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Issue 18, 2014
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Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation

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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 σ70/σA 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-σ70/σA2.2 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.

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

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Publication details

The article was received on 28 Feb 2014, accepted on 17 Mar 2014 and first published on 18 Mar 2014


Article type: Paper
DOI: 10.1039/C4OB00460D
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2014,12, 2882-2894
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    Synthesis and biological activity of novel bis-indole inhibitors of bacterial transcription initiation complex formation

    M. Mielczarek, R. V. Devakaram, C. Ma, X. Yang, H. Kandemir, B. Purwono, D. StC. Black, R. Griffith, P. J. Lewis and N. Kumar, Org. Biomol. Chem., 2014, 12, 2882
    DOI: 10.1039/C4OB00460D

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