dc.contributor.author |
Lam, CFC |
en |
dc.contributor.author |
Pearce, Allison |
en |
dc.contributor.author |
Tan, SH |
en |
dc.contributor.author |
Kaiser, M |
en |
dc.contributor.author |
Copp, Brent |
en |
dc.coverage.spatial |
Switzerland |
en |
dc.date.accessioned |
2017-10-18T00:01:11Z |
en |
dc.date.available |
2013-08-30 |
en |
dc.date.issued |
2013-09-09 |
en |
dc.identifier.citation |
Marine Drugs, 11(9):3472-3499, 09 Sep 2013 |
en |
dc.identifier.issn |
1660-3397 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/36129 |
en |
dc.description.abstract |
Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC₅₀ 3.1 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC₅₀ 3.3 μM) while exhibiting low levels of cytotoxicity (L6, IC₅₀ 167 μM). A series of C-7 amide and Δ²(³) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC₅₀ 0.62-6.5 μM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ²(³)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ²(³)-phenethylamide 8e (IC₅₀ 0.67 μM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC₅₀ 0.34-0.035 μM) combined with excellent selectivity (SI 560-4000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively. |
en |
dc.description.uri |
https://www.ncbi.nlm.nih.gov/pubmed/24022732 |
en |
dc.language |
English |
en |
dc.publisher |
MDPI |
en |
dc.relation.ispartofseries |
Marine Drugs |
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. Details obtained from http://sherpa.ac.uk/romeo/issn/1660-3397/
http://www.mdpi.com/about/openaccess |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.rights.uri |
https://creativecommons.org/licenses/by/3.0/ |
en |
dc.subject |
Antimalarials |
en |
dc.subject |
Inhibitory Concentration 50 |
en |
dc.subject |
Parasitic Sensitivity Tests |
en |
dc.subject |
Plasmodium falciparum |
en |
dc.subject |
Quinones |
en |
dc.subject |
Trypanocidal Agents |
en |
dc.subject |
Trypanosoma brucei rhodesiense |
en |
dc.title |
Discovery and evaluation of thiazinoquinones as anti-protozoal agents |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.3390/md11093472 |
en |
pubs.issue |
9 |
en |
pubs.begin-page |
3472 |
en |
pubs.volume |
11 |
en |
dc.rights.holder |
Copyright: The authors |
en |
dc.identifier.pmid |
24022732 |
en |
pubs.author-url |
http://www.mdpi.com/1660-3397/11/9/3472 |
en |
pubs.end-page |
3499 |
en |
pubs.publication-status |
Published online |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
406437 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Chemistry |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1660-3397 |
en |
dc.identifier.pii |
md11093472 |
en |
pubs.record-created-at-source-date |
2017-10-18 |
en |
pubs.dimensions-id |
24022732 |
en |