title: Synthesis and biological evaluation of novel 2,4'-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitors.
abstract: 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 microM). 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 IC(50) values ranging 0.73-2.38 microM. 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box, 11562, Egypt. saharshaarawy_69@yahoo.com
authors.forename: Sahar Mahmoud
authors.initials: SM
authors.lastname: Abou-Seri
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004159:Diphenylamine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D004159:Diphenylamine; D066246:ErbB Receptors