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Synthesis and Bioactivities of Kanamycin B-Derived Cationic Amphiphiles.

Abstract：

:Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Fosso MY,Shrestha SK,Green KD,Garneau-Tsodikova S

doi

10.1021/acs.jmedchem.5b01375

subject

Has Abstract

pub_date

2015-12-10 00:00:00

pages

9124-32

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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