Synthesis, Molecular Docking, MD Simulation and Evaluation of Anticancer Activity of Novel 1,3,4-Oxadiazole Derivatives against Ehrlich Ascites Carcinoma (EAC) Cell Lines

Abstract

In this study, a new series of 1,3,4-oxadiazole derivatives (3a- 3h) was synthesized, characterized using various analytical techniques (FT-IR, 1H- and 13C-NMR, mass spectrometry), and tested for their effectiveness against Ehrlich's Ascites Carcinoma (EAC) cell lines in vitro. After 48 h of exposure to these test compounds, the EAC cells exhibited a dose-dependent reduction in their viability. Among the tested compounds, 3b and 3e demonstrated the most potent anticancer effects, with IC50 values of 352.69 μM and 177.44 μ M, respectively. Consequently, these compounds were chosen for further investigation into their mechanisms of action on EAC cell lines. The assessment included the induction of apoptosis and the analysis of DNA damage, which were evaluated using fluorescence staining and the comet assay. These assessments revealed distinctive apoptotic characteristics such as nuclear fragmentation, cytoplasmic shrinkage and DNA damage. As a result, these compounds hold promise as potential anticancer agents. The study also delved into the binding affinities of these compounds through molecular docking analysis, and the findings showed that compounds 3b and 3e exhibited a strong binding affinity with the receptor Transforming Growth Factor-Beta Receptor I (TGF-βRI) kinase (PDB ID: 1PY5), surpassing the reference compound 5-fluorouracil. Additionally, calculations related to Molecular Mechanics Generalized Born Surface Area (MM-GBSA) indicated favorable free binding energy. The compounds also displayed acceptable ADMET properties. To validate the stability of the bond between compounds 3b and 3e with the 1PY5 receptor, a molecular dynamics simulation lasting 100 ns was carried out. © 2024 World Scientific Publishing Company.