dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Kmentova, I |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Franzblau, SG |
en |
dc.contributor.author |
Wan, B |
en |
dc.contributor.author |
Wang, Y |
en |
dc.contributor.author |
Ma, Z |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2011-11-18T02:16:41Z |
en |
dc.date.issued |
2011 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 54(19):6563-6585 2011 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9382 |
en |
dc.description.abstract |
New analogues of antitubercular drug PA-824 were synthesized, featuring alternative side chain ether linkers of varying size and flexibility, seeking drug candidates with enhanced metabolic stability and high efficacy. Both α-methyl substitution and removal of the benzylic methylene were broadly tolerated in vitro, with a biaryl example of the latter class exhibiting an 8-fold better efficacy than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection and negligible fragmentation to an alcohol metabolite in liver microsomes. Extended linkers (notably propenyloxy, propynyloxy, and pentynyloxy) provided greater potencies against replicating M. tb (monoaryl analogues), with propynyl ethers being most effective under anaerobic (nonreplicating) conditions (mono/biaryl analogues). For benzyloxybenzyl and biaryl derivatives, aerobic activity was maximal with the original (OCH(2)) linker. One propynyloxy-linked compound displayed an 89-fold higher efficacy than the parent drug in the acute model, and it was slightly superior to antitubercular drug OPC-67683 in a chronic infection model. |
en |
dc.publisher |
American Chemical Society |
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. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0022-2623/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Synthesis and structure-activity relationships of varied ether linker analogues of the antitubercular drug (6 S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5 H -imidazo[2,1- b ][1,3]oxazine (PA-824) |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm200377r |
en |
pubs.issue |
19 |
en |
pubs.begin-page |
6563 |
en |
pubs.volume |
54 |
en |
dc.rights.holder |
Copyright: 2011 American Chemical Society |
en |
dc.identifier.pmid |
21846109 |
en |
pubs.end-page |
6585 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
235208 |
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 |
2011-11-18 |
en |
pubs.dimensions-id |
21846109 |
en |