title: Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation.
abstract: The increasing resistance of bacteria against clinically approved antibiotics is resulting in an alarming decrease in therapeutic options for today's clinicians. We have targeted the essential interaction between bacterial RNA polymerase and σ(70)/σ(A) for the development of lead molecules exhibiting a novel mechanism of antibacterial activity. Several classes of structurally related bis-indole inhibitors of bacterial transcription initiation complex formation were synthesized and their antimicrobial activities were evaluated. Condensation of indole-7- and indole-2-carbohydrazides with 7- and 2-trichloroacetylindoles or indole-7- and indole-2-glyoxyloyl chlorides resulted in the successful synthesis of 7,7'-, 2,2'-, 2,7'- and 3,2'-linked bis-indole derivatives with -CO-NH-NH-CO- and -CO-CO-NH-NH-CO- linkers. Indole-7-glyoxyloyl chlorides were reacted with hydrazine hydrate in different ratios to afford respective -CO-CO-NH-NH-CO-CO- bis-indole or hydrazide derivatives. The resulting compounds were found to be active against the β'-CH-σ(70)/σ interaction in ELISA assays and inhibited the growth of both Gram-positive and Gram-negative bacteria. Structure-activity relationship (SAR) studies were performed in order to identify the structural features of the synthesized inhibitors required for biological activity.
authors.affiliation: School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia. n.kumar@unsw.edu.au.
authors.forename: Marcin
authors.initials: M
authors.lastname: Mielczarek
authors.forename: Ruth V
authors.initials: RV
authors.lastname: Devakaram
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Hakan
authors.initials: H
authors.lastname: Kandemir
authors.forename: Bambang
authors.initials: B
authors.lastname: Purwono
authors.forename: David StC
authors.initials: DS
authors.lastname: Black
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lewis
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
mesh_terms: D000900:Anti-Bacterial Agents / 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; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061785:Transcription Initiation, Genetic / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D007211:Indoles; C030374:indole; D012321:DNA-Directed RNA Polymerases