Issue 18, 2014

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 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

Supplementary files

Article information

Article type
Paper
Submitted
28 Feb 2014
Accepted
17 Mar 2014
First published
18 Mar 2014

Org. Biomol. Chem., 2014,12, 2882-2894

Author version available

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

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements