Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4-oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents

In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of 1H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC50 concentration range from 1.25 μM to 7.60 μM against the T cells, and the IC50 of positive control (csa) is 2.12 μM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC50 = 1.25 μM and 4.75 μM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.

A series of 1,3,4-oxadiazole derivatives (5a–5q, 6a–6q) have been first synthesized for their potential immunosuppressive activity. Among them, compound 5o and 6f displayed the most potential biological activity against T cells (IC50 = 1.25 μM and 4.75 μM for T cells) and the IC50 of positive control (csa) is 2.12 μM. The preliminary mechanism of compound 5o and 6f inhibition effects was also detected by flow cytometry (FCM) and the compounds exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 5o and 6f into the PI3Kγ structure active site to determine the probable binding model.Figure optionsDownload as PowerPoint slide