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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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Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, Et3N, NaI, DMA, microwave, 150 °C; (b) R1R2NH, n-BuOH, microwave, 170 °C; (c) R3PhB(OH)2, Pd(PPh3)4, copper(I) thiophene carboxylate, dioxane, microwave, 150 °C.
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f0035: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, Et3N, NaI, DMA, microwave, 150 °C; (b) R1R2NH, n-BuOH, microwave, 170 °C; (c) R3PhB(OH)2, Pd(PPh3)4, copper(I) thiophene carboxylate, dioxane, microwave, 150 °C.

Mentions: Considering the enhanced enzyme binding affinity that had resulted from the presence of a 3-cyano or 3-sulfonyl group on the phenyl ring in the disubstituted variants (Table 2), these substituents were introduced into the trisubstituted pyrimidines aiming for a corresponding increase in enzyme potency and activity against M. tuberculosis. Starting with 4,6-dichloro-2-(methylthio)pyrimidine 12, the cyclopropylaminopyrazole group and the basic amine side-chain were sequentially introduced under nucleophilic displacement conditions. This was followed by a Liebeskind–Srogl coupling9 under microwave heating on the S-methyl pyrimidine 14 to install the desired aryl group (Scheme 4). However, the resultant compounds displayed modest gains in enzyme affinity (approximately twofold for 15b and 15c) and no significant improvement in activity against M. tuberculosis (Table 4), which remained between 31 and 63 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, Et3N, NaI, DMA, microwave, 150 °C; (b) R1R2NH, n-BuOH, microwave, 170 °C; (c) R3PhB(OH)2, Pd(PPh3)4, copper(I) thiophene carboxylate, dioxane, microwave, 150 °C.
© Copyright Policy
Related In: Results  -  Collection

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

f0035: Reagents and conditions: (a) 3-Amino-5-cyclopropylpyrazole, Et3N, NaI, DMA, microwave, 150 °C; (b) R1R2NH, n-BuOH, microwave, 170 °C; (c) R3PhB(OH)2, Pd(PPh3)4, copper(I) thiophene carboxylate, dioxane, microwave, 150 °C.
Mentions: Considering the enhanced enzyme binding affinity that had resulted from the presence of a 3-cyano or 3-sulfonyl group on the phenyl ring in the disubstituted variants (Table 2), these substituents were introduced into the trisubstituted pyrimidines aiming for a corresponding increase in enzyme potency and activity against M. tuberculosis. Starting with 4,6-dichloro-2-(methylthio)pyrimidine 12, the cyclopropylaminopyrazole group and the basic amine side-chain were sequentially introduced under nucleophilic displacement conditions. This was followed by a Liebeskind–Srogl coupling9 under microwave heating on the S-methyl pyrimidine 14 to install the desired aryl group (Scheme 4). However, the resultant compounds displayed modest gains in enzyme affinity (approximately twofold for 15b and 15c) and no significant improvement in activity against M. tuberculosis (Table 4), which remained between 31 and 63 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