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Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis.

Chapman TM, Bouloc N, Buxton RS, Chugh J, Lougheed KE, Osborne SA, Saxty B, Smerdon SJ, Taylor DL, Whalley D - Bioorg. Med. Chem. Lett. (2012)

Bottom Line: Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis.However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis.Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained.

View Article: PubMed Central - PubMed

Affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. tim.chapman@tech.mrc.ac.uk

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f0005: HTS hit 1.

Mentions: A high throughput screen of our compound collection against the isolated PknB enzyme was performed through measuring the effect on the in vitro phosphorylation of the substrate GarA,7 and this identified compound 1 (Fig. 1) as a 1.35 μM inhibitor of PknB, which formed the starting point for our chemistry programme.


Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis.

Chapman TM, Bouloc N, Buxton RS, Chugh J, Lougheed KE, Osborne SA, Saxty B, Smerdon SJ, Taylor DL, Whalley D - Bioorg. Med. Chem. Lett. (2012)

HTS hit 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368261&req=5

f0005: HTS hit 1.
Mentions: A high throughput screen of our compound collection against the isolated PknB enzyme was performed through measuring the effect on the in vitro phosphorylation of the substrate GarA,7 and this identified compound 1 (Fig. 1) as a 1.35 μM inhibitor of PknB, which formed the starting point for our chemistry programme.

Bottom Line: Although a significant improvement in enzyme affinity was achieved, the aminoquinazolines showed little or no cellular activity against M. tuberculosis.However, switching to an aminopyrimidine core scaffold and the introduction of a basic amine side chain afforded compounds with nanomolar enzyme binding affinity and micromolar minimum inhibitory concentrations against M. tuberculosis.Replacement of the pyrazole head group with pyridine then allowed equipotent compounds with improved selectivity against a human kinase panel to be obtained.

View Article: PubMed Central - PubMed

Affiliation: Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK. tim.chapman@tech.mrc.ac.uk

Show MeSH
Related in: MedlinePlus