2,5-Bis(2,2,2-trifluoroethoxy)phenyl-tethered 1,3,4-Oxadiazoles Derivatives: Synthesis, In Silico Studies, and Biological Assessment as Potential Candidates for Anti-Cancer and Anti-Diabetic Agent

In the present work, a series of new 1-{5-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-3-acetyl-2-aryl-2H/methyl derivatives were synthesized through a multistep reaction sequence. The compounds were synthesized by the condensation of various aldehydes and acetophenones with the laboratory-synthesized acid hydrazide, which afforded the Schiff's bases. Cyclization of the Schiff bases yielded 1,3,4-oxadiazole derivatives. By spectral analysis, the structures of the newly synthesized compounds were elucidated, and further, their anti-cancer and anti-diabetic properties were investigated. To examine the dynamic behavior of the candidates at the binding site of the protein, molecular docking experiments on the synthesized compounds were performed, followed by a molecular dynamic simulation. ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) prediction revealed that most of the synthesized compounds follow Lipinski's rule of 5. The results were further correlated with biological studies. Using a cytotoxic assay, the newly synthesized 1,3,4-Oxadiazoles were screened for their in vitro cytotoxic efficacy against the LN229 Glioblastoma cell line. From the cytotoxic assay, the compounds 5b, 5d, and 5m were taken for colony formation assay and tunnel assay have shown significant cell apoptosis by damaging the DNA of cancer cells. The in vivo studies using a genetically modified diabetic model, Drosophila melanogaster, indicated that compounds 5d and 5f have better anti-diabetic activity among the different synthesized compounds. These compounds lowered the glucose levels significantly in the tested model.

Automated summary

In this study, a series of new 1,3,4-oxadiazole derivatives were synthesized and their structures were characterized. The compounds were found to exhibit anti-cancer and anti-diabetic properties. Molecular docking and dynamic simulation studies were performed to investigate the binding behavior of the candidates. In vitro and in vivo experiments confirmed the cytotoxic and anti-diabetic efficacy of some compounds.