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A Novel Tetrazole-Oxadiazole Hybrid: Synthesis, Computational Insights, and Biological Evaluation as a Potential Anticancer Agent
This study reports the design, synthesis, and comprehensive experimental and computational evaluation of a novel isopropyl 2-((5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)acetate. As the first investigation in a planned series, this proof-of-concept study concentrates on a single model compound to validate the virtually unexplored tetrazole–oxadiazole hybrid class as a promising scaffold for anticancer agents. The target compound was synthesized via S-alkylation of 5-((5-phenyl-2H-tetrazol-2-yl)methyl)-1,3,4-oxadiazole-2-thiol and characterized by NMR, IR, HRMS (ESI), HPLC, UV-vis and single-crystal X-ray diffraction. Comprehensive thermal analysis (simultaneous TGA-DTA and DSC) demonstrated moderate stability (ΔHfus = 71.4 J/g) and a multistage atmosphere-independent decomposition pathway initiated by tetrazole ring cleavage. DFT calculations revealed a HOMO–LUMO energy gap of 9.10 eV, indicating its high electronic stability. The compound's DNA-binding ability was assessed using UV-vis spectroscopy and a competitive ethidium bromide displacement assay. The binding constant with SS-DNA was 1.57 × 106 M-1. Molecular docking studies revealed that the compound preferentially binds to the DNA minor groove. In MTT assays, the compound reduced viability to 59% of control in A549 and MCF-7 cells at 250 µM, whereas Capan-1 pancreatic cancer cells exhibited greater sensitivity (viability 26%; IC50 = 160 µM). Furthermore, in silico metabolism prediction revealed that the Phase I biotransformation of the compound is exclusively mediated by human Cytochrome P450 1A2 (CYP1A2), suggesting a specific and predictable metabolic pathway. These promising results highlight the potential of the tetrazole–oxadiazole hybrid class and provide a solid foundation for extending the study to analogs and structure–activity relationship (SAR) analysis.