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).
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.
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: †Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Sutherland
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: Iveta
authors.initials: I
authors.lastname: Kmentova
authors.affiliation: ‡Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
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, Illinois 60612, United States.
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, Illinois 60612, United States.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: §Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States.
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
authors.affiliation: †Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D002908:Chronic Disease; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; C410767:pretomanid