Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation

Mielczarek, Marcin; Devakaram, Ruth V.; Ma, Cong; Yang, Xiao; Kandemir, Hakan; Purwono, Bambang; Black, David StC.; Griffith, Renate; Lewis, Peter J.; Kumar, Naresh

Title: Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation
Creator: Mielczarek, Marcin; Devakaram, Ruth V.; Ma, Cong; Yang, Xiao; Kandemir, Hakan; Purwono, Bambang; Black, David StC.; Griffith, Renate; Lewis, Peter J.; Kumar, Naresh
Relation: Organic and Biomolecular Chemistry Vol. 12, Issue 18, p. 2882-2894
Publisher Link: http://dx.doi.org/10.1039/c4ob00460d
Publisher: Royal Society of Chemistry
Resource Type: journal article
Date: 2014
Description: 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 σ⁷⁰/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′-CHσ⁷⁰/σ^A_2.2 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.
Subject: bacteria; antibiotics resistance; RNA polymerase
Identifier: http://hdl.handle.net/1959.13/1300365
Identifier: uon:20055
Identifier: ISSN:1477-0520
Language: eng
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