title: Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains.
abstract: Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. h.sutherland@auckland.ac.nz
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Sutherland
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.forename: Iveta
authors.initials: I
authors.lastname: Kmentova
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Brian D
authors.initials: BD
authors.lastname: Palmer
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D010078:Oxazines; D011720:Pyrazoles