Ultrasonic-promoted green synthesis of new 1, 3, 4-oxadiazoles: Anti-esophageal cancer evaluation, apoptosis morphology, DFT-calculations, in silico ADME, and molecular docking study

A new series of 3-acetyl-2, 3-dihydro-1, 3, 4-oxadiazole derivatives (8a-j) was synthesized under ultrasonic technique to explore their antiproliferative efficacy towards esophageal cancer. The chemical structures of the target derivatives were authenticated by different spectroscopic tools including ¹H and ¹³C NMR, FTIR, and Mass spectra. Using ultrasonic technique offers a simple operation, high scalable yields solvent-free, saving energy, and being agreement with green chemistry. The potential enantiomers found in the target derivatives were separated by an enantioselective HPLC technique. The HPLC analysis confirmed these derivatives are a racemic mixture. The target derivatives were tested against three esophageal cell lines (KYSE-150, EC9706, and SLMT-1). Interestingly, the separated (R)-(+) enantiomers are found to show high antiproliferative activity than their racemic and corresponding (S)-(−) forms. Among the (R)-(+) enantiomers, (R)-(+) 8a, (R)-(+) 8b, (R)-(+) 8c and (R)-(+) 8j showed high potency with a range of IC₅₀ values (1.68 ± 0.01 to 2.89 ± 0.11 μM) compared to cisplatin (IC₅₀ = 1.32 ± 0.01 to 2.63 ± 0.21 μM). By using a dual staining assay (annexin V-FITC and PI), the morphological data demonstrated that the most potent (R)-(+) enantiomers are able to trigger the apoptotic process of the aforementioned cells in a characteristic pathway compared with their effects in the NE-3 and HET-1A (normal cells). In DFT calculations, the findings revealed that the major (R)-(+) enantiomers found in the target derivatives (8a-j) were more stable compared to their corresponding (S)-(−) enantiomers. The ADME predictions of the most potent derivatives (8a, 8b, 8c, and 8j) displayed no Lipinski's violation as they have favorable oral drug-likeness criteria. The docking scores of the above derivatives with some targeting proteins (PDB ID: 2LEO, 5HZN, and 6DUK), confirmed favorable binding interactions with the aforementioned proteins. Overall, the most potent derivatives emerge as a promising candidate for esophageal cancer diseases.