Accessing the Thiol Toolbox: Synthesis and Structure-Activity Studies on Fluoro-Thiol Conjugated Antimicrobial Peptides.

The para-fluoro-thiol reaction (PFTR) is a modern name for the much older concept of a nucleophilic aromatic substitution reaction in which the para-position fluorine of a perfluorinated benzene moiety is substituted by a thiol. As a rapid and mild reaction, the PFTR is a useful technique for the post-synthetic modification of macromolecules like peptides on the solid phase. This reaction is of great potential since it allows for peptide chemists to access the vast catalogue of commercially available thiols with diverse structures to conjugate to peptides, which may impart favorable biological activity, particularly in antimicrobial sequences. This work covers the generation of a library of antimicrobial peptides by modifying a relatively inactive tetrapeptide with thiols of various structures using the PFTR to grant antimicrobial potency to the core sequence. In general, nucleophilic substitution of the peptide scaffold by hydrophobic thiols like cyclohexanethiol and octanethiol imparted the greatest antimicrobial activity over that of hydrophilic thiols bearing carboxylic acid or sugar moieties, which were ineffectual at improving the antimicrobial activity. The general trend here follows expected structure-activity relationship outcomes like that of changing the acyl group of lipopeptide antibiotics and is encouraging for the use of this reaction for structural modifications of antimicrobial sequences further.