Minimalistic bis-triarylpyridinium cations: effective antimicrobials against bacterial and fungal pathogens

A series of twelve compounds from the family of 2,4,6-triarylpyridinium cations have been synthesized, chemically characterized (¹H, ¹³C NMR, HRMS), and microbiologically evaluated (MIC determination against <i>S. aureus</i>, <i>E. faecalis</i>, <i>E. coli</i>, <i>P. aeruginosa</i>, and <i>C. albicans</i>). These compounds are quaternary ammonium cations (QACs), classified as either mono-QACs or bis-QACs. The mono-QACs are further divided into those with short (three-carbon) and long (twelve-carbon) pendant chains. An additional structural variable is the number of bromine atoms attached to the aromatic rings, ranging from zero to three. The major findings of this study are: (a) bis-QACs exhibit notably higher antimicrobial activity than mono-QACs; (b) an increased number of bromine atoms on the structure appears to diminish antimicrobial properties and (c) one of the compounds (1a) shows particularly promising properties as a broad spectrum antimicrobial, given its low MICs across all five pathogenic microorganisms studied. Preliminary assays with <i>C. albicans</i> show that 1a has a strong mitochondrial activity, causing a remarkable mitochondrial membrane depolarization in this organelle. Taken together, this study positions triarylpyridinium cations-previously unexplored as antimicrobials-as promising candidates for future drug development, especially in light of the growing concern over drug-resistant microorganisms.