title: Design and synthesis of novel protein kinase R (PKR) inhibitors.
abstract: Protein kinase RNA-activated (PKR) plays an important role in a broad range of intracellular regulatory mechanisms and in the pathophysiology of many human diseases, including microbial and viral infections, cancer, diabetes and neurodegenerative disorders. Recently, several potent PKR inhibitors have been synthesized. However, the enzyme's multifunctional character and a multitude of PKR downstream targets have prevented the successful transformation of such inhibitors into effective drugs. Thus, the need for additional PKR inhibitors remains. With the help of computer-aided drug-discovery tools, we designed and synthesized potential PKR inhibitors. Indeed, two compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One compound, 6-amino-3-methyl-2-oxo-N-phenyl-2,3-dihydro-1H-benzo[d]imidazole-1-carboxamide, also showed anti-apoptotic properties. The novel molecules diversify the existing pool of PKR inhibitors and provide a basis for the future development of compounds based on PKR signal transduction mechanism.
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel.
authors.forename: Sagiv
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, 7610001, Rehovot, Israel.|The Fritz Haber Research Center for Molecular Dynamics, The Hebrew University, 91904, Jerusalem, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Yarnitzky
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel.
authors.forename: Shirin
authors.initials: S
authors.lastname: Kahremany
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences and Center for Gene Manipulation in the Brain, University of Haifa, 3498838, Haifa, Israel.
authors.forename: Iliana
authors.initials: I
authors.lastname: Barrera
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Viskind
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences and Center for Gene Manipulation in the Brain, University of Haifa, 3498838, Haifa, Israel.
authors.forename: Kobi
authors.initials: K
authors.lastname: Rosenblum
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, 7610001, Rehovot, Israel.|The Fritz Haber Research Center for Molecular Dynamics, The Hebrew University, 91904, Jerusalem, Israel.
authors.forename: Masha Y
authors.initials: MY
authors.lastname: Niv
authors.affiliation: Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel. gruzmaa@biu.ac.il.
authors.forename: Arie
authors.initials: A
authors.lastname: Gruzman
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D047428:Protein Kinase Inhibitors; D019892:eIF-2 Kinase
keywords: Benzoimidazole derivatives; C16; Computer modelling; PKR inhibitors