Pentacyclic triterpenoids from Ziziphus jujuba Lamk. fruits as dual inhibitors of PTP1B and α-glucosidase: in vitro and in silico evaluations

Abstract

Ziziphus jujuba Lamk. (Táo Ta) is widely used in traditional Asian medicine as a superfruit. An ethanol extract of the Z. jujuba fruit exhibited remarkable inhibition against PTP1B and was isolated via bioassay-guided fractionation, resulting in the identification of fifteen active triterpenoids (1–15), namely, betulinic acid (1), corosolic acid (2), oleanolic acid (3), alphitolic acid (4), maslinic acid (5), 3-O-cis-p-coumaroyl alphitolic acid (6), 3-O-trans-p-coumaroyl alphitolic acid (7), 2-O-trans-p-coumaroyl alphitolic acid (8), 2-O-cis-p-coumaroyl alphitolic acid (9), ceanothic acid (10), zizyberanalic acid (11), trans-p-coumaroyl betulinic acid (12), betulonic acid (13), ursolic acid (14), and oleanonic acid (15). Their chemical structures were identified using nuclear magnetic resonance (NMR) spectroscopy and compared with those reported in other papers. Among the compounds tested for their effect against PTP1B and α-glucosidase, compounds 1–3 displayed the most potent inhibitory activity, with their IC₅₀ values ranging from 6.75 to 17.02 µM. Besides, compounds 4, 10, and 13 exhibited weak PTP1B inhibitory activity (IC₅₀ = 53.42 to 90.90 µM), while 5–15 showed no inhibitory effect at all tested concentrations. Additionally, molecular docking and molecular dynamics simulations were performed to evaluate the binding affinity of compounds 1–3 toward PTP1B and α-glucosidase, two key enzymes involved in glucose homeostasis. These interactions may contribute to the modulation of insulin signaling pathways and postprandial glucose levels, thereby improving glycemic control in diabetes. Moreover, in silico ADME and toxicity prediction further suggested that 1–3 possessed favorable pharmacokinetic properties and lower predicted toxicity. These findings provide a rational basis for using Ziziphus sourced from Vietnam to develop potential PTP1B and α-glucosidase dual inhibitors, warranting further investigations, and are considered the first report on the chemical and bioactive investigation of this species.