Abstract
This study presents the first comprehensive phytochemical analysis of Hydrangea macrophylla var. acuminata leaves, resulting in the isolation of 41 secondary metabolites, including four new compounds: one phenolic (3) and three bis-iridoid glycosides (30-32). The inhibitory activities of these compounds against PTP1B and α-glucosidase were evaluated. Among them, compound 12 exhibited the most potent dual inhibition, with IC(50) values of 8.0 ± 1.1 µM for PTP1B and 3.4 ± 0.2 µM for α-glucosidase. Compounds 8 and 9 showed notable α-glucosidase inhibitory activity, with IC(50) values of 21.9 ± 0.4 µM and 43.8 ± 2.1 µM, respectively. Enzyme kinetics and molecular docking studies revealed their inhibition mechanisms and binding interactions. This study is the first detailed phytochemical investigation of H. macrophylla var. acuminata and highlights its potential as a natural source of PTP1B and α-glucosidase inhibitors. These findings underscore the plant's promise for developing antidiabetic agents targeting PTP1B and α-glucosidase.