title: Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation.
abstract: Our ongoing research focused on targeting transcription initiation in bacteria has resulted in synthesis of several classes of mono-indole and mono-benzofuran inhibitors that targeted the essential protein-protein interaction between RNA polymerase core and σ(70)/σ(A) factors in bacteria. In this study, the reaction of indole-2-, indole-3-, indole-7- and benzofuran-2-glyoxyloyl chlorides with amines and hydrazines afforded a variety of glyoxyloylamides and glyoxyloylhydrazides. Similarly, condensation of 2- and 7-trichloroacetylindoles with amines and hydrazines delivered amides and hydrazides. The novel molecules were found to inhibit the RNA polymerase-σ(70)/σ(A) interaction as measured by ELISA, and also inhibited the growth of both Gram-positive and Gram-negative bacteria in culture. Structure-activity relationship (SAR) studies of the mono-indole and mono-benzofuran inhibitors suggested that the hydrophilic-hydrophobic balance is an important determinant of biological activity.
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Marcin
authors.initials: M
authors.lastname: Mielczarek
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Ruth V
authors.initials: RV
authors.lastname: Thomas
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia; School of Chemistry, Faculty of Art and Science, Namik Kemal University, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Kandemir
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Mohan
authors.initials: M
authors.lastname: Bhadbhade
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.affiliation: School of Medical Sciences, Department of Pharmacology, UNSW Australia, Sydney, NSW 2052, Australia.
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lewis
authors.affiliation: School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia; Australian Centre for Nanomedicine, University of New South Wales, Sydney 2052, Australia. Electronic address: n.kumar@unsw.edu.au.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001572:Benzofurans; D007211:Indoles; C030374:indole; D012321:DNA-Directed RNA Polymerases; C105430:benzofuran
keywords: Antibacterial activity; Mono-benzofurans; Mono-indoles; RNA polymerase; Structure–activity relationship (SAR); σ(70)/σ(A) factors