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).

Show simple item record Palmer, Brian en Sutherland, Hamish en Blaser, Adrian en Kmentova, Iveta en Franzblau, Scott G en Wan, Baojie en Wang, Yuehong en Ma, Zhenkun en Denny, William en Thompson, Andrew en 2018-10-16T22:18:14Z en 2015-04 en
dc.identifier.issn 0022-2623 en
dc.identifier.uri 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 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 en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype Journal Article en
pubs.elements-id 479417 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en 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

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