title: Novel diphenylamine 2,4'-dicarboxamide based azoles as potential epidermal growth factor receptor inhibitors: synthesis and biological activity.
abstract: Several hybrid molecules of diphenylamine-2,4'-dicarboxamide with various azolidinones and related heterocyclic rings have been synthesized and explored as epidermal growth factor receptor (EGFR) kinase inhibitors. Most of them displayed promising in vitro tyrosine kinase inhibition as well as potent cellular antiproliferative activity in the EGFR over-expressing breast cancer cell line (MCF-7). Compounds 12b and 13b that exhibited the highest inhibition in the kinase assay (89, 81% inhibition at 10 μM, respectively), showed potent antiproliferative effect against MCF-7 tumor cell line (IC(50) 1.04, 0.91 μM respectively). Molecular docking studies revealed that these compounds can bind to ATP binding site of the EGFR kinase domain and were involved in H-bonding with Met 793, in analogy to the known EGFR tyrosine kinase inhibitors. Moreover, compounds 15a-c possessed profound antitumor activity (IC(50) 0.59-0.73 μM) and significant EGFR-TK inhibition, making them of particular interest. In summary, the newly synthesized compounds provide promising new lead for the future design and development of anticancer agents of potential EGFR-TK inhibitory activity.
authors: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Egypt. saharshaarawy_69@yahoo.com
authors: Sahar Mahmoud
authors: SM
authors: Abou-Seri
authors: Nahla Ahmed
authors: NA
authors: Farag
authors: Ghaneya Sayed
authors: GS
authors: Hassan
mesh_terms: D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C568880:2,4'-bis(N-(3-allyl-4,5-dioxo-2-thioxoimidazolidin-1-yl)carbamoyl)diphenylamine; C568879:2,4'-bis-((4-cyclohexyl-3,5,6-trioxo-1,2,4-triazinane-1-yl)carbonyl)-diphenylamine; D000577:Amides; D000970:Antineoplastic Agents; D001393:Azoles; D048289:Imidazolidines; D004159:Diphenylamine; D066246:ErbB Receptors