dc.contributor.author |
Thompson AM |
|
dc.contributor.author |
O'Connor PD |
|
dc.contributor.author |
Marshall AJ |
|
dc.contributor.author |
Francisco AF |
|
dc.contributor.author |
Kelly JM |
|
dc.contributor.author |
Riley J |
|
dc.contributor.author |
Read KD |
|
dc.contributor.author |
Perez CJ |
|
dc.contributor.author |
Cornwall S |
|
dc.contributor.author |
Thompson RCA |
|
dc.contributor.author |
Keenan M |
|
dc.contributor.author |
White KL |
|
dc.contributor.author |
Charman SA |
|
dc.contributor.author |
Zulfiqar B |
|
dc.contributor.author |
Sykes ML |
|
dc.contributor.author |
Avery VM |
|
dc.contributor.author |
Chatelain E |
|
dc.contributor.author |
Denny WA |
|
dc.date.accessioned |
2020-11-09T01:19:27Z |
|
dc.date.available |
2020-11-09T01:19:27Z |
|
dc.date.issued |
2020-12-1 |
|
dc.identifier.citation |
European journal of medicinal chemistry 207:112849 Dec 2020 |
|
dc.identifier.issn |
1768-3254 |
|
dc.identifier.uri |
http://hdl.handle.net/2292/53505 |
|
dc.description.abstract |
Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class. |
|
dc.publisher |
Elsevier |
|
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 |
Chagas disease |
|
dc.subject |
Pretomanid |
|
dc.subject |
Library screening |
|
dc.subject |
In vivo efficacy |
|
dc.subject |
Pharmacokinetics |
|
dc.subject |
Bioluminescence imaging |
|
dc.subject |
0304 Medicinal And Biomolecular Chemistry |
|
dc.subject |
1115 Pharmacology And Pharmaceutical Sciences |
|
dc.subject |
0305 Organic Chemistry |
|
dc.title |
Re-evaluating pretomanid analogues for Chagas disease: hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1016/j.ejmech.2020.112849 |
|
pubs.volume |
207 |
|
dc.date.updated |
2020-10-08T20:12:30Z |
|
dc.rights.holder |
Copyright: 2020 Elsevier Masson SAS. |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Article |
|
pubs.elements-id |
817681 |
|
pubs.number |
112849 |
|
pubs.online-publication-date |
2020-9-18 |
|