Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae,including drug-resistant strains |
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| Institution: | 1. Drug Information Platform Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;2. Korea University of Science and Technology, Daejeon 34114, Republic of Korea;3. Center for Convergent Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea;4. Discovery Biology Department, Antibacterial Resistance Research Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea;1. CNRS, UMR7242 Biotechnologie et Signalisation Cellulaire, 300 Boulevard Sébastien Brant, 67400 Illkirch-Graffenstaden, France;2. Université de Strasbourg, Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg (IREBS), 67400 Illkirch-Graffenstaden, France;3. Laboratoire de Bactériologie, UMR 6249 CNRS Chrono-Environnement, Faculté de Médecine-Pharmacie, Université de Franche-Comté, Besançon, France;4. Prestwick Chemical, PC SAS, 220 Boulevard Gonthier d''Andernach, 67400 Illkirch-Graffenstaden, France;1. Department of Chemistry, Emory University, United States;2. Division of Infectious Diseases, Rhode Island Hospital, United States;1. Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA;2. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA;3. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA;1. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;2. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea |
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| Abstract: | New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo3,2,1-ij]quinolone and pyrido3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC50 = 0.92, 0.75, and 0.77 µM), 7d (IC50 = 0.57, 0.66, and 0.38 µM) and 12a (IC50 = 0.27, 1.03, and 0.62 µM) showed submicromolar IC50 values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency. |
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| Keywords: | Pneumococcal infection Multidrug resistance 19A strain 1 2-Dihydroquinoline |
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