title: 3'-bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC(50) = 1 microg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC(50) = 1-2 microg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 microg/mL concentration) than extracellular mycobacteria (75% reduction at 10 microg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC(50) > 100-200 microg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.
authors.affiliation: Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Shakya
authors.forename: Naveen C
authors.initials: NC
authors.lastname: Srivastav
authors.forename: Nancy
authors.initials: N
authors.lastname: Desroches
authors.forename: Babita
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: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001087:Arabinonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C550159:3'-bromo-3'-deoxyarabinofuranosylthymine; D000995:Antitubercular Agents; D001087:Arabinonucleosides; D011741:Pyrimidine Nucleosides; D007538:Isoniazid; D012293:Rifampin