Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

@article{Cleghorn2018IdentificationOM,
  title={Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB},
  author={Laura A. T. Cleghorn and Peter C. Ray and J. Odingo and Anuradha Kumar and H. Wescott and A. Korkegian and T. Masquelin and Abraham Lopez Moure and Caroline Wilson and S. Davis and Margaret Huggett and Penelope A. Turner and Alasdair R C Smith and O. Epemolu and F. Zuccotto and Jennifer Riley and P. Scullion and Y. Shishikura and L. Ferguson and J. Rull{\'a}s and L. Guijarro and K. Read and S. Green and P. Hipskind and T. Parish and P. Wyatt},
  journal={Journal of Medicinal Chemistry},
  year={2018},
  volume={61},
  pages={6592 - 6608}
}
With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino–thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure–activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with… Expand

Paper Mentions

Identification of 4-Amino-Thieno[2,3-d]Pyrimidines as QcrB Inhibitors in Mycobacterium tuberculosis
TLDR
A new series of antimycobacterial compounds, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit the growth of M. tuberculosis growth in vitro are reported. Expand
New antituberculosis drugs targeting the respiratory chain
TLDR
This review summarizes the main features and the electron transfer process of the mycobacterial respiratory chain, and the recent progress in the search for new small molecule inhibitors targeting the three main potential targets in the respiratory chain of Mycrobacterium tuberculosis. Expand
Molecule Property Analyses of Active Compounds for Mycobacterium Tuberculosis.
TLDR
The molecule-centred cheminformatics analyses points to the need to dramatically increase the diversity of chemical libraries tested and get outside of the historic Mtb property space if the authors are to generate novel improved antitubercular leads. Expand
Inhibitors of enzymes in the electron transport chain of Mycobacterium tuberculosis
TLDR
Progress is indeed promising, although the predominant focus on just three targets (NADH dehydrogenase-2, QcrB in the cytochrome bc1-aa3 supercomplex, and ATP synthase) may need to be reconsidered in light of recent findings. Expand
QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents
TLDR
The structure, function, and importance of targeting Cytochrome bcc are described, throwing light on all chemical classes of QcrB inhibitors discovered to date, to enable the development of new chemical entities. Expand
SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis
TLDR
This review describes potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes. Expand
Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds
TLDR
Imidazo[2,1-b]thiazole-5-carboxamides compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks and was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. Expand
Small organic molecules targeting the energy metabolism of Mycobacterium tuberculosis.
TLDR
This review is convinced that targeting the OP pathway can combat resistant TB and latent TB, leading to more efficient anti-TB chemotherapy and promising small organic molecules targeting OP. Expand
Targeting the cytochrome oxidases for drug development in mycobacteria.
TLDR
Current knowledge about the two mycobacterial aerobic respiratory branches, their potential as drug targets, as well as potential drawbacks are discussed. Expand
Structural modification of zolpidem led to potent antimicrobial activity in imidazo[1,2-a]pyridine/pyrimidine-1,2,3-triazoles
Ambien (zolpidem), an imidazo[1,2-a]pyridine derivative, is a commercial drug to treat insomnia which also possesses antitubercular activity against Mycobacterium tuberculosis H37Rv. In this paper,Expand
...
1
2
3
...

References

SHOWING 1-10 OF 72 REFERENCES
Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB
TLDR
Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG demonstrating a common target. Expand
SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors.
TLDR
It is identified that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex. Expand
Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium tuberculosis Appear to Target QcrB
TLDR
The most potent compounds had minimum inhibitory concentrations against Mycobacterium tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells as well as activity against intracellular bacteria. Expand
Bactericidal Activity of an Imidazo[1, 2-a]pyridine Using a Mouse M. tuberculosis Infection Model
TLDR
Findings indicate ND-09759 might be a potent candidate for the treatment of active TB in combination with current standard anti-TB drugs and histopathological analysis revealed that infected mice treated with ND- 09759 had significantly reduced inflammation relative to untreated mice. Expand
Identification of a small molecule with activity against drug-resistant and persistent tuberculosis
TLDR
In vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents. Expand
Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels
TLDR
The hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB is supported, providing further evidence of an effect on the electron transport chain. Expand
Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis
TLDR
The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. Expand
A High-Throughput Screen To Identify Inhibitors of ATP Homeostasis in Non-replicating Mycobacterium tuberculosis
TLDR
The development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole Mycobacteria is described and represents a valuable resource to decipher the biology of persistent myc Cobacteria. Expand
Design, synthesis, and X-ray analysis of a glycoconjugate bound to Mycobacterium tuberculosis antigen 85C.
TLDR
The structure of the Antigen 85 (Ag85) complex shows the compound bound within the active site of the enzyme with the thiophene moiety positioned in the putative α-chain binding site of TMM and the arabinofuranoside moiety within the known carbohydrate-binding site as exhibited for the Ag85B-trehalose crystal structure. Expand
Design , Synthesis , and X ‐ ray Analysis of a Glycoconjugate Bound to Mycobacterium tuberculosis Antigen 85 C
Tuberculosis (TB) is a global health threat with nearly 500 000 new cases of multidrug-resistant TB estimated to occur every year, so new drugs are desperately needed. A number of currentExpand
...
1
2
3
4
5
...