Design and development of new class of Mycobacterium tuberculosis l-alanine dehydrogenase inhibitors |
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| Institution: | 1. Department of Pharmacy, “Drug Discovery” Laboratory, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy;2. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy;3. Department of Biomedical Sciences, Dentistry, and Morpho-functional Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy;4. Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy;5. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany;1. Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China;2. Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China;3. Department of Orthopedics, Traditional Chinese Medicine Hospital of Harbin, Harbin 150000, Heilongjiang Province, China;4. Department of Orthopedics, Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China;1. Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA;2. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA;1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University, 300 Pasteur Drive, HH333, Stanford, CA 94305-5317, USA;2. Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA, USA;1. Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China;2. University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China;3. The Key Laboratory of Regenerative Biology, The Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;1. Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States;2. Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, United States;3. Department of Basic Sciences, Touro University—California, Mare Island, Vallejo, CA 94592, United States;4. Department of Pharmaceutical Chemistry, University of California San Francisco, CA 94143, United States;5. Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States;6. Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States |
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| Abstract: | Mycobacterium tuberculosis l-alanine dehydrogenase (MTB l-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB l-AlaDH bound with cofactor NAD+ as a structural framework for virtual screening of our in-house database to identified new classes of l-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC50 of 9.22 ± 0.72 μM. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N2,N4-bis(benzod]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with l-AlaDH IC50 of 3.83 ± 0.12 μM, 2.0 log reduction in nutrient starved dormant MTB model and MIC of 11.81 μM in actively replicative MTB. |
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| Keywords: | Tuberculosis Alanine dehydrogenase Azetidine-2 4-dicarboxamide |
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