Cationic Peptidomimetic Amphiphiles Having a -Aryl- or -Naphthyl-1,2,3-Triazole Core Structure Targeting () : Synthesis, Antibacterial Evaluation, and an In Vivo Infection Model.

(also known as ) is a Gram-positive anaerobic, spore producing bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are inadequate, expensive, and limited, and thus inexpensive drug treatments for infection (CDI) with improved efficacy and specificity are urgently needed. To improve the solubility of our cationic amphiphilic 1,1'-binaphthylpeptidomimetics developed earlier that showed promise in an in vivo murine CDI model we have synthesized related compounds with an -arytriazole or -naphthyltriazole moiety instead of the 1,1'-biphenyl or 1,1'-binaphthyl moiety. This modification was made to increase the polarity and thus water solubility of the overall peptidomimetics, while maintaining the aromatic character. The dicationic -naphthyltriazole derivative was identified as a -selective antibacterial with MIC values of 8 µg/mL against strains ATCC 700057 and 132 (both ribotype 027). This compound displayed increased water solubility and reduced hemolytic activity (32 µg/mL) in an in vitro hemolysis assay and reduced cytotoxicity (CC 32 µg/mL against HEK293 cells) relative to lead compound . Compound exhibited mild efficacy (with 80% survival observed after 24 h compared to the DMSO control of 40%) in an in vivo murine model of infection by reducing the severity and slowing the onset of disease.