title: Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents.
abstract: A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 ± 0.39 μM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 ± 2.05 μM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 ± 1.15 and 6.3 ± 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
authors.forename: Wagdy M
authors.initials: WM
authors.lastname: Eldehna
authors.affiliation: Industrial Biotechnology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University, Egypt.
authors.forename: Ayman
authors.initials: A
authors.lastname: Altoukhy
authors.affiliation: Industrial Biotechnology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Sadat City University, Egypt.
authors.forename: Hoda
authors.initials: H
authors.lastname: Mahrous
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt. Electronic address: hatem_741@yahoo.com.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Abdel-Aziz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D007510:Isatin / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D007510:Isatin; C023666:pyridine
keywords: Anti-proliferative; Hybrids; Isatin; Pyridine; Synthesis