Article

Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth.

GLSynthesis Inc., One Innovation Drive, Worcester, Massachusetts 01605, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 07/2003; 46(13):2731-9. DOI: 10.1021/jm020591z
Source: PubMed

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.

0 Bookmarks
 · 
200 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the title mol-ecule, C19H21FN6O4, the dihedral angles between the benzene ring and essentially planar pyrimidine rings [maximum deviations of 0.036 (2) and 0.056 (2) Å] are 73.32 (7) and 63.81 (8)°. The dihedral angle between the mean planes of the pyrimidine rings is 61.43 (6)°. In the crystal, N-H⋯O hydrogen bonds link mol-ecules, forming a two-dimensional network parallel to (001) and in combination with weak C-H⋯O hydrogen bonds, a three-dimensional network is formed. Weak C-H⋯π inter-actions and π-π inter-actions, with a centroid-centroid distance of 3.599 (2) Å are also observed.
    Acta Crystallographica Section E Structure Reports Online 10/2014; 70(Pt 10):o1098-o1099. · 0.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
  • Source
    [Show abstract] [Hide abstract]
    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. DOI:10.1016/j.cub.2013.12.049 · 9.92 Impact Factor