition by both compounds, with 1a exhibiting superior binding affinity (lower Ki). Synergistic α-glucosidase inhibition was observed in specific 1b:1a ratios (9:1, 8:2, 2:8, and 1:9). Furthermore, these combinations displayed reduced hemolytic toxicity compared to individual compounds. The findings highlight the 1b:1a diastereomeric combination as a promising lead for anti-diabetic drug development, offering enhanced efficacy and safety through synergistic interactions.