Small molecule inhibitors of bacterial transcription complex formation. Issue 18 (15th September 2017)

• Record Type: Journal Article
• Authors: Wenholz, Daniel S.; Zeng, Ming; Ma, Cong; Mielczarek, Marcin; Yang, Xiao; Bhadbhade, Mohan; Black, David St. C.; Lewis, Peter J.; Griffith, Renate; Kumar, Naresh
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 18(2017)
• Page Start: 4302
• Page End: 4308
• Publication Date: 2017-09-15
• Subjects: CH clamp helix -- DOPE Discrete Optimized Protein Energy -- DS Discovery Studio -- GOLD Genetic Optimized Ligand Docking -- HE holoenzyme -- PPI proteinprotein interaction -- PDF probability density function -- RMSD root mean-square-deviation -- RNAP RNA polymerase; Antibacterial activity -- Bacterial transcription -- RNA polymerase -- Structure-activity relationship (SAR) -- Indole; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.08.036
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase- σ 70 / σ A interaction in bacteria. Synthesis was achieved via reactions between a variety of indole-7-carbaldehydes and rhodanine, N -allylrhodanine, barbituric acid or thiobarbituric acid. A library of structurally diverse compounds was examined by enzyme-linked immunosorbent assay (ELISA) to assess the inhibition of the targeted protein–protein interaction. Inhibition of bacterial growth was also evaluated using Bacillus subtilis and Escherichia coli cultures. The structure–activity relationship studies demonstrated the significance of particular structural features of the synthesized molecules for RNA polymerase- σ 70 / σ A interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds.