title: Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent.
abstract: A series of novel substituted pyridyl phenyl oxazolidinone analogues were synthesized and their structure-activity relationship (SAR) was investigated based on in vitro and in vivo antibacterial activities. The minimum inhibitory concentrations (MICs) of the synthesized compounds against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) ranged from 0.12 to 2.0 μg/mL, and against Haemophilus influenzae (Hi) from 2.0 to 8.0 μg/mL. Compared to linezolid, only four compounds (11, 12, 21 and 29) showed higher in vitro antibacterial activities and better in vivo protective effects in mice. To improve the aqueous solubility, various prodrugs of compound 11 (DA-7157), which exerted a potency that was enhanced by 2-8-fold compared to that of linezolid, were synthesized. Among the prodrugs, the phosphate compound 42 exhibited excellent aqueous solubility (>50mg/mL in DW) and good pharmacokinetic profiles, along with better in vivo efficacy than linezolid. This compound 42 is currently undergoing clinical trials with the brand name Torezolid.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, San 5, Woncheon, Yeongtong, Suwon 443-749, Republic of Korea.
authors.forename: Weon Bin
authors.initials: WB
authors.lastname: Im
authors.forename: Sun Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Sung Hak
authors.initials: SH
authors.lastname: Choi
authors.forename: John
authors.initials: J
authors.lastname: Finn
authors.forename: Sung-Hwa
authors.initials: SH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D055808:Drug Discovery; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D023303:Oxazolidinones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D013777:Tetrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D011355:Prodrugs; D013777:Tetrazoles; C546016:tedizolid