2-(R-benzylthio)-5-((5-phenyl-2 H -tetrazol-2-yl)methyl)-1,3,4-oxadiazoles: Synthesis, DFT calculations, molecular docking studies and biological evaluation for anticancer activity

Novel 2-(R-benzylthio)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazoles were synthesized and evaluated for anticancer activity using spectroscopic, computational, and in vitro methods. 2-(benzylthio)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazole demonstrated potent cytotoxicity against A549, HCT116, MCF-7, and HepG2 lines (IC50: 1.8–10.6 μM). Molecular docking identified the epidermal growth factor receptor (EGFR) as a primary target, with 2-((4-chlorobenzyl)thio)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazole (3) exhibiting the highest binding affinity (−8.12 kcal/mol) and consistent potency (IC50: 2.4–8.1 μM). DFT analysis (B3LYP/6–311++G(d,p)) showed that compound 2 possesses the narrowest HOMO-LUMO gap (5.3468 eV), indicating optimal reactivity. SASA analysis confirmed the aqueous stability of 2-(benzylthio)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazole. Furthermore, ADMET profiling predicted low gastrointestinal absorption and favorable metabolic stability for both derivatives.