From Indole to Pyrrole, Furan, Thiophene and Pyridine: Search for Novel Small Molecule Inhibitors of Bacterial Transcription Initiation Complex Formation

Publication date: Available online 21 January 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Oscar Thach, Marcin Mielczarek, Cong Ma, Samuel K. Kutty, Xiao Yang, David StC. Black, Renate Griffith, Peter J. Lewis, Naresh Kumar
The search for small molecules capable of inhibiting transcription initiation in bacteria has resulted in the synthesis of N,N′-disubstituted hydrazines and imine-carbohydrazides comprised of indole, pyridine, pyrrole, furan and thiophene using the respective trichloroacetyl derivatives, carbohydrazides and aldehydes. Replacement of the indole moiety by smaller heterocycles linked by -CO-NH-N=C- linkers afforded a broad variety of compounds efficiently targeting the RNA polymerase-σ⁷⁰/σ^A interaction as determined by ELISA and exhibiting increased inhibition of the growth of Escherichia coli compared to Bacillus subtilis in culture. The structural features of the synthesized transcription initiation inhibitors needed for antibacterial activity were identified employing molecular modelling and structure-activity relationship (SAR) studies.

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