2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3493-8. doi: 10.1016/j.bmcl.2014.05.062.
Garrett C Moraski 1,  Allen G Oliver 2,  Lowell D Markley 2,  Sanghyun Cho 3,  Scott G Franzblau 3,  Marvin J Miller 4
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
  • 3 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
  • 4 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: mmiller1@nd.edu.
PMID: 24909079 DOI: 10.1016/j.bmcl.2014.05.062
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).

Keywords

5,6-Fused bicyclic system; Antituberculosis; Imidazo[1,2-a]pyridine; Imidazo[1,2-a]pyrimidine; Scaffold hopping.

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