Identification of Potential α‐Amylase and α‐Glucosidase Inhibitors From <i>Croton Macrostachyus</i> Stem Bark: Kinetic Studies and In Silico ADMET Prediction

Abstract

A total of 14 known bioactive compounds 1-14, were isolated from Croton macrostachyus, and characterized using chromatographic, spectroscopic techniques and in comparison, with reported literature data. Compounds 1, 2, and 13, 14 exhibited potent enzyme inhibition against α-amylase (IC₅₀; 9.41-9.50 µM), whereas 1, 2, 7, 9, 13, and 14 against α-glucosidase (IC₅₀ 8.25-8.32 µM), closely mirroring acarbose (9.34 and 7.96 µM, respectively) (p > 0.05). Mechanistic studies indicated diverse modes of inhibition, reflecting the structural heterogeneity of the isolates; smaller cyclohexane diepoxides (1 and 2) showed competitive inhibition, likely targeting the active sites. Whereas the bulky diterpenes exhibited noncompetitive and Mixed, suggesting interaction with allosteric binding sites. Molecular docking results supported the strong inhibitory data, with favorable binding energies (ranging from -9.7 to -7.1 kcal/mol for α-amylase and -8.1 to -6.5 kcal/mol for α-glucosidase). Compound 3 displayed the strongest predicted binding affinity (-9.7 kcal/mol) for α-amylase. Compounds 1, 2, and 10 demonstrated promising pharmacokinetic profiles with high oral absorption and limited penetration of the blood-brain barrier, suggesting their potential as systemically bio-available agents with reduced central nervous system side effects.