title: Design, synthesis, docking and QSAR study of substituted benzimidazole linked oxadiazole as cytotoxic agents, EGFR and erbB2 receptor inhibitors.
abstract: The synthesis of benzimidazole linked oxadiazole derivatives designed as potential EGFR and erbB2 receptor inhibitors with anticancer and apoptotic activity were studied. Compounds 7a specifically inhibit EGFR and erbB2 receptor at 0.081 and 0.098 μM concentration. Some of the compounds showed strong, broad-spectrum antiproliferative activitiy when tested against five human cancer cell lines. Compounds 7a and 7n were more cytotoxic than 5-fluorouracil against MCF-7 cancer cell, with IC50values of 5.0 and 2.55 μM whereas, only 7a led to cell cycle arrest at G2/M phase accompanied by an increase in apoptosis. Compounds 7a and 7n showed normal architecture of myofibrils in cardiomyopathy study whereas only compound 7a showed nearly equal biochemical parameters (SGOT and SGPT) when compared to control. Molecular docking & 3D-QSAR studies were used to establish interactions of 7a and 7n within the active site of enzyme for ATP binding site of kinase domain.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi-110062, India.
authors.forename: Md Jawaid
authors.initials: MJ
authors.lastname: Akhtar
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi-110062, India.
authors.forename: Anees Ahmad
authors.initials: AA
authors.lastname: Siddiqui
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi-110062, India.
authors.forename: Ahsan Ahmed
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi-110062, India.
authors.forename: Zulphikar
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Lab No 405, Institute of Genomics and Integrative Biology, New Delhi, India.
authors.forename: Rikeshwer Prasad
authors.initials: RP
authors.lastname: Dewangan
authors.affiliation: Lab No 405, Institute of Genomics and Integrative Biology, New Delhi, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Pasha
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi-110062, India. Electronic address: yarmsy@rediffmail.com.
authors.forename: M Shahar
authors.initials: MS
authors.lastname: Yar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: 3D-QSAR studies; Anticancer; Apoptosis; Benzimidazole linked oxadiazole