Naproxen Based 1,3,4-Oxadiazole Derivatives as EGFR Inhibitors: Design, Synthesis, Anticancer, and Computational Studies

• Main Authors: Mohammad Mahboob Alam, Syed Nazreen, Abdulraheem S. A. Almalki, Ahmed A. Elhenawy, Nawaf I. Alsenani, Serag Eldin I. Elbehairi, Azizah M. Malebari, Mohammad Y. Alfaifi, Meshari A. Alsharif, Sulaiman Y. M. Alfaifi
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Pharmaceuticals
• Subjects: naproxen; 1,3,4-oxadiazole; cytotoxicity; EGFR; computational study
• Online Access: https://www.mdpi.com/1424-8247/14/9/870
• ISSN: 1424-8247

A library of novel naproxen based 1,3,4-oxadiazole derivatives (<b>8</b>–<b>16</b> and <b>19</b>–<b>26</b>) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hybrids, compound2-(4-((5-((<i>S</i>)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1<i>H</i>-1,2,3-triazol-1-yl)phenol(<b>15</b>) was the most potent compound against MCF-7 and HepG2cancer cells with IC₅₀ of 2.13 and 1.63 µg/mL, respectively, and was equipotent to doxorubicin (IC₅₀ 1.62 µg/mL) towards HepG2. Furthermore, compound <b>15</b> inhibited EGFR kinase with IC₅₀ 0.41 μM compared to standard drug Erlotinib (IC₅₀ 0.30 μM). The active compound induces a high percentage of necrosis towards MCF-7, HePG2 and HCT 116 cells. The docking studies, DFT and MEP also supported the biological data. These results demonstrated that these synthesized naproxen hybrids have EGFR inhibition effects and can be used as leads for cancer therapy.