title: Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB.
abstract: Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure-activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values <10 nM and toxicity >100 μM. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome bd oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with Mtb.
authors.affiliation: Department of Chemistry and Biochemistry, Montana State University , 103 Chemistry and Biochemistry Building, Bozeman, Montana 59717, United States.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Moraski
authors.affiliation: Department of Chemistry and Biochemistry, Montana State University , 103 Chemistry and Biochemistry Building, Bozeman, Montana 59717, United States.
authors.forename: Natalie
authors.initials: N
authors.lastname: Seeger
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Allen G
authors.initials: AG
authors.lastname: Oliver
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: 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: 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: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D007093:Imidazoles; D013844:Thiazoles
keywords: SAR; antituberculosis; imidazothiazoles; respiration target