Synthesis, Characterization, and Cytotoxicity Assessment of Novel S- Naproxen- based 1,3,4-Oxadiazole Thioethers against A549 Lung Carcinoma

Novel S-naproxen- 1,3,4-oxadiazole derivatives were developed and synthesized. via a multi-step route. The synthesis began with conversion of S-(+)-naproxen to an ethyl ester, followed by hydrazide formation and cyclization to yield a 1,3,4-oxadiazole-2-thiol intermediate. Alkylation of this intermediate with various substituted phenacyl bromides produced nine final 1,3,4-oxadiazole thioether derivatives (N1–N9). The structures of all compounds were confirmed by melting point, Rf, Fourier-transform infrared (FT-IR) spectroscopy, and nuclear magnetic resonance (NMR) (1H ,13C-NMR) analysis. Preliminary in vitro cytotoxicity was evaluated against human lung adenocarcinoma A549 cells using the MTT assay. All compounds demonstrated significant growth inhibition, with IC50 values in the low microgram per milliliter range. Notably, compound N6 showed an IC50 of 2.94 μg/mL at 24 h (versus 5.31 μg/mL for the reference drug Osimertinib)​ ​. After 72 h exposure, the most potent derivative, N9, achieved an IC50 of 2.95 μg/mL, slightly surpassing Osimertinib (3.10 μg/mL)​ ​. These findings indicate that S-naproxen 1,3,4-oxadiazole thioethers are promising anticancer agents. The incorporation of the 2-(6-methoxynaphthyl) (naproxen) moiety and various aromatic substituents yielded compounds with potent antiproliferative activity, warranting further development and in-depth biological studies.