title: Pentacyclic nitrofurans with in vivo efficacy and activity against nonreplicating Mycobacterium tuberculosis.
abstract: The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis.
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Rakesh
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: David F
authors: DF
authors: Bruhn
authors: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Michael S
authors: MS
authors: Scherman
authors: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Lisa K
authors: LK
authors: Woolhiser
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Dora B
authors: DB
authors: Madhura
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Marcus M
authors: MM
authors: Maddox
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America ; Biomedical Sciences Program, Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Aman P
authors: AP
authors: Singh
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Robin B
authors: RB
authors: Lee
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Julian G
authors: JG
authors: Hurdle
authors: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Michael R
authors: MR
authors: McNeil
authors: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Anne J
authors: AJ
authors: Lenaerts
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Bernd
authors: B
authors: Meibohm
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America ; Biomedical Sciences Program, Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Richard E
authors: RE
authors: Lee
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D009581:Nitrofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D009581:Nitrofurans