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Design, synthesis, and structure-activity relationships of benzophenone-based tetraamides as novel antibacterial agents.

Abstract：

:The increase in the incidence of both hospital- and community-acquired antibiotic-resistant infections is a major concern to the healthcare community. There have been only two new classes of antibiotics approved by the FDA over the past 40 years, and clearly there is a growing need for additional antimicrobial agents. In this paper, we present our work on the discovery of a class of benzophenone containing compounds that possess good activity against MRSA, VISA, VRSA, and VRE and moderate activity against E. coli. These compounds display MIC values in the 0.5-2.0 mg/L range and are not cytotoxic against mammalian cells. Extensive structure-activity relationship studies revealed that the benzophenone was absolutely essential for antibacterial activity as was the presence of a cationic group. Although these agents display DNA binding activity, we observed that these compounds do not inhibit any macromolecular synthesis reliant upon DNA nor do they inhibit lipid or cell wall biosynthesis. Instead, we found that these agents cause membrane depolarization, indicating that the bacterial membrane was the primary site of action for these agents. Our studies suggest that caution should be taken in assigning the mechanism of action for DNA binding antibiotics.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Vooturi SK,Cheung CM,Rybak MJ,Firestine SM

doi

10.1021/jm900519b

subject

Has Abstract

pub_date

2009-08-27 00:00:00

pages

5020-31

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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