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.

Preparation and Evaluation of Potent Pentafluorosulfanyl‐Substituted Anti‐Tuberculosis Compounds

“…When screened against the Mtb cydKO strain, all compounds showed at least a 10-fold increase in potency, suggesting that QcrB is likely the target. [10,14] The trend of greater potency against this mutant strain was similarly observed with compounds 1 and 2 (Q203), two compounds that were reported to specifically inhibit the QcrB enzyme. [8a, 8c] Additionally, as expected, none of the negative controls (para-aminosalicylic acid (PAS), linezolid (LIN) or rifampicin (RIF) showed any significant potency enhancement in the cydKO stain.…”

“…Syntheses of our related SF 5 -bearing targets ( 13 – 20 , Fig 3) began with preparation of the desired imidazo[1,2- a ]pyridine-3-carboxylic acid (general structure, 7 ) and 2,6-dimethylimidazo[2,1- b ]thiazole-5-carboxylic acid ( 8 ) cores by following established literature procedures. [4,10] Straightforward amide bond formation was accomplished by an EDC-mediated coupling with the commercially available 3-(pentafluorosulfur)benzylamine ( 9 ) and 4-(pentafluorosulfur)benzylamine ( 10 ) (Scheme 1). …”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…identified an analogue of Q203 ( 348 ), which displayed exciting in vitro biological activity and a good pharmacokinetic profile, while Moraski et al. uncovered a series of imidazothiazoles (e.g., 349 ) which showed potent M. tuberculosis inhibitory activity in vitro, and importantly is a slight departure from the intensely explored imiazopyridines …”

Synthesis of novel derivatives of 7,8‐dihydro‐6H‐imidazo[2,1‐b][1,3]benzothiazol‐5‐one and their virus‐inhibiting activity against influenza A virus

“…Similarly, 2‐amino‐5,5‐dimethyl‐5,6‐dihydrobenzo[ d ]thiazol‐7‐(4 H )‐one ( 1b ) was also prepared from 5,5‐dimethylcyclohexane‐1,3‐dione in 82% yield. Both the compounds 1a and 1b were fully characterized by their NMR, IR, and ESI‐mass spectral data …”

“…Imidazo[2,1‐ b ]thiazole is one such fused ring system represented well in the literature . Derivatives of this scaffold have been shown to possess a wide range of biological activity, from kinase inhibition, antiviral, anticancer, and antioxidant activities to their use as potential antitubercular agents . Interest in the biological activity of these compounds is also reflected in both the number of synthetic methods found to access them and the possibility for diverse functionalization .…”