Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa |
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| Institution: | 1. Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA;2. Drug Safety and Metabolism Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA;3. AstraZeneca, Pharmaceutical Development, Chemical Sciences, Silk Road Business Park, Macclesfield, Cheshire, England SK10 4TG, United Kingdom;4. Adesis Inc., 27 McCullough Drive, New Castle, DE 19720, USA;1. Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland;2. Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland;1. Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea;2. Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, South Korea;3. Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea;4. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, South Korea;1. Research & Development Microbiology, bioMérieux SA, 3 route de Port Michaud, 38 390 La-Balme-les-Grottes, France;2. Department of Applied Sciences, Northumbria University, Newcastle upon Tyne NE7 7DN, UK;3. Department of Microbiology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK;1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK;2. AstraZeneca, Hodgkin Building, Chesterford Research Campus, Little Chesterford, Saffron Walden, Cambs. CB10 1XL, UK;1. Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa;2. Piramal Health Care Ltd, Goregaon, Mumbai, India;3. S.P.P. School of Pharmacy and Technology Management, NMIMS University, Vile Parle, Mumbai 400056, India;1. Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States;2. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States;3. Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;4. Department of Inflammation Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States |
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| Abstract: | Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and log D) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa. |
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| Keywords: | Bacterial toposisomerases Gyrase hERG |
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