Synthesis and antimycotic activity of quaternary ammonium salts based on pyridoxine

The in vitro screening of the antifungal activity in a series of quaternary ammonium salts based on pyridoxine revealed a highly active bis-ammonium compound, N,N′-{[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5,6-diyl]bis(methylene)} bis(N-dodecyl-N,N-dimethylammonium) dichloride (KFU-04), which exhibited pronounced antimycotic activity against a panel of various mycelial and yeast fungal pathogens, in particular, 3 reference strains and 15 clinical isolates, including drug-resistant ones. It was found that KFU-04 exerts a rapid dose-dependent effect, allowing to reduce the number of CFU of the pathogen by two to three orders of magnitude within two days, with a significant effect being observed already after 8 h from the start of incubation. In contrast to fluconazole and terbinafine, which are used world-wide to treat onychomycosis (fungal nail infections), KFU-04 under the conditions of a model experiment was found to efficiently and dose-dependently inhibit the formation of fungal biofilms of the aggressive clinical isolate C. albicans isolated from nail plates. Using two different types of high-resolution microscopy, confocal laser scanning and electron microscopy, it was shown that the membrane and possibly the cell wall of fungi are among the main targets of compound KFU-04. The described powerful and complex antimicrobial effects were not accompanied by toxicity both when applied externally and when administered systemically: in vivo experiments on rodents demonstrated the high safety of KFU-04 (LD50 > 2000 mg kg−1). In general, the obtained experimental results provided strong grounds for continuing studies of compound KFU-04 as a potential highly efficient broad-spectrum antifungal agent for combating dangerous infections.