Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase |
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| Institution: | 1. Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave., S321 Pharmacy Building, Iowa City, IA 52242, USA;2. Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA;1. Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, People’s Republic of China;2. Sichuan Institute for Food and Drug Control, Chengdu 611731, People’s Republic of China;3. Department of Chemistry, School of Science, Beijing Technology and Business University, Beijing 100048, People’s Republic of China;1. Center of Chemical Innovation for Sustainability (CIS) and School of Science, Mae Fah Luang University, Chiang Rai 57100, Thailand;2. Medicinal Plants Innovation Center of Mae Fah Luang University, Chiang Rai 57100, Thailand;3. School of Integrative Medicine, Mae Fah Luang University, Chiang Rai 57100, Thailand;4. Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada;5. School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia;1. College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian 116044, PR China;2. Department of Hematology, Institute of Respiratory Diseases, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Dalian Buyun Biological Technology Co., Ltd., 116085, PR China;1. Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;2. Laboratory of Natural Product, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya 468-8503, Japan;3. Advanced Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan;4. Division of Chemistry and Materials, Graduate School of Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan;1. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;3. Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Weifang 262700, Shandong, China;4. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China;1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, 13, I-98168 Messina, Italy;2. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria;3. Department of Microbiology and Immunology, Lab. of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium |
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| Abstract: | Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections and target bacterial type-II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones, however potent, are susceptible to bacterial resistance with prolonged use, which limits their use in the clinic. Quinazoline-2,4-diones also target bacterial type-II topoisomerases and are not susceptible to bacterial resistance similar to fluoroquinolones, however, their potency pales in comparison to fluoroquinolones. To meet the increasing demand for antibacterial development, nine modified quinazoline-2,4-diones were developed to probe quinazoline-2,4-dione structure modification for possible new binding contacts with the bacterial type-II topoisomerase, DNA gyrase. Evaluation of compounds for inhibition of the supercoiling activity of DNA gyrase revealed a novel ethyl 5,6-dihydropyrazolo1,5-c]quinazoline-1-carboxylate derivative as a modest inhibitor of DNA gyrase, having an IC50 of 3.5 μM. However, this ethyl 5,6-dihydropyrazolo1,5-c]quinazoline-1-carboxylate does not trap the catalytic intermediate like fluoroquinolones or typical quinazoline-2,4-diones do. Thus, the ethyl 5,6-dihydropyrazolo1,5-c]quinazoline-1-carboxylate derivative discovered in this work acts as a catalytic inhibitor of DNA gyrase and therefore represents a new structural type of catalytic inhibitor of DNA gyrase. |
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| Keywords: | DNA gyrase Quinazolinediones Fluoroquinolones Topoisomerase |
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