7-Alkyl-N(2)-substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity |
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Authors: | Xu Wei-Chu Wright George E Brown Neal C Long Zheng-Yu Zhi Cheng-Xin Dvoskin Sofya Gambino Joseph J Barnes Marjorie H Butler Michelle M |
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Affiliation: | a GLSynthesis Inc., One Innovation Drive, Worcester, MA 01605, USA b Microbiotix Inc., One Innovation Drive, Worcester, MA 01605, USA |
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Abstract: | Several 2-anilino- and 2-benzylamino-3-deaza-6-oxopurines [3-deazaguanines] and selected 8-methyl and 8-aza analogs have been synthesized. 7-Substituted N2-(3-ethyl-4-methylphenyl)-3-deazaguanines were potent and selective inhibitors of Gram+ bacterial DNA polymerase (pol) IIIC, and 7-substituted N2-(3,4-dichlorobenzyl)-3-deazaguanines were potent inhibitors of both pol IIIC and pol IIIE from Gram+ bacteria, but weakly inhibited pol IIIE from Gram− bacteria. Potent enzyme inhibitors in both classes inhibited the growth of Gram+ bacteria (MICs 2.5-10 μg/ml), and were inactive against the Gram− organism Escherichia coli. Several derivatives had moderate protective activity in Staphylococcus aureus-infected mice. |
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Keywords: | Synthesis Deazaguanines Antibacterial Polymerase Gram+ |
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