Oxadiazole-Functionalized Glycerol Ether Lipids: Synthesis, Biological Evaluation, and In Silico Studies

A new library of nature-derived ether lipid analogs constructed on the 1-O-alkyl-sn-glycerol (1-O-AKG) backbone was strategically developed and synthesized. Structural diversification was accomplished by introducing a phenyl-oxadiazole unit in combination with a medium-chain fatty acid fragment and examining their biological performance. Thirteen novel 1-O-AKG derivatives were prepared, purified, and structurally confirmed through ¹H NMR, ¹³C NMR, fourier transform infrared (FT-IR), and high-resolution mass spectrometry (HRMS) analyses. The antioxidant capacity of the synthesized compounds was examined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and thiobarbituric acid reactive species (TBARS) assays, along with differential scanning calorimetry (DSC) studies. Several derivatives demonstrated strong free-radical scavenging ability comparable to standard antioxidants. Antiproliferative activity was evaluated against three human cancer cell lines, where molecules exhibited moderate to good cytotoxic effects. To gain mechanistic insight, molecular docking analysis of the most active compounds was performed against the Wnt3 protein, revealing favorable binding interactions that suggest possible association with Wnt-related signaling pathways.