From indole to pyrrole, furan, thiophene and pyridine: Search for novel small molecule inhibitors of bacterial transcription initiation complex formation

Oscar Thach, Marcin Mielczarek, Cong Ma, Samuel K. Kutty, Xiao Yang, David St C. Black, Renate Griffith, Peter J. Lewis, Naresh Kumar

Research output: Journal article publicationJournal articleAcademic researchpeer-review

7 Citations (Scopus)

Abstract

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/σAinteraction 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.
Original languageEnglish
Pages (from-to)1171-1182
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number6
DOIs
Publication statusPublished - 15 Mar 2016
Externally publishedYes

Keywords

  • Antibacterial activity
  • Indole-carbohydrazides
  • Pyrrole-carbohydrazides
  • RNA polymerase
  • Thiophene-carbohydrazides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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