Find in Library

<i>Clostridioides</i> (also known as <i>Clostridium</i>) <i>difficile</i> 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 <i>C. difficile</i> 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 <i>N</i>-arytriazole or <i>N</i>-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 <i>N</i>-naphthyltriazole derivative <b>40</b> was identified as a <i>C. difficile</i>-selective antibacterial with MIC values of 8 µg/mL against <i>C. difficile</i> 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 (CC₅₀ 32 µg/mL against HEK293 cells) relative to lead compound <b>2</b>. Compound <b>40</b> exhibited mild efficacy (with 80% survival observed after 24 h compared to the DMSO control of 40%) in an in vivo murine model of <i>C. difficile</i> infection by reducing the severity and slowing the onset of disease.