Isolation, structural elucidation, and integrated biological and computational evaluation of antidiabetic labdane...

The phytochemical investigation of the EtOAc-soluble extract of the rhizomes of Curcuma zedoaria (Berg.) Roscoe led to the isolation of five labdane-type diterpenes, including a previously undescribed norditerpene, zedolabdin A (CZ1), and four known compounds (CZ2-CZ5). The structures of these compounds were elucidated using NMR, HR-ESI-MS, and IR spectroscopy, supported by comparisons with literature data. The anti-α-glucosidase evaluation revealed that all compounds exhibited potent inhibitory activity, with zerumin (CZ3) and coronarin C (CZ4) displaying the most potent inhibition, achieving IC₅₀ values of 6.2 μM and 3.0 μM, respectively, significantly lower than the positive control, acarbose (IC₅₀ = 190.6 μM). Molecular docking and dynamics studies identified coronarin C (CZ4) and zedolabdin A (CZ1) as the most promising candidates for α-glucosidase inhibition, exhibiting strong interactions and structural stability. In silico ADMET and toxicity predictions indicated that CZ1 and CZ4 had favorable safety and pharmacokinetic profiles, whereas CZ2 and CZ3 posed higher toxicity risks, with CZ3 also showing potential CYP3A4 inhibition. These findings suggest that CZ1 and CZ4 hold significant potential as novel α-glucosidase inhibitors (AGIs), supporting their further development as safe and effective antidiabetic agents. Moreover, the structural features of CZ1, particularly its hydrogen bonding and hydrophobic interactions, contribute to its enhanced binding affinity and stability within the enzyme's active site. Similarly, CZ4's favorable interactions and pharmacokinetic properties reinforce its potential as a promising AGI candidate, warranting further optimization for drug development.