A series of Schiff bases derived from 4-methylsalicylic acid (4a–4s) were synthesized, 14 of which (4a–4h, 4j–4l, 4n, 4q, and 4s) were reported for the first time. All the synthesized compounds were evaluated for their immunosuppressive activities for the first time. Among them, compound 4o displayed the most potent biological activity against lymph node cells (IC50 = 1.02 lM for lymph node cells and IC50 = 2.17 lM for PI3Kc). The results of apoptosis and western-blot assays demonstrated that the immunosuppressive activity of compound 4o might be mediated by the inhibition of PI3K/AKT signaling pathway. Docking simulation was performed to position compound 4o into the PI3Kc structure active site to determine the probable binding model.