Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: in vitro and in vivo appraisal

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dc.contributor.author Thompson, Andrew M
dc.contributor.author O’Connor, Patrick D
dc.contributor.author Marshall, Andrew J
dc.contributor.author Yardley, Vanessa
dc.contributor.author Maes, Louis
dc.contributor.author Gupta, Suman
dc.contributor.author Launay, Delphine
dc.contributor.author Braillard, Stephanie
dc.contributor.author Chatelain, Eric
dc.contributor.author Wan, Baojie
dc.contributor.author Franzblau, Scott G
dc.contributor.author Ma, Zhenkun
dc.contributor.author Cooper, Christopher B
dc.contributor.author Denny, William A
dc.date.accessioned 2020-12-08T23:52:36Z
dc.date.available 2020-12-08T23:52:36Z
dc.date.issued 2020-10-1
dc.identifier.citation European journal of medicinal chemistry 112914 10 Oct 2020
dc.identifier.issn 0223-5234
dc.identifier.uri http://hdl.handle.net/2292/53944
dc.description.abstract © 2020 Elsevier Masson SAS Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.
dc.language en
dc.publisher Elsevier BV
dc.relation.ispartofseries European Journal of Medicinal Chemistry
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.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject 0304 Medicinal and Biomolecular Chemistry
dc.subject 0305 Organic Chemistry
dc.subject 1115 Pharmacology and Pharmaceutical Sciences
dc.title Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: in vitro and in vivo appraisal
dc.type Journal Article
dc.identifier.doi 10.1016/j.ejmech.2020.112914
pubs.begin-page 112914
dc.date.updated 2020-11-17T20:25:41Z
dc.rights.holder Copyright: Elsevier en
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Journal Article
pubs.elements-id 823477
dc.identifier.eissn 1768-3254
pubs.number 112914

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