Synthesis, Characterization, and Cytotoxicity Assessment of Novel S- Naproxen- based 1,3,4-Oxadiazole Thioethers against A549 Lung Carcinoma
DOI:
https://doi.org/10.32947/ajps.v25i5.1320Keywords:
1,3,4-Oxadiazole, Naproxen, Lung cancer, Synthesis, Cytotoxic activityAbstract
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.
References
1- Schneider B, Benzekry S, Mochel J. Comprehensive joint modeling of first line therapeutics in non small cell lung cancer. arXiv preprint 2401.07719; 2024. doi:10.48550/arXiv.2401.07719
2- Alam MM, Nazreen S, Almalki ASA, et al. Naproxen based 1,3,4 oxadiazole derivatives as EGFR inhibitors: design, synthesis, anticancer and computational studies. Pharmaceuticals. 2021;14(9):870. doi:10.3390/ph14090870
3- Deng Y, Ma Y, Ni N, et al. Synthesis and biological evaluation of novel 1,3,4 oxadiazole derivatives as potential EGFR tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2015;25(3):579 583. doi: 10.1016/j.bmcl.2014.12.037
4- Kumar D, Patel G, Chittepu VCSR, et al. 1,3,4 Oxadiazole derivatives as anticancer agents: a review. Mini Rev Med Chem. 2016;16(11):869 885. doi:10.2174/1389557516666160219145313
5- Harris RE. Cyclo oxygenase 2 (COX 2) and the inflammogenesis of cancer. Subcell Biochem. 2007; 42:93 126. doi:10.1007/978 1 4020 5687 1_5
6- Kolawole OR, Kashfi K. NSAIDs and cancer resolution: new paradigms beyond cyclo oxygenase. Int J Mol Sci. 2022;23(3):1432. doi:10.3390/ijms23031432.
7- Hagras M, Saleh MA, Ezz Eldin RR, et al. 1,3,4 Oxadiazole–naphthalene hybrids as potential VEGFR 2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect and in silico studies. J Enzyme Inhib Med Chem. 2022; 37:380 396. doi:10.1080/14756366.2021.2015342
8- Akter M, Al Mahmud Z, Uddin MM, Das R, Rahman SA. Synthesis of naproxen esters and evaluation of their in vivo and in silico analgesic and anti inflammatory activities. Dhaka Univ J Pharm Sci. 2023;22(1):105 114. doi:10.3329/dujps.v22i1.67101
9- Solomons TWG, Fryhle CB. Organic chemistry. 12th ed. 2023;1164.
10- Yarmohammadi E, Beyzaei H, Aryan R, Moradi A. Ultrasound-assisted, low-solvent and acid/base-free synthesis of 5-substituted 1, 3, 4-oxadiazole-2-thiols as potent antimicrobial and antioxidant agents. Molecular Diversity. 2021;25:2367-78. doi:10.1007/s11030-020-10125-y.
11- Hamlin TA, Swart M, Bickelhaupt FM. Nucleophilic substitution (SN2): dependence on nucleophile, leaving group, central atom, substituents, and solvent. ChemPhysChem. 2018 Jun 5;19(11):1315-30, DOI: 1002/cphc.201701363.
12- Mirzaei S, Eisvand F, Nejabat M, Ghodsi R, Hadizadeh F. Anticancer Potential of a Synthetic Quinoline, 9IV-c, by Inducing Apoptosis in A549 Cell and In vivo BALB/c Mice Models. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents). 2024 Feb 1;24(3):185-92.
13- Pavia DL, Lampman GM, Kriz GS. Introduction to Spectroscopy. 5th ed. Boston: Cengage Learning; 2014.
14- Ge X, Zhang Y, Huang F, et al. EGFR tyrosine kinase inhibitor almonertinib induces apoptosis and autophagy mediated by reactive oxygen species in non small cell lung cancer cells. Hum Exp Toxicol. 2021;40(12 Suppl):S49 S62. doi:10.1177/09603271211030554
15- Mohamed MF, Ahmed EA, Alshazly O, et al. Synthesis, anticancer and anti inflammatory evaluation of novel quinoxaline 1,3,4 oxadiazole derivatives as EGFR and COX 2 inhibitors. J Mol Struct. 2025;141651. doi:10.1016/j.molstruc.2025.141651
16- Rahimi S, Chen Y, Zareian M, Pandit S, Mijakovic I. Cellular and subcellular interactions of graphene based materials with cancerous and non cancerous cells. Adv Drug Deliv Rev. 2022;189:114467. doi:10.1016/j.addr.2022.114467
17- Farah Haidar, Monther Faisal Mahdi, Ayad Kareem Khan. Synthesis, Molecular Docking, Characterization, and Preliminary Evaluation of Some New 1, 3-Diazetidin-2-One Derivatives as Anticancer Agents. (2024). Al Mustansiriyah Journal of Pharmaceutical Sciences, 24(1), 48-58. https://doi.org/10.32947/ajps.v24i1.1026.
18- Zaid Nazar Ibrahim, Ayad Kareem Khan, Mohammed Dheyaa Hamdi, Atheer Awad Mehde. Drug Design, In Silico-Profiling of New Pyrrole Derivatives: Promising Anticancer Agents Against Acute Myeloid Leukemia. (2024). Al Mustansiriyah Journal of Pharmaceutical Sciences, 24(3), 252-263. https://doi.org/10.32947/ajps.v24i3.1063.
19- Ding S, Gao Z, Hu Z, et al. Design, synthesis and biological evaluation of novel osimertinib derivatives as reversible EGFR kinase inhibitors. Eur J Med Chem. 2022;238:114492. doi:10.1016/j.ejmech.2022.114492.
20- Yasir F. Muhsin, Shakir M. Alwan, Ayad Kareem Khan. Design, Molecular Docking, Synthesis of Aromatic Amino Acids Linked to Cephalexin. (2022). Al Mustansiriyah Journal of Pharmaceutical Sciences, 21(3), 25-34. https://doi.org/10.32947/ajps.v21i3.794.
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