title: Biarylmethoxy 2-nitroimidazooxazine antituberculosis agents: Effects of proximal ring substitution and linker reversal on metabolism and efficacy.
abstract: Certain biaryl analogues of antitubercular drug PA-824 displayed enhanced in vivo efficacies yet retained some susceptibility towards oxidative metabolism; therefore, two new strategies were explored to address this. Ortho-substitution of the proximal aryl ring with larger electron-withdrawing substituents maintained or improved compound stability but reduced aerobic potency; however, fluoro and cyano were well tolerated. In vivo, only 2'- or 3'-fluoro mono-substitution preserved high efficacy against acute infection, although one example was twofold more effective than delamanid against chronic infection. Reversal of the 6-oxymethylene linkage also permitted high potency and improved stability towards human liver microsomes, albeit, in vivo results were inferior. These novel findings provide further insight into the preferred structural features for lead candidates in this important drug class.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: am.thompson@auckland.ac.nz.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Global Alliance for TB Drug Development, 40 Wall St, New York 10005, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D010080:Oxazoles
keywords: Delamanid; In vivo efficacy; Metabolism; Nitroimidazole; PA-824; Tuberculosis