Novel Yunaconitine Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors and Radical Scavenger: Design, Synthesis, in Vitro Cellular Evaluation, and Molecular Docking Study

Diabetes and oxidative stress are serious threats to human health and well-being. Protein tyrosine phosphatase 1B (PTP1B) and oxidative stress are important targets for managing diabetes. In this work, a series of new Yunaconitine derivatives (1-25) were synthesized and characterized; their inhibitory activity on PTP1B was first evaluated. Among them, derivatives 2 and 25 showed remarkable bioactivities with half-maximal inhibitory concentration values of 7.724 and 8.981 µM, respectively. Furthermore, derivatives 2 and 25 were evaluated for their free radical scavenging activity in vitro. Notably, derivative 25 exhibited significant free radical scavenging: 50% effective concentration = 58.76 µM. In addition, molecular docking analysis indicated that derivative 25 has a binding affinity for PTP1B and nicotinamide adenine dinucleotide phosphate-oxidase, with a binding energy of -5.03 and -2.66 kcal/mol, respectively. These results suggested that derivative 25 possesses great potential as a dual-target (PTP1B Inhibitor and radical scavenger) drug candidate for the treatment of diabetes.