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.

Show simple item record Thompson, Andrew en O'Connor, Patrick D en Marshall, Andrew J en Blaser, Adrian en Yardley, Vanessa en Maes, Louis en Gupta, Suman en Launay, Delphine en Braillard, Stephanie en Chatelain, Eric en Wan, Baojie en Franzblau, Scott G en Ma, Zhenkun en Cooper, Christopher B en Denny, William en 2018-12-02T22:28:14Z en 2018-03-06 en
dc.identifier.issn 0022-2623 en
dc.identifier.uri en
dc.description.abstract 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 6 R 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. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Journal of medicinal chemistry en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.subject Animals en
dc.subject Mice, Inbred BALB C en
dc.subject Mesocricetus en
dc.subject Mice en
dc.subject Rats en
dc.subject Rats, Sprague-Dawley en
dc.subject Leishmania donovani en
dc.subject Leishmania infantum en
dc.subject Mycobacterium tuberculosis en
dc.subject Leishmaniasis, Visceral en
dc.subject Chagas Disease en
dc.subject Oxazines en
dc.subject Antiparasitic Agents en
dc.subject Microbial Sensitivity Tests en
dc.subject Drug Evaluation, Preclinical en
dc.subject Cell Membrane Permeability en
dc.subject Structure-Activity Relationship en
dc.subject Dose-Response Relationship, Drug en
dc.subject Cricetinae en
dc.subject Cytochrome P-450 CYP3A en
dc.subject Cytochrome P-450 CYP3A Inhibitors en
dc.subject ERG1 Potassium Channel en
dc.title 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. en
dc.type Journal Article en
dc.identifier.doi 10.1021/acs.jmedchem.7b01581 en
pubs.issue 6 en
pubs.begin-page 2329 en
pubs.volume 61 en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 29461823 en
pubs.end-page 2352 en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 731831 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1520-4804 en
pubs.record-created-at-source-date 2018-02-21 en
pubs.dimensions-id 29461823 en

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