title: Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships.
abstract: The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here, we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogues. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple four-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.forename: Sunhee
authors.initials: S
authors.lastname: Kang
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
authors.forename: Margaret
authors.initials: M
authors.lastname: Collins
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Singh
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.forename: Pornwaratt
authors.initials: P
authors.lastname: Niyomrattanakit
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Goodwin
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000332:Aerobiosis; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D010078:Oxazines