Small molecule inhibitors of bacterial transcription complex formation

Daniel S Wenholz; Ming Zeng; Cong Ma; Marcin Mielczarek; Xiao Yang; Mohan Bhadbhade; David St C Black; Peter J Lewis; Renate Griffith; Naresh Kumar

doi:10.1016/j.bmcl.2017.08.036

Small molecule inhibitors of bacterial transcription complex formation

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4302-4308. doi: 10.1016/j.bmcl.2017.08.036. Epub 2017 Aug 19.

Authors

Affiliations

¹ School of Chemistry, UNSW Sydney, Kensington, NSW 2052, Australia.
² School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
³ School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
⁴ School of Medical Sciences, UNSW Sydney, Kensington, NSW 2052, Australia.
⁵ School of Chemistry, UNSW Sydney, Kensington, NSW 2052, Australia; Australian Centre for Nanomedicine, UNSW Sydney, Kensington, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.

PMID: 28866270
DOI: 10.1016/j.bmcl.2017.08.036

Abstract

Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase-σ⁷⁰/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-σ⁷⁰/σ^A interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds.

Keywords: Antibacterial activity; Bacterial transcription; Indole; RNA polymerase; Structure-activity relationship (SAR).

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacillus subtilis / drug effects*
Bacillus subtilis / genetics
Dose-Response Relationship, Drug
Escherichia coli / drug effects*
Escherichia coli / genetics
Microbial Sensitivity Tests
Molecular Structure
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Transcription, Genetic / drug effects*

Substances

Anti-Bacterial Agents
Small Molecule Libraries