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.

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents

“…We also observed that all of our bisbenzimidazole derivatives displayed no activity (≥31.2 µg/mL) against A. flavus ATCC MYA-3631 (strain K ). As we and others previously discovered that the addition of long alkyl chains to aminoglycosides such as kanamycin A (KANA), 34 kanamycin B (KANB), 12, 35 and tobramycin (TOB) 11, 13 results in killing of fungal cells through membrane perturbation, we decided to functionalize the bisbenzimidazole core with various alkyl chains hoping for an additive action against fungal growth. The divergent synthetic strategy allowed us to introduce various alkyl chains on either side of the molecule efficiently.…”

Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

“…This phenomenon of increased growth in the presence of small quantities of xenobiotics has been previously observed. 21–25 Due to this effect, cotreatment with KAN and Eis inhibitors may result in a faster cell growth than that for KAN alone.…”

A complex game of hide and seek: the search for new antifungals

“…5) and B ( 2d , Fig. 5), 69, 70 have been alkylated and found to display antifungal activity, while the parent drugs do not. Additionally, the strategy of generating membrane-disrupting amphiphilic molecules displays one major advantage over the traditional method of modifying existing azoles: there is less likelihood of resistance for these compounds.…”