title: Scaffold-switching: an exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates.
abstract: A set of 5,6-fused bicyclic heteroaromatic scaffolds were investigated for their in vitro anti-tubercular activity versus replicating and non-replicating strains of Mycobacterium tuberculosis (Mtb) in an attempt to find an alternative scaffold to the imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines that were previously shown to have potent activity against replicating and drug resistant Mtb. The five new bicyclic heteroaromatic scaffolds explored in this study include a 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxamide (7), a 2,6-dimethyl-1H-indole-3-carboxamide (8), a 6-methyl-1H-indazole-3-carboxamide (9), a 7-methyl-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide (10), and a 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide (11). Additionally, imidazo[1,2-a]pyridines isomers (2 and 12) and a homologous imidazo[1,2-a]pyrimidine isomer (6) were prepared and compared. Compounds 2 and 6 were found to be the most potent against H37Rv Mtb (MIC's of 0.1 μM and 1.3 μM) and were inactive (MIC >128 μM) against Staphylococcus aureus, Escherichia coli and Candida albicans. Against other non-tubercular mycobacteria strains, compounds 2 and 6 had activity against Mycobacterium avium (16 and 122 μM, respectively), Mycobacterium kansasii (4 and 19 μM, respectively), Mycobacterium bovis BCG (1 and 8 μM, respectively) while all the other scaffolds were inactive (>128 μM).
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Moraski
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Allen G
authors.initials: AG
authors.lastname: Oliver
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Lowell D
authors.initials: LD
authors.lastname: Markley
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
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, IL 60612, USA.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: mmiller1@nd.edu.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001643:Bridged Bicyclo Compounds; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D007093:Imidazoles; C000595763:N-benzyl-2,6-dimethylimidazo(1,2-a)pyridine-3-carboxamide; C000595764:N-benzyl-2,6-dimethylimidazo(1,2-a)pyrimidine-3-carboxamide; D011725:Pyridines; D011743:Pyrimidines
keywords: 5,6-Fused bicyclic system; Antituberculosis; Imidazo[1,2-a]pyridine; Imidazo[1,2-a]pyrimidine; Scaffold hopping