Synthesis, Antimicrobial Effect and Lipophilicity‐Activity Dependence of Three Series of Dichained N‐Alkylammonium Salts

Abstract

Quaternary ammonium salts belong to the group of cationic surfactants and their structure, especially the length of the alkyl chain, plays a significant role in its activity against various microorganisms. Globally, there is a growing need to develop novel compounds due to the increasing resistance of microorganisms to antimicrobial agents. Three series of quaternary ammonium compounds based on dichained N‐alkylammonium salts were synthesized with different carbon chain lengths (C8, C10, C12, C14, C16). These compounds were characterized with analytical methods and tested in vitro for antibacterial, antifungal, antiviral and antialgal activities. In addition, the determination of their critical micelle concentrations, lipophilicity and cytotoxicity were likewise performed to assess potential lipophilicity‐activity dependence. Almost all compounds showed a high efficacy against bacterial and fungal strains. Significant effects against Varicella zoster virus and algae were also noticed. Some of novel drugs outperformed standard benzalkonium salts. The expected trend of the correlation of an increase of cytotoxicity with the length of carbon chain was confirmed. These compounds show a higher potential as disinfectants rather than antiseptics due to their cytotoxic potential and low selectivity for microbes over mammalian cells.

Wide-Antimicrobial Spectrum of Picolinium Salts

“…Lipophilicity is an important molecular descriptor governing the intercalation of the QAS side chain into the cell membrane, with its subsequent disruption and cell death. The lipophilicity of the compounds was estimated by chromatographic study using a simple HPLC-MS method with isocratic elution, as described previously [ 18 , 26 ]. The expected linear relationship between the prolongation of the alkyl chain of QAS 4a – 6c and the increasing lipophilicity driven by the length of the alkyl chain was observed with a high correlation coefficient (R 2 < 0.97; values are listed in Figure 2 ).…”

“…A specific characteristic of surfactants is their ability to create micelles characterized as the critical micelle concentration (CMC) [ 4 , 11 , 50 , 51 ]. CMC was measured using a conductometric method, and the parameters of the experiment were set according to our previous investigations [ 9 , 26 ]. Elongation of the alkyl chains decreases the CMC value according to the Traube rule ( Figure 2 ).…”

“…The HPLC-MS analysis of intermediates and final products was performed using a Dionex UltiMate 3000 analytical system coupled with a Q Exactive Plus hybrid quadrupole-orbitrap spectrometer (ThermoFisher Scientific, Bremen, Germany) according to a gradient method using a Waters Atlantis dC18 (2.1 × 100 mm/3 μm; Waters, Ireland) column previously described by Benkova et al (2019) [ 26 ]. The purity of samples was determined from UV chromatograms recorded at a wavelength of 254 nm, and the HRMS results were determined from the total ion current spectra.…”

“…Interestingly, the relationship between the alkyl side-chain length and antibacterial activity is nonlinear. Optimal bioactivity is exhibited by C 12 –C 14 chains for G+, and C 14 –C 16 chains for G- bacteria [ 5 , 15 , 18 , 26 ]. However, the lipophilicity of the side chains seems to be a crucial factor [ 4 , 27 ], although the precise mechanism of action and structure–activity relationship is not yet fully understood.…”

“…Picolinium salts are pyridinium derivatives and can be prepared by modification of the Menshutkin reaction commonly used for the preparation of QAS [ 18 , 26 , 28 , 29 , 30 , 31 ]. Picolinium salts have, in many cases, been used as intermediates for the preparation of donor-acceptor molecules for the construction of promising photo- and electro-active materials [ 29 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”