Synthesis, Reduction Potentials, and Antitubercular Activity of Ring A/B Analogues of the Bioreductive Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)
| Autor: | Scott G. Franzblau, Sujata S. Shinde, Andrew M. Thompson, William Alexander Gossamer Drive Denny, Zhenkun Ma, Robert F. Anderson, Brian Desmond Palmer, Adrian Blaser |
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| Rok vydání: | 2008 |
| Předmět: |
chemistry.chemical_classification
Bicyclic molecule Stereochemistry Chemistry Antitubercular Agents Substituent Nitro compound Mycobacterium tuberculosis Ring (chemistry) Chemical synthesis chemistry.chemical_compound Nitroimidazoles Chlorocebus aethiops Oxazines Drug Discovery Nitro One-electron reduction Animals Molecular Medicine Oxidation-Reduction Vero Cells Antibacterial agent |
| Zdroj: | Journal of Medicinal Chemistry. 52:637-645 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801087e |
| Popis: | The nitroimidazooxazine S-1 (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron reduction potentials E(1) (from -570 to -338 mV, compared with -534 mV for S-1). The observed E(1) values closely correlated with the sigma(m) values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compounds spanned a range of E(1) values around that of S-1, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this reduction pathway, which is determined by the nature of the substituent at the 2-position of the 4-nitroimidazole ring. |
| Databáze: | OpenAIRE |
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