Synthesis of Cationic Antimicrobial β^2,2-Amino Acid Derivatives with Potential for Oral Administration

Abstract

We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.

Membrane‐Active Small Molecules: Designs Inspired by Antimicrobial Peptides

“…The most potent compounds were those in which the lipophilic moiety was based on tert-butyl-substituted benzenes. [62] As et of novel cationic amphiphilic small-molecule biocides was also reported by our group (Table 9, Structure 29). Three important features of these compounds include:1)variable hydrophobic character,n ot only from pendentl ipophilic alkyl chainsb ut also from the lipophilic spacer chains in their design; 2) inclusion of non-peptidica mide bonds in the lipophilic alkyl chains;a nd 3) permanent positivec harges from quaternary ammonium groups instead of soft charges provided by naturala mino acids.…”

N-Terminally Modified Linear and Branched Spermine Backbone Dipeptidomimetics against Planktonic and Sessile Methicillin-Resistant Staphylococcus aureus

“…molecules for therapeutic applications (41)(42)(43)(44). Extending our previous findings with the N-terminally tagged dipeptide spermidine template, in the present work we designed two series of peptidomimetics (series 1 and 2) with linear or branched arrangements of Trp residues on the spermine backbone to explore the effects on antibacterial activity and selectivity and the mode of action.…”

An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2‐amino acids with activity against multiresistant bacteria

“…Thus, SMAMPs are versatile for optimization of both antimicrobial potency, pharmacokinetic properties, and reduction of toxicity. We have reported a series of α,α‐disubstituted β 2,2 ‐amino amides, as represented by the SMAMP 7b in Figure , that display high antimicrobial activity against gram‐positive bacteria . In the present study, we have incorporated two halogenated α,α‐disubstituted β 2,2 ‐amino acid residues into an amphipathic 13‐membered cyclic tetrapeptide scaffold and explored their antimicrobial activity (Figure ).…”

“…Two series of peptides were synthesized each containing one of two selected α,α‐disubstituted β 2,2 ‐amino acids (Figure ). The substituents on the α‐carbon of the achiral β 2,2 ‐amino acids were either 4‐trifluoromethylbenzyl or 3,5‐di‐trifluoromethylbenzyl, in which previous studies has shown to improve antimicrobial potency of small SMAMPs and minimize hepatic Phase I oxidation by including lipophilic side‐chains with a trifluoromethyl substituent . The effects of charge and lipophilicity were further varied by substituting one of the three α‐amino acids with l ‐Lys, Gly, l ‐Ala, or l ‐Phe residues, i.e., residue Xaa in the general cyclic tetrapeptide sequence c(Lys‐β 2,2 ‐Xaa‐Lys) (Figure ).…”