A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen’s and acetal carbon was synthesized. Thirteen compounds exhibited antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25–16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1–3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound 5c₁₂ on biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli or Pseudomonas aeruginosa was comparable or even higher than that of the benzalkonium chloride. In vivo 5c₁₂ was considerably less toxic (LD₅₀ 1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of 5c₁₂ (0.2%) was shown to be comparable to reference drugs efficiency on the rat’s skin model. The molecular target of 5c₁₂ seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.

The review considers new quaternary ammonium compounds based on pyridoxine derivatives, which were obtained and studied in 2013–2023 at the Research and Educational Center for Pharmacy of the Kazan (Volga Region) Federal University. Four structurally related classes of compounds are discussed, including mono- and bis-ammonium derivatives of pyridoxine, pyridoxine derivatives with cleavable linkers bearing an ammonium moiety, and ammonium derivatives of the unnatural pyridoxine mimetic, 3-hydroxypyridine. Synthetic schemes, biological properties, and key structure–activity relationships of the target structural series are described. For the lead-compounds belonging to specific structural chemotypes, a comprehensive profile of pharmacological properties is described, including antibacterial activity against a wide panel of Gram-positive and Gram-negative bacterial strains including clinical isolates; in vitro and in vivo toxicity; influence on the development of drug resistance. The mechanisms of action of the considered compounds as well as the prospects for their practical use are discussed.

BACKGROUND: Preventive care and successful treatment of infectious diseases (including hospital-acquired infections) are among the most important tasks of modern healthcare. Not many effective antiseptics and disinfectants available can solve this problem. Quaternary ammonium salts are currently one of the promising classes of disinfectants; however, their use is limited by the ability of microorganisms to develop resistance to the compounds. Modification of quaternary ammonium salts with substituents of various profiles is a possible way to solve this problem. AIM: To conduct a comparative analysis of the bactericidal activity of two original quaternary ammonium compounds based on pyridoxine in comparison with benzalkonium chloride. MATERIALS AND METHODS: The bactericidal profiles of 0.1 and 0.2% aqueous solutions of original quaternary ammonium salts based on pyridoxine were studied against two widespread pathogens: Staphylococcus aureus and Escherichia coli. Antibacterial activity data were obtained using a standard in vitro test (bactericidal activity test on a metal surface; exposure time of 1, 5, and 15 min). In addition to standard conditions, antibacterial efficacy was studied under protein loading conditions, in which BSA solution was added to the surface. RESULTS: For the studied compounds, the reduction factor (RF, reduction lgCFU of microorganisms) was on average ≥3. Protein loading led to a decrease in efficiency by 1–3 times. An interesting effect of exposure time-dependent specificity reversal to the S. aureus and E. coli was observed. CONCLUSIONS: The results showed the high activity of the studied compounds, which corresponds to the effectiveness criterion of RF ≥3 for commercial compounds used in this field.