dc.contributor.author |
Kmentova, I |
en |
dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Palmer, Brian |
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.contributor.author |
Thompson, Andrew |
en |
dc.date.accessioned |
2011-11-18T01:48:43Z |
en |
dc.date.issued |
2010-11 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 53(23):8421-8439 Nov 2010 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9366 |
en |
dc.description.abstract |
New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model. |
en |
dc.language |
ENG |
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 |
ONE-POT SYNTHESIS |
en |
dc.subject |
BIOLOGICAL EVALUATION |
en |
dc.subject |
ASYMMETRIC-SYNTHESIS |
en |
dc.subject |
DERIVATIVES |
en |
dc.subject |
INHIBITORS |
en |
dc.subject |
REAGENTS |
en |
dc.subject |
ACIDS |
en |
dc.subject |
ASSAY |
en |
dc.subject |
CORE |
en |
dc.title |
Synthesis and Structure-Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm101288t |
en |
pubs.issue |
23 |
en |
pubs.begin-page |
8421 |
en |
pubs.volume |
53 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
21069962 |
en |
pubs.end-page |
8439 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
177516 |
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 |
21069962 |
en |