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Discovery of novel bacterial elongation condensing enzyme inhibitors by virtual screening

Affiliation:	1. Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, TN 38105, USA;2. Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, TN 38105, USA;3. Department of Structural Biology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA;1. Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41 Shinagawa-ku, Tokyo 142-8501, Japan;2. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki City, Kagawa 769-2193, Japan;3. Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia;1. Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark;2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark;1. Department of Discovery Chemistry, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Metabolic and Vascular Diseases, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;3. Drug Metabolism and Pharmacokinetics, Pharmaceutical Research and Early Drug Development, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;1. Department of Pharmaceutical Sciences, Nesbitt School of Pharmacy, Wilkes University, 84 W. South Street, Wilkes-Barre, PA 18766, USA;2. Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland;3. Department of Organic Chemistry, University of Lodz, Lodz 91-403, Poland;1. Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, China;2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China;1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan;2. Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo Nishi 6-chome, Kita-ku, Sapporo 060-0812, Japan;3. RIKEN Center for Life Science Technologies, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan

Abstract:	The elongation condensing enzymes in the bacterial fatty acid biosynthesis pathway represent desirable targets for the design of novel, broad-spectrum antimicrobial agents. A series of substituted benzoxazolinones was identified in this study as a novel class of elongation condensing enzyme (FabB and FabF) inhibitors using a two-step virtual screening approach. Structure activity relationships were developed around the benzoxazolinone scaffold showing that N-substituted benzoxazolinones were most active. The benzoxazolinone scaffold has high chemical tractability making this chemotype suitable for further development of bacterial fatty acid synthesis inhibitors.

Keywords:	Virtual screening Fatty acid synthesis Condensing enzymes Antibiotics
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