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 antitubercular 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).

Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis

“…Screening of a collection of 53 small molecules in the presence or absence of Q203 led to the identification of two quinazolin-4-amine small molecules. The small molecules were selected from a larger library assembled during an NIH project focused on the design and discovery of novel small molecules for tuberculosis treatment (Moraski et al, 2012;Tiwari et al, 2013;Moraski et al, 2014). The representative molecule ND-011992 ( Fig 1A) depleted ATP levels only in the presence of Q203 at an inhibitory concentration 50% (IC 50 ) of 0.5-1.6 lM in M. bovis BCG ( Fig 1B).…”

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…Structurally similar to the IPs, the pyrazolopyridine carboxamide series were designed as novel anti-tubercular agents through a scaffold hopping strategy [150,151] Several promising hits belonging to the chemical class of imidazopyridines (IPs) have been identified in independent screening programs [12,75,[137][138][139]. Extensive efforts have been undertaken to optimise and to explore the SAR of this scaffold [126,[140][141][142][143]. To date, the most advanced QcrB inhibitor is Q203, an IP derivative in Phase 2 clinical trials.…”

New structural classes of antituberculosis agents

“…Moreover, enhancement in activity was observed, when compound 189 was given in combination with isoniazid or rifampin . Further derivatization of the scaffold revealed compounds 190 and 191 that exhibit activity against M. tuberculosis H37Rv with MIC values of 0.1 and 1.3 μM, respectively, and nontoxic nature against Vero cells up to a test dose of 128 μM . The scaffold switching strategy resulted in compounds 192 and 193 displaying MIC values of 0.004 and 0.03 μM, respectively, against M. tuberculosis H37Rv and also impressive activity against a panel of drug‐sensitive (MIC < 0.03 μM), MDR (MIC values in range of 0.03–0.33 μM), and XDR (MIC < 0.03 μM) strains .…”