Synthesis and Bioactivities of Kanamycin B‑Derived Cationic Amphiphiles

• Published in: Journal of medicinal chemistry Vol. 58; no. 23; pp. 9124 - 9132
• Main Authors: Fosso, Marina Y, Shrestha, Sanjib K, Green, Keith D, Garneau-Tsodikova, Sylvie
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-12-2015
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Bacteria - drug effects; Bacterial Infections - drug therapy; Cell Line; Cell Survival - drug effects; Drug Design; Drug Resistance, Microbial; Fungi - drug effects; Hemolysis - drug effects; Humans; Kanamycin - analogs & derivatives; Kanamycin - chemical synthesis; Kanamycin - chemistry; Kanamycin - pharmacology; Kanamycin - toxicity; Mice; Mycoses - drug therapy; Surface-Active Agents - chemical synthesis; Surface-Active Agents - chemistry; Surface-Active Agents - pharmacology; Surface-Active Agents - toxicity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01375

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.