title: Synthesis and biological activity of 3'-hydroxy-5'-aminobenzoxazinorifamycin derivatives.
abstract: As a part of our studies on the syntheses of benzoxazinorifamycin derivatives, 3'-hydroxy-5'-aminobenzoxazinorifamycin derivatives were synthesized, and tested for their antimicrobial activities. The antimicrobial activities of these compounds against gram-positive and gram-negative bacteria were almost identical to those of rifampicin (RFP) and rifabutain (RFB), however, antimicrobial activities against Mycobacterium tuberculosis were superior to RFP, while being similar to RFB. 3'-Hydroxy-5'-(4-alkyl-1-piperazinyl)benzoxazinorifamycin derivatives also had in vitro potent activities against Mycobacterium avium complex (MAC). Their minimal inhibitory concentration values against MAC were 2-256 times greater than RFP and RFB. Their in vivo efficacies against M. tuberculosis and MAC, after oral administration to mice, were superior to RFP and RFB, except for RFB against M. tuberculosis activity in vivo. Although they were absorbed from the gastrointestinal tract, their plasma levels were lower than that of RFP. Among these 5'-(4-alkyl-1-piperazinyl) derivatives, 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, compound 19 (KRM-1648), was selected as the most promising and its preliminary pharmacokinetic characteristics in mice were investigated. Compound 19 was distributed much more in tissues, especially in spleen and lung, than in plasma and had a long elimination time from tissues.
authors.affiliation: Biochemical Research Laboratories, Kaneka Corporation, Hyogo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamane
authors.forename: T
authors.initials: T
authors.lastname: Hashizume
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: E
authors.initials: E
authors.lastname: Konishi
authors.forename: K
authors.initials: K
authors.lastname: Hosoe
authors.forename: T
authors.initials: T
authors.lastname: Hidaka
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Kawaharada
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: F
authors.initials: F
authors.lastname: Kuze
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D012294:Rifamycins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins