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Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors. 2020

Xuwei Shao, and Steven Pak, and Uday Kiran Velagapudi, and Shruthi Gobbooru, and Sai Shilpa Kommaraju, and Woon-Kai Low, and Gopal Subramaniam, and Sanjai Kumar Pathak, and Tanaji T Talele
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.

Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC50 = 12 μM), 4 (IC50 = 5.8 μM), and 10 (IC50 = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC50 = 0.082 μM) as the most potent inhibitor of PARP1 from the series.

UI MeSH Term Description Entries
D004147 Dioxins A family of compounds that contain the 1,4-dioxin structure. Many specific dioxin derivatives are listed as CARCINOGENS; TERATOGENS; or MUTAGENS. Dioxin
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067856 Poly(ADP-ribose) Polymerase Inhibitors Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES. Inhibitors of Poly(ADP-ribose) Polymerase,PARP Inhibitor,Poly(ADP-Ribose) Polymerase Inhibitor,Poly(ADP-ribosylation) Inhibitor,Inhibitors of Poly(ADP-ribose) Polymerases,PARP Inhibitors,Poly(ADP-ribosylation) Inhibitors,Inhibitor, PARP,Inhibitors, PARP
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D057166 High-Throughput Screening Assays Rapid methods of measuring the effects of an agent in a biological or chemical assay. The assay usually involves some form of automation or a way to conduct multiple assays at the same time using sample arrays. High-Throughput Screening,High-Throughput Biological Assays,High-Throughput Chemical Assays,High-Throughput Screening Methods,Assay, High-Throughput Biological,Assay, High-Throughput Chemical,Assay, High-Throughput Screening,Biological Assay, High-Throughput,Chemical Assay, High-Throughput,High Throughput Biological Assays,High Throughput Chemical Assays,High Throughput Screening,High Throughput Screening Assays,High Throughput Screening Methods,High-Throughput Biological Assay,High-Throughput Chemical Assay,High-Throughput Screening Assay,High-Throughput Screening Method,High-Throughput Screenings,Screening Assay, High-Throughput,Screening Method, High-Throughput,Screening, High-Throughput
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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