Synthesis and biological evaluation of novel 2,4′-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitors

Four new series of 2,4′-bis diphenylamine hydrazones 14, 2,4′-bis aminothiadiazole 16, 2,4′-bis mercaptotriazole 17–18 and 2,4′-bis mercapto-oxadiazole diphenylamine derivatives 19–20 were synthesized and evaluated for their ability to inhibit EGFR tyrosine kinase. Compound N-ethyl-5-{2-[4-(5-(ethylamino)-1,3,4-thiadiazol-2-yl)- phenylamino]phenyl}-1,3,4-thiadiazol-2-amine 16a was the most active enzyme inhibitor (98% inhibition at 10 μM). Moreover, all compounds that showed enzyme inhibition activity were tested in vitro on human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. The tested compounds exploited potent antitumor activity with IC50 values ranging 0.73–2.38 μM. Molecular modeling and docking of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results. The present work represents a novel class of diphenylamine based derivatives with potent cytotoxicity and promising EGFR PTK inhibition activity.

Graphical abstractSeveral analogues 2,4′-bis substituted diphenylamines were synthesized and evaluated as EGFR tyrosine kinase inhibitors as well as for their antiprolifertive properties on human breast cancer cell lines (MCF-7). Figure optionsDownload full-size imageDownload as PowerPoint slide