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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, i-PrOH, 50 °C; (b) R1B(OH)2, Pd(PPh3)2Cl2, Et3N, MeOH, microwave, 150 °C or R1NH2, DIPEA, i-PrOH, microwave, 170 °C.
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f0025: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, i-PrOH, 50 °C; (b) R1B(OH)2, Pd(PPh3)2Cl2, Et3N, MeOH, microwave, 150 °C or R1NH2, DIPEA, i-PrOH, microwave, 170 °C.

Mentions: In order to improve the physical properties of the compounds with the aim of improving their cellular activity, it was decided to reduce the log D of the compounds and explore the effect of this in advancing the SAR. The quinazoline core was switched to a pyrimidine, and while retaining the cyclopropylaminopyrazole at the 4-position, a range of substituents including aryl and amino groups were introduced at the 2-position to allow exploration of the SAR (Scheme 2). This afforded compounds with improved potency against the enzyme (Table 2), and amongst the aryl variants, the 3-sulfonylphenyl compound 8d and 3-cyanophenyl derivative 8f showed the highest affinities at 86 and 87 nM, respectively. For the amino compounds, in addition to the cyclohexyl and cyclopentyl examples 8h and 8n at 84 and 115 nM, the substituted phenylethylamines 8k and 8l showed promising enzyme affinities of 74 and 64 nM, respectively. These compounds also demonstrated improved efficacy against M. tuberculosis although this was still relatively weak, with the majority of minimum inhibitory concentrations (MICs) falling in the 63–250 μM range. The most active example was the 3-sulfonamidophenyl variant 8c at 31 μM.


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, i-PrOH, 50 °C; (b) R1B(OH)2, Pd(PPh3)2Cl2, Et3N, MeOH, microwave, 150 °C or R1NH2, DIPEA, i-PrOH, microwave, 170 °C.
© Copyright Policy
Related In: Results  -  Collection

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

f0025: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, DIPEA, i-PrOH, 50 °C; (b) R1B(OH)2, Pd(PPh3)2Cl2, Et3N, MeOH, microwave, 150 °C or R1NH2, DIPEA, i-PrOH, microwave, 170 °C.
Mentions: In order to improve the physical properties of the compounds with the aim of improving their cellular activity, it was decided to reduce the log D of the compounds and explore the effect of this in advancing the SAR. The quinazoline core was switched to a pyrimidine, and while retaining the cyclopropylaminopyrazole at the 4-position, a range of substituents including aryl and amino groups were introduced at the 2-position to allow exploration of the SAR (Scheme 2). This afforded compounds with improved potency against the enzyme (Table 2), and amongst the aryl variants, the 3-sulfonylphenyl compound 8d and 3-cyanophenyl derivative 8f showed the highest affinities at 86 and 87 nM, respectively. For the amino compounds, in addition to the cyclohexyl and cyclopentyl examples 8h and 8n at 84 and 115 nM, the substituted phenylethylamines 8k and 8l showed promising enzyme affinities of 74 and 64 nM, respectively. These compounds also demonstrated improved efficacy against M. tuberculosis although this was still relatively weak, with the majority of minimum inhibitory concentrations (MICs) falling in the 63–250 μM range. The most active example was the 3-sulfonamidophenyl variant 8c at 31 μM.

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