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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Moraski, Garrett C.^1,3  Oliver, Allen G.¹  Markley, Lowell D.¹  Cho, Sanghyun²  Franzblau, Scott G.²  Miller, Marvin J.¹ 

[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

[2] Univ Illinois, Coll Pharm, Inst TB Res, Chicago, IL 60612 USA

[3] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA

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

DOI  :  10.1016/j.bmcl.2014.05.062

来源: Elsevier

【 摘 要 】

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 H(37)Rv Mtb (MIC's of 0.1 mu M and 1.3 mu M) and were inactive (MIC >128 mu M) 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 mu M, respectively), Mycobacterium kansasii (4 and 19 mu M, respectively), Mycobacterium bovis BCG (1 and 8 mu M, respectively) while all the other scaffolds were inactive (>128 mu M). (C) 2014 Elsevier Ltd. All rights reserved.

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