期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 12, 期 18, 页码 2882-2894出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c4ob00460d
关键词
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资金
- National Health and Medical Research Council (NHMRC) Australia [1008014]
- University of New South Wales
- Living Allowance Scholarship
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 sigma(70)/sigma(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 beta'-H-sigma(70)/sigma(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.
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