title: Growth inhibition of Mycobacterium bovis, Mycobacterium tuberculosis and Mycobacterium avium in vitro: effect of 1-beta-D-2'-arabinofuranosyl and 1-(2'-deoxy-2'-fluoro-beta-D-2'-ribofuranosyl) pyrimidine nucleoside analogs.
abstract: The resurgence of tuberculosis and the emergence of multiple-drug-resistant strains of Mycobacteria necessitate the search for new classes of antimycobacterial agents. We synthesized a series of 1-beta-D-2'-arabinofuranosyl and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl) pyrimidine nucleosides possessing diverse sets of alkynyl, alkenyl, alkyl, and halo substituents at the C-5 position of the uracil and investigated their effect on activity against M. tuberculosis, M. bovis, and M. avium. Among these molecules, 5-alkynyl-substituted derivatives emerged as potent inhibitors of M. bovis, M. tuberculosis, and M. avium. Nucleosides 1-beta-D-2'-arabinofuranosyl-5-dodecynyluracil (5), 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-dodecynyluracil (24), and 1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)-5-tetradecynyluracil (25) showed the highest antimycobacterial potency against M. bovis and M. tuberculosis. The MIC90 exhibited by compounds 5, 24, and 25 was similar or close to that of the reference drug rifampicin. The most active compounds 5, 24, and 25 were also found to retain sensitivity against a rifampicin-resistant strain of M. tuberculosis H37Rv at similar concentrations. Some of these analogs also revealed in vitro antimicrobial effect against several other gram-positive pathogens.
authors.affiliation: Department of Laboratory Medicine and Pathology, 1-71 Medical Sciences Building, University of Alberta, Edmonton, AB, Canada T6G 2H7.
authors.forename: Monika
authors.initials: M
authors.lastname: Johar
authors.forename: Tracey
authors.initials: T
authors.lastname: Manning
authors.forename: Christopher
authors.initials: C
authors.lastname: Tse
authors.forename: Nancy
authors.initials: N
authors.lastname: Desroches
authors.forename: B
authors.initials: B
authors.lastname: Agrawal
authors.forename: Dennis Y
authors.initials: DY
authors.lastname: Kunimoto
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D024881:Drug Resistance, Bacterial; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects* / Q000254:growth & development; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C523424:1-(2'-deoxy-2'-fluororibofuranosyl)-5-dodecynyluracil; C523425:1-(2'-deoxy-2'-fluororibofuranosyl)-5-tetradecynyluracil; C523423:1-2'-arabinofuranosyl-5-dodecynyluracil; D011741:Pyrimidine Nucleosides; D005467:Floxuridine; D001086:Arabinofuranosyluracil; D012293:Rifampin