Antimicrobial peptides (AMPs) are generally membrane-active compounds that physically disrupt bacterial membranes. Despite extensive research, the precise mode of action of AMPs is still a topic of great debate. This work demonstrates that the initial interaction between the Gram-negative E. coli and AMPs is driven by lipopolysaccharides (LPS) that act as kinetic barriers for the binding of AMPs to the bacterial membrane. A combination of SPR and NMR experiments provide evidence suggesting that cationic AMPs first bind to the negatively charged LPS before reaching a binding place in the lipid bilayer. In the event that the initial LPS-binding is too strong (corresponding to a low dissociation rate), the cationic AMPs cannot effectively get from the LPS to the membrane, and their antimicrobial potency will thus be diminished. On the other hand, the AMPs must also be able to effectively interact with the membrane to exert its activity. The ability of the studied cyclic hexapeptides to bind LPS and to translocate into a lipid membrane is related to the nature of the cationic charge (arginine vs. lysine) and to the distribution of hydrophobicity along the molecule (alternating vs. clumped tryptophan).
Herein, we describe a rapid microwave‐assisted, metal‐free synthesis of substituted quinoxalinones and quinoxalines using the carbene‐mediated reaction between aryldiazo esters and 1,2‐diamines. The reaction can encompass a range of substituents and structural variations to afford quinoxalin‐2‐ones in 14–80 % yield and corresponding quinoxalines in good to excellent yields upon oxidation (67–96 %). The approach can be employed to generate symmetrical and unsymmetrical 2,3‐diarylquinoxalines, bis‐quinoxalines as well as novel quinoxaline‐substituted diazo esters and should be a valuable addition to the heterocycle synthesis toolbox.
The absolute configuration of cyclic peptides with two chiral centers can be unambiguously assigned with VCD. This is however not possible with three or four chiral centers. Hence, other techniques are needed to supplement VCD.
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