Chiral dithiophosphonic acids with antibacterial properties

The development of phosphorus-containing compounds with specific biocidal action and low toxicity profile is a promising direction in medicinal chemistry. Chiral properties of such compounds may contribute to their selective interactions with biological targets. In this study, racemic alcohols were reacted with 2,4-diaryl-1,3,2,4-dithiophosphetane-2,4-disulfides to yield chiral dithiophosphonic acids. O-2-Ethylhexyl-4-methoxyphenyldithiophosphonic acid 1 was prepared by the reaction of Lawesson’s reagent with 2-ethylhexanol in benzene upon moderate heating. The reaction of diethyl malate with Lawesson’s reagent was carried out at ambient temperature to form O-[1,2-di(ethoxycarbonyl)ethyl-1] 4-methoxyphenyldithiophosphonic acid 2. The compound 1 was reacted with ammonia, (S)-(–)-α-methylbenzylamine, (R)-(+)-α-methylbenzylamine, α-methylbenzylamine, pyridine, and pyridoxine to give corresponding ammonium, chiral methylbenzylammonium, pyridinium, and pyridoxinium dithiophosphonates. Hexadecylammonium O-[1,2-di(ethoxycarbonyl)ethyl-1] 4-methoxyphenyldithiophosphonate was obtained by the reaction of the compound 2 with hexadecylamine.

The synthesized salts of dithiophosphonic acids were evaluated for their in vitro bacteriostatic/bactericidal properties against Staphylococcus aureus, Bacillus subtilis, and Bacillus cereus using broth microdilution method. According to minimal inhibitory concentrations (MIC) revealed, the compounds showed good antibacterial activity with MIC in the range from 7 to 116 μg mL⁻¹. Hexadecylammonium salt of dithiophosphonic acid on the basis of diethyl malate was the most effective against the bacterial growth. The study was supported by the Subsidy Allocated to Kazan Federal University for the State Assignment in the Sphere of Scientific Activities (project FZSM-2025-0002).