dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Kmentova, I |
en |
dc.contributor.author |
Franzblau, SG |
en |
dc.contributor.author |
Wan, BJ |
en |
dc.contributor.author |
Wang, YH |
en |
dc.contributor.author |
Ma, ZK |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Thompson, Andrew |
en |
dc.date.accessioned |
2011-11-18T01:49:03Z |
en |
dc.date.issued |
2010-01 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 53(2):855-866 Jan 2010 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9368 |
en |
dc.description.abstract |
Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility. |
en |
dc.language |
EN |
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.subject |
NONREPLICATING MYCOBACTERIUM-TUBERCULOSIS |
en |
dc.subject |
INSECTICIDAL ACTIVITY |
en |
dc.subject |
IN-VITRO |
en |
dc.subject |
PA-824 |
en |
dc.subject |
DRUG |
en |
dc.subject |
DERIVATIVES |
en |
dc.subject |
REDUCTION |
en |
dc.subject |
ANALOGS |
en |
dc.subject |
KETONES |
en |
dc.subject |
ESTERS |
en |
dc.title |
Synthesis and Structure-activity Relationships of Antitubercular 2-Nitroimidazooxazines Bearing Heterocyclic Side Chains |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm901378u |
en |
pubs.issue |
2 |
en |
pubs.begin-page |
855 |
en |
pubs.volume |
53 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
19968290 |
en |
pubs.end-page |
866 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
118562 |
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 |
pubs.record-created-at-source-date |
2011-11-18 |
en |
pubs.dimensions-id |
19968290 |
en |