title: Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and "Anagrams" Generated Potent Antituberculosis Agents.
abstract: Zolpidem (Ambien,1) is an imidazo[1,2-a]pyridine-3-acetamide and an approved drug for the treatment of insomnia. As medicinal chemists enamored by how structure imparts biological function, we found it to have strikingly similar structure to the antitubercular imidazo[1,2-a]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10-50 μM) when screened against replicatingMycobacterium tuberculosis(Mtb) H37Rv. Manipulation of the Zolpidem structure, notably, to structural isomers ("anagrams"), attains remarkably improved potency (5, MIC of 0.004 μM) and impressive potency against clinically relevant drug-sensitive, multi- and extensively drug-resistantMtbstrains (MIC < 0.03 μM). Zolpidem anagrams and analogues were synthesized and evaluated for their antitubercular potency, toxicity, and spectrum of activity against nontubercular mycobacteria and Gram-positive and Gram-negative bacteria. These efforts toward the rational design of isomeric anagrams of a well-known sleep aid underscore the possibility that further optimization of the imidazo[1,2-a]pyridine core may well "put TB to rest".
authors.affiliation: Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Moraski
authors.affiliation: Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
authors.forename: Mai Ann
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
authors.forename: Juliane
authors.initials: J
authors.lastname: Ollinger
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, Seattle, Washington 98102, United States.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Anderson
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
keywords: Ambien; anti-TB; imidazopyridine analogues; tuberculosis; zolpidem