- Structural optimization of natural product nordihydroguaretic acid to discover novel analogues as AcrB inhibitors
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Drug efflux pumps confer multidrug resistance to dangerous bacterial pathogens which makes these proteins promising drug targets. Herein, we present initial chemical optimization and structure-activity relationship (SAR) data around a previously described efflux pump inhibitor, nordihydroguaretic acid (NDGA). Four series of novel NDGA analogues that target Escherichia coli AcrB were designed, synthesized and evaluated for their ability to potentiate the activity of antibiotics, to inhibit AcrB-mediated substrate efflux and reduce off-target activity. Nine novel structures were identified that increased the efficacy of a panel of antibiotics, inhibited drug efflux and reduced permeabilization of the bacterial outer and inner membranes. Among them, WA7, WB11 and WD6 possessing broad-spectrum antimicrobial sensitization activity were identified as NDGA analogues with favorable properties as potential AcrB inhibitors, demonstrating moderate improvement in potency as compared to NDGA. In particular, WD6 was the most broadly active analogue improving the activity of all four classes of antibacterials tested.
- Alenzy, Rawaf,Liu, Xingbang,Ma, Shutao,Ma, Yingang,Mowla, Rumana,Polyak, Steven W.,Song, Di,Teng, Yuetai,Venter, Henrietta,Wang, Yinhu
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- Synthesis and photochemical properties of photo-cleavable crosslinkers
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We report herein the synthesis and the development of homo-bifunctional photo-cleavable sulfhydryl group cross-linkers that are able to react and then to photorelease two cysteines leading to the photoregulation of cross-linkers cleavage.
- Omran, Ziad,Specht, Alexandre
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supporting information; experimental part
p. 2434 - 2436
(2009/08/07)
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- Synthesis and structure activity relationships of fibrinolytic 1,ω diphenyl 1,ω alkanediamines
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The promising results obtained in animal clot lysis experiments with the fibrinolytic bis(tetrahydroiso quinolines) VI prompted the preparation of a related series of 1,ω diphenyl 1,ω alkanediamines V. As measured in the standard rat screen (ip) the compo
- Fliedner Jr,Myers,Schor,Pachter
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p. 749 - 754
(2007/10/06)
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