title: Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.
abstract: In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.
authors.affiliation: Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sasaki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Haraguchi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Itotani
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kuroda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hashizume
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tomishige
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Komatsu
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tsubouchi
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D010080:Oxazoles; D012293:Rifampin