187235-58-1Relevant articles and documents
Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H -imidazo[2,1- b] [1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis
Thompson, Andrew M.,O'Connor, Patrick D.,Marshall, Andrew J.,Blaser, Adrian,Yardley, Vanessa,Maes, Louis,Gupta, Suman,Launay, Delphine,Braillard, Stephanie,Chatelain, Eric,Wan, Baojie,Franzblau, Scott G.,Ma, Zhenkun,Cooper, Christopher B.,Denny, William A.
supporting information, p. 2329 - 2352 (2018/03/26)
Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.
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)
Thompson, Andrew M.,Blaser, Adrian,Anderson, Robert F.,Shinde, Sujata S.,Franzblau, Scott G.,Ma, Zhenkun,Denny, William A.,Palmer, Brian D.
experimental part, p. 637 - 645 (2009/12/01)
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 om 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.
