Synthesis of cationic antimicrobial β2′2-amino acid derivatives with potential for oral administration

Article abstract of DOI:10.1021/jm101327d

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 423.6exhibiting 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 druglike molecules with high commercial potential.