The synthesis and screening of 1,4,5,8-naphthalenetetracarboxylic diimide–peptide conjugates with antibacterial activity

We have employed an initial combinatorial approach followed by systematic lead optimization to investigate a series of novel molecules that exhibit antimicrobial activity against Gram-negative and Gram-positive bacteria. The new molecules contain various sequences of amino acids, generally l-lysine and glycine, attached to the 1,4,5,8-naphthalenetetracarboxylic diimide aromatic unit. Systematic structure–activity studies found that increasing positive charge enhanced activity and molecules containing one naphthalenetetracarboxylic diimide unit as well as at least seven lysine residues were optimum for antimicrobial activity. The naphthalenetetracarboxylic diimide derivatives were found to be inactive against mammalian cell lines, making them excellent antimicrobial candidates. Our results indicate that combining positive charge with aromatic and/or hydrophobic elements may be an interesting new approach to antimicrobial agents and adds an important new dimension to the field of cationic peptides.

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