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Synthesis of novel bridged dinitrogen heterocycles and their evaluation as potential fragments for the design of biologically active compounds |
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| Authors: | Konstantin V Kudryavtsev Dmitry A Shulga Vladimir I Chupakhin Elena I Sinauridze Fazly I Ataullakhanov Sergey Z Vatsadze |
| Institution: | 1. Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russian Federation;2. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432 Moscow Region, Russian Federation;3. National Research Center for Hematology, 125167 Moscow, Russian Federation;4. Department of Physics, M.V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation;5. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russian Federation;6. Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, 117513 Moscow, Russian Federation |
| Abstract: | A library of saturated bridged heterocycles based on 3,6-diazabicyclo3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligand–enzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin. |
| Keywords: | Molecular complexity Bridged azaheterocycles Fragment based drug discovery Molecular docking Thrombin Inhibitors |
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