title: From indole to pyrrole, furan, thiophene and pyridine: Search for novel small molecule inhibitors of bacterial transcription initiation complex formation.
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 CONHNC linkers afforded a broad variety of compounds efficiently targeting the RNA polymerase-σ(70)/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.
authors: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors: Oscar
authors: O
authors: Thach
authors: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors: Marcin
authors: M
authors: Mielczarek
authors: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors: Cong
authors: C
authors: Ma
authors: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors: Samuel K
authors: SK
authors: Kutty
authors: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors: Xiao
authors: X
authors: Yang
authors: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors: David StC
authors: DS
authors: Black
authors: School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia.
authors: Renate
authors: R
authors: Griffith
authors: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors: Peter J
authors: PJ
authors: Lewis
authors: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.
authors: Naresh
authors: N
authors: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061785:Transcription Initiation, Genetic / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D005663:Furans; D007211:Indoles; D046912:Multiprotein Complexes; D011725:Pyridines; D011758:Pyrroles; D054852:Small Molecule Libraries; D013876:Thiophenes; D012321:DNA-Directed RNA Polymerases; C023666:pyridine; C039281:furan
keywords: Antibacterial activity; Indole-carbohydrazides; Pyrrole-carbohydrazides; RNA polymerase; Thiophene-carbohydrazides