Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents |
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| Institution: | 1. Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China;2. Changzhou Yinsheng Pharmacy Co., Ltd., Weitang Chemical Industry Zone, Changzhou 213000, China;3. WuXi AppTec. Co. Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China;4. Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China;1. Covance, 1121 East 3900 South, Salt Lake City, UT 84124, USA;2. Otsuka Pharmaceutical Development & Commercialization (OPDC), 2440 Research Boulevard, Rockville, MD 20850, USA;1. Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation;2. Lomonosov Institute of Fine Chemical Technologies, MIREA − Russian Technological University, Moscow, 119571, Russian Federation;3. Saint Petersburg Research Institute of Phthisiopulmonology, 2-4 Ligovsky Prospekt, Saint Petersburg, 191036, Russian Federation;4. Pasteur Institute of Epidemiology and Microbiology, 14 Mira Street, Saint Petersburg, 197101, Russian Federation;1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, United States;2. 9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, United States;3. BioIVT, 1450 S Rolling Rd, Halethorpe, MD, 21227, United States;1. Department of Pharmaceutical Chemistry, Humera Khan College of Pharmacy, Relief Road, Oshiwara, Jogeshwari West, Pratiksha nagar, Mumbai, Maharashtra 400102, India;2. Head of Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Opp. Lalbagh Main Gate, Hosur Road, Bengaluru, Karnataka 560027, India;1. Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC (ID: 60014618)), Dokki, Giza 12622, Egypt;2. Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu 02792, Republic of Korea;3. Department of Biomolecular Science, University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea;4. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt;5. University of Science & Technology (UST), Daejeon, Yuseong-gu 34113, Republic of Korea;6. Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates;7. Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates;8. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt;9. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea;10. Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea;11. Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea;1. Department of Pharmacology, Physiology, and Neuroscience, Rutgers University – New Jersey Medical School, Newark, NJ, USA;2. Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University – New Jersey Medical School, Newark, NJ, USA;3. Public Health Research Institute, Rutgers University – New Jersey Medical School, Newark, NJ, USA |
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| Abstract: | New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation. |
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| Keywords: | Nitroimidazoles Antitubercular agents Physicochemical properties |
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