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

Abstract

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

Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance

“…168 Stephen G. Pyne's group extensively worked on the design and synthesis of small peptidomimetic antimicrobial agents. [169][170][171][172][173] Recently, they reported the design and synthesis of a series of biphenyl positional isomers (Fig. 9d), and among these isomers, the 4,4′-isomer (compound 36) showed potent antifungal activity against C. albicans with a MIC 80 of 1 μg mL −1 .…”

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

“…In 2021, Mahadari et al disclosed new antimicrobial peptidomimetics (AMPs; 43a – 43c , Figure ) derived from the previously reported cationic amphiphilic 1,1′-binaphthyl-peptidomimetics 41 and 42 (Figure ) active against Clostridium difficile infection (CDI) and having MIC values between 4 and 8 μg/mL. − The new chemotype was designed by replacing the 1,1′-binaphthyl moiety of the parent compounds with an N -naphthyl-triazole, in order to improve the water solubility and increase the polarity of molecules while maintaining their aromatic character. In fact, the hydrophobic binaphthyl head connected to a dicationic peptide represents an important pharmacophoric portion of the molecule.…”

Introduction to the Special Issue on Clostridioides difficile

“…Another innovative anti-CDI compound was described in the contribution by Mahadari et al [19]. This research group synthesized a compound with acceptable water solubility and a CD-selective antibacterial activity.…”

“…This research group synthesized a compound with acceptable water solubility and a CD-selective antibacterial activity. Promisingly, this novel compound exhibited mild efficacy in an in vivo murine model of CDI, reducing the severity and slowing the onset of disease [19].…”