title: Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle.
abstract: The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50value of 0.031μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.
authors.affiliation: Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India. Electronic address: hpatel_38@yahoo.com.
authors.forename: Harun M
authors.initials: HM
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Pawara
authors.affiliation: Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
authors.forename: Azim
authors.initials: A
authors.lastname: Ansari
authors.affiliation: Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim (Surat) 3941110, Gujarat, India.
authors.forename: Malleshappa
authors.initials: M
authors.lastname: Noolvi
authors.affiliation: Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District Dhule 425 405, Maharashtra, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Surana
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D019073:HT29 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Non Small Cell Lung Cancer; Quinazoline; T790M EGFR