dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
O'Connor, Patrick D |
en |
dc.contributor.author |
Marshall, Andrew J |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Yardley, Vanessa |
en |
dc.contributor.author |
Maes, Louis |
en |
dc.contributor.author |
Gupta, Suman |
en |
dc.contributor.author |
Launay, Delphine |
en |
dc.contributor.author |
Braillard, Stephanie |
en |
dc.contributor.author |
Chatelain, Eric |
en |
dc.contributor.author |
Wan, Baojie |
en |
dc.contributor.author |
Franzblau, Scott G |
en |
dc.contributor.author |
Ma, Zhenkun |
en |
dc.contributor.author |
Cooper, Christopher B |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2018-12-02T22:28:14Z |
en |
dc.date.issued |
2018-03-06 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/44743 |
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 |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Animals |
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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 |
http://purl.org/eprint/accessRights/RestrictedAccess |
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 |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
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 |