title: Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids.
abstract: Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment of drug resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring hybrids was successfully performed producing hybrids that maintained antitubercular activity and had improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.lastname: Rakesh
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Aman P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: richard.lee@stjude.org.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D002908:Chronic Disease; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D023303:Oxazolidinones; C410767:pretomanid
keywords: Antibiotic; Antituberculosis; Oxazolidinone; PA-824; Pretomanid; Tuberculosis