Abstract
The aim of this research is the synthesis of benzimidazole-1,3,4-oxadiazole derivatives that could be potential anticancer leads inhibiting VEGFR2. The compounds were evaluated for their cytotoxicity against cancer cell lines PANC-1, MCF-7, and A549 using the MTT assay. Two different normal cell lines (hTERT-HPNE and CCD-19Lu) were used to calculate the selectivity indices of the compounds. Compound 4r showed the highest anticancer activities, with IC50 = 5.5, 0.3, and 0.5 μM against the PANC-1, A549, and MCF-7 cell lines, respectively. Also, compounds 4r and 4s were further evaluated for their inhibitory activity against VEGFR2. VGFRA immunolocalizations of compounds 4r and 4s were visualized by the VEGFA immunofluorescent staining method. Molecular docking studies have proven that, as in sorafenib, compounds 4r and 4s show hydrogen bond formation with Asp1046 and Cys919 and hydrophobic interactions with other active site amino acids. Molecular dynamics simulations were carried out for compounds 4r and 4s to examine the stability and behavior of the protein-ligand complex obtained from molecular docking under in silico physiological conditions. An in silico ADME investigation was undertaken to confirm the druglikeness of the synthesized compounds. Furthermore, the stable geometries of the ligands were determined through the application of density functional theory (DFT). The optimized geometries were confirmed to correspond to true minima, as no imaginary frequencies were observed in the vibration frequency survey. The rotations of the thio and benzimidazole groups with respect to the 1,3,4-oxadiazole rings are 180 deg, and the molecules are planar.