Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): A new lead for visceral leishmaniasis

by Thompson AM, O’Connor PD, Marshall AJ, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Braillard S, Chatelain E, Wan B, Franzblau SG, Ma Z, Cooper CB, and Denny WA. Journal of Medicinal Chemistry 2018. doi: 10.1021/acs.jmedchem.7b01581

Summary: As part of the VL lead optimization program, back-up compounds were sought by examining scaffolds inspired by the 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 which have potent antileishmanial effects. However, the results for these were less attractive and so a 900-compound nitroimidazooxazine analogue library was then screened, and the hits from this were developed. The authors report the findings of their wide-ranging structure activity relationship studies, including the detailed in vitro/ in vivo profiling of selected new leads, which resulted in the identification of a very promising VL backup candidate.

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