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

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

doi:10.3390/ph14090870

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

Pharmaceuticals (Basel). 2021 Aug 28;14(9):870. doi: 10.3390/ph14090870.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Albaha University, Albaha 65731, Saudi Arabia.
² Department of Chemistry, Faculty of Science, Taif University, Taif 21974, Saudi Arabia.
³ Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Egypt.
⁴ Department of Biology, Faculty of Science, King Khalid University, Abha 9004, Saudi Arabia.
⁵ Cell Culture Laboratory, Egyptian Organization for Biological Products and Vaccines, VACSERA Holding Company, Giza 22311, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
⁷ Chemistry Department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21421, Saudi Arabia.
⁸ Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Abstract

A library of novel naproxen based 1,3,4-oxadiazole derivatives (8-16 and 19-26) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hybrids, compound2-(4-((5-((S)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol(15) 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 15 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.

Keywords: 1,3,4-oxadiazole; EGFR; computational study; cytotoxicity; naproxen.

Grants and funding

TURSP-2020/44/Taif University