title: Synthesis and in vitro evaluation of the antitubercular and antibacterial activity of novel oxazolidinones bearing octahydrocyclopenta[c]pyrrol-2-yl moieties.
abstract: A novel series of oxazolidinone-class antimicrobial agents with 5-substituted octahydrocyclopenta[c]pyrrole moieties at the C-ring of linezolid and an acetamide or 1,2,3-triazole ring as the C-5 side chain of the oxazolidinone ring were prepared. The resulting series of compounds were evaluated for in vitro antimicrobial activity against Mycobacterium tuberculosis and a panel of clinically important resistant Gram-positive and -negative bacteria. Among them, endo-alcohol 2a and exo-alcohol 2b showed potent inhibitory activity against M. tuberculosis H37Rv, which was superior to that of linezolid. Several analogues in this series showed potent in vitro antibacterial activity against the clinically important vancomycin-resistant bacteria and showed similar or better potency against linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains. The hydroxyl group in the azabicyclic C-ring interacted with the same hydrophobic pocket as linezolid based on a docking study. Selected compounds with high antimicrobial activity showed good human microsomal stability and low CYP isozyme and monoamine oxidase (MAO) inhibition.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST).
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhattarai
authors.forename: Ju-hyeon
authors.initials: JH
authors.lastname: Lee
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Seo
authors.forename: Ghilsoo
authors.initials: G
authors.lastname: Nam
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Soon Bang
authors.initials: SB
authors.lastname: Kang
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Kwak
authors.forename: Taegwon
authors.initials: T
authors.lastname: Oh
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Eunice Eunkyeong
authors.initials: EE
authors.lastname: Kim
authors.forename: Nakcheol
authors.initials: N
authors.lastname: Jeong
authors.forename: Gyochang
authors.initials: G
authors.lastname: Keum
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D057166:High-Throughput Screening Assays; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D053961:Azabicyclo Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D011759:Pyrrolidines