dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
Sutherland, Hamish |
en |
dc.contributor.author |
Blaser, Adrian |
en |
dc.contributor.author |
Kmentova, Iveta |
en |
dc.contributor.author |
Franzblau, Scott G |
en |
dc.contributor.author |
Wan, Baojie |
en |
dc.contributor.author |
Wang, Yuehong |
en |
dc.contributor.author |
Ma, Zhenkun |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Thompson, Andrew |
en |
dc.date.accessioned |
2018-10-16T22:18:14Z |
en |
dc.date.issued |
2015-04 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/42159 |
en |
dc.description.abstract |
Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat. |
en |
dc.format.medium |
Print-Electronic |
en |
dc.language |
eng |
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. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Microsomes, Liver |
en |
dc.subject |
Animals |
en |
dc.subject |
Mice, Inbred Strains |
en |
dc.subject |
Mice, Inbred BALB C |
en |
dc.subject |
Humans |
en |
dc.subject |
Rats, Sprague-Dawley |
en |
dc.subject |
Mycobacterium tuberculosis |
en |
dc.subject |
Tuberculosis |
en |
dc.subject |
Disease Models, Animal |
en |
dc.subject |
Chronic Disease |
en |
dc.subject |
Nitroimidazoles |
en |
dc.subject |
Oxazoles |
en |
dc.subject |
Antitubercular Agents |
en |
dc.subject |
Microbial Sensitivity Tests |
en |
dc.subject |
Administration, Oral |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.subject |
Biological Availability |
en |
dc.subject |
Male |
en |
dc.subject |
Chemistry Techniques, Synthetic |
en |
dc.title |
Synthesis and structure-activity relationships for extended side chain 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/jm501608q |
en |
pubs.issue |
7 |
en |
pubs.begin-page |
3036 |
en |
pubs.volume |
58 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
25781074 |
en |
pubs.end-page |
3059 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
479417 |
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 |
2015-03-18 |
en |
pubs.dimensions-id |
25781074 |
en |