Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.
ABSTRACT Certain substituted 6-anilinouracils are potent and selective inhibitors of Gram+ bacterial DNA polymerase IIIC (pol IIIC). In addition, analogues with 3-substituents in the uracil ring have potent antibacterial activity against Gram+ organisms in culture. In an attempt to find optimal anilino substituents for pol IIIC binding and optimal 3-substituents for antibacterial activity, we have prepared several series of 3-substituted-6-aminouracils and assayed their activity against pol IIIC from Bacillus subtilis and a panel of Gram+ and Gram- bacteria in culture. The 6-(3-ethyl-4-methylanilino) group and closely related substituent patterns maximized pol IIIC inhibition potency. Among a series of 3-(substituted-butyl)-6-(3-ethyl-4-methylanilino)uracils, basic amino substituents increased pol IIIC inhibition, but decreased antibacterial activity. The most potent antibacterials were simple hydroxybutyl and methoxybutyl derivatives, and hydrophobically substituted piperidinylbutyl derivatives.
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ABSTRACT: Condensin—an SMC-kleisin complex—is essential for efficient segregation of sister chromatids in eukaryotes [1, 2, 3 and 4]. In Escherichia coli and Bacillus subtilis, deletion of condensin subunits results in severe growth phenotypes and the accumulation of cells lacking nucleoids [ 5 and 6]. In many other bacteria and under slow growth conditions, however, the reported phenotypes are much milder or virtually absent [ 7, 8, 9 and 10]. This raises the question of what role prokaryotic condensin might play during chromosome segregation under various growth conditions. In B. subtilis and Streptococcus pneumoniae, condensin complexes are enriched on the circular chromosome near the single origin of replication by ParB proteins bound to parS sequences [ 11 and 12]. Using conditional alleles of condensin in B. subtilis, we demonstrate that depletion of its activity results in an immediate and severe defect in the partitioning of replication origins. Multiple copies of the chromosome remain unsegregated at or near the origin of replication. Surprisingly, the growth and chromosome segregation defects in rich medium are suppressed by a reduction of replication fork velocity but not by partial inhibition of translation or transcription. Prokaryotic condensin likely prevents the formation of sister DNA interconnections at the replication fork or promotes their resolution behind the fork.Current Biology 01/2014; 24. · 9.49 Impact Factor
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ABSTRACT: Gram-positive (Gm+) bacteria express three distinct DNA polymerase-exonucleases. One of these, Gm+ DNA polymerase IIIC (DNA pol IIIC), is a highly conserved enzyme with little homology to mammalian DNA polymerase α and Gram-negative (Gm–) DNA polymerases. DNA pol IIIC has been shown to be essential in the replicative DNA synthesis of Gm+ bacteria and, as such, represents an attractive, hitherto unexploited target for antimicrobial drug development. This article briefly reviews claims for DNA pol IIIC inhibitors for the treatment of bacterial infections, registered during the period 1996 – 2004. Biological data are sparse in these patents and few claims are backed up with in vivo animal model data. Although DNA pol IIIC has clearly been validated as a bona fide target for antimicrobial drug development, the effectiveness of such an agent in the clinic, particularly against resistant strains of Gm+ bacteria, remains to be determined.08/2005; 15(8):947-953.
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ABSTRACT: In the present work, we had synthesized some novel pyrimidine-2,4-diones by condensing various substituted amines with 3-substituted -6-chlorouracil. The structure of the synthesized compounds was characterized using physical & spectral data. Novel pyrimidine-2,4-(1H,3H)-diones were then screened for their antimicrobial profile using Kirby Bauer Disc Diffusion(KBDD) method. The anti-bacterial data reveals that compounds OBP-08 and OBP-10 had better activity against tested gram-positive organism whereas OBP-06 found to have better anti-fungal activity than rest of the compounds when tested against Aspergillus niger & Penicillium marneffei. This study lead us to conclude that pyrimidine-2,4(1H,3H)-diones may be the desired scaffold to generate lead anti-infective agents. INTRODUCTION In spite of remarkable growth in human medicines, infectious diseases caused by bacteria, fungi, viruses and parasites are still a major threat to public health. There impact is particularly large in developing countries due to relative unavailability of medicines and the emergence of widespread drug resistance.12/2012;