New Niflumic Acid Derivatives as EGFR Inhibitors: Design, Synthesis, In Silico Studies, and Anti-proliferative Assessment



1,3,4-oxadizole and pyrazole derivatives, are very important scaffold for medicinal chemistry. Literature survey revealed that they possess wide spectrum of biological activities among which are anti-inflammatory and antitumor.



To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 4AE) and pyrazole derivatives (compounds 5 and 6) as EGFR tyrosine kinase inhibitors in silico and in vitro.



The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies.



A series of niflumic acid derivatives (3, 4A-E, 5 and 6) were successfully created and FT-IR, 1H, 13CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG) and the majority of the tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities show that it is a promising EGFR tyrosine kinase inhibitor.
