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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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Related in: MedlinePlus

Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, NaI, DMA, 100 °C; (b) R1R2NH, n-BuOH, microwave, 150–170 °C or R1OH, t-BuOK, THF, microwave, 160 °C.
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f0030: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, NaI, DMA, 100 °C; (b) R1R2NH, n-BuOH, microwave, 150–170 °C or R1OH, t-BuOK, THF, microwave, 160 °C.

Mentions: Further improvements to the physical properties of the compounds were sought, and a basic amine side chain was introduced to give compounds with a lower log D. The 6-position was chosen as a suitable point for appending this side-chain as modelling studies suggested that this region of the molecule was solvent exposed, so would be amenable to the introduction of this group. A range of basic side chains were introduced into this position, initially with a phenyl group fixed at the 2-position (Scheme 3). The products, shown in Table 3 demonstrated sub-100 nM enzyme potency and generally improved MIC values, and compound 11e containing the (R)-3-dimethylaminopyrrolidine basic side-chain displayed an IC50 of 53 nM against the enzyme and a 16 μM MIC against M. tuberculosis. Oxygen-linked basic side chains were also well tolerated, for example compound 11f, which showed an IC50 of 56 nM against the enzyme and 31 μM MIC against the Mycobacterium.


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)

Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, NaI, DMA, 100 °C; (b) R1R2NH, n-BuOH, microwave, 150–170 °C or R1OH, t-BuOK, THF, microwave, 160 °C.
© Copyright Policy
Related In: Results  -  Collection

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

f0030: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, NaI, DMA, 100 °C; (b) R1R2NH, n-BuOH, microwave, 150–170 °C or R1OH, t-BuOK, THF, microwave, 160 °C.
Mentions: Further improvements to the physical properties of the compounds were sought, and a basic amine side chain was introduced to give compounds with a lower log D. The 6-position was chosen as a suitable point for appending this side-chain as modelling studies suggested that this region of the molecule was solvent exposed, so would be amenable to the introduction of this group. A range of basic side chains were introduced into this position, initially with a phenyl group fixed at the 2-position (Scheme 3). The products, shown in Table 3 demonstrated sub-100 nM enzyme potency and generally improved MIC values, and compound 11e containing the (R)-3-dimethylaminopyrrolidine basic side-chain displayed an IC50 of 53 nM against the enzyme and a 16 μM MIC against M. tuberculosis. Oxygen-linked basic side chains were also well tolerated, for example compound 11f, which showed an IC50 of 56 nM against the enzyme and 31 μM MIC against the Mycobacterium.

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