Kratomines A-E, a series of diastereomeric indole alkaloids with α-glucosidase inhibition from the leaves of Mitragyna speciosa.

Phytochemical investigation of Mitragyna speciosa Korth. leaves yielded five previously undescribed indole alkaloids, kratomines A-E (1-5), together with four known analogues (6-9). Their structures and absolute configurations were established using 1D and 2D NMR, single-crystal X-ray diffraction, and chemical derivatization. The isolated compounds exhibited moderate α-glucosidase inhibitory activity with IC50 values of 0.172-0.351 mM. To further elucidate the structure-activity relationship, the main alkaloid named mitragynine (6), was chemically modified to produce some derivatives. Although these derivatives did not enhance the inhibitory potency, kinetic study revealed distinct inhibitory mechanism, suggesting that subtle structural changes may modulate the enzyme-inhibitor interaction. Kinetic analyses revealed that kratomine D (4), mitragynine (6), and 7-hydroxymitragynine (6c) inhibited α-glucosidase through noncompetitive, uncompetitive, and mixed mechanisms, respectively.