Synthesis and characterization of pyridoxine, nicotine and nicotinamide salts of dithiophosphoric acids as antibacterial agents against resistant wound infection

• Published in: Bioorganic & medicinal chemistry 2019-01, Vol.27 (1), p.100-109
• Main Authors: Dang, Trinh, Nizamov, Ilyas S., Salikhov, Ramazan Z., Sabirzyanova, Leysan R., Vorobev, Vyacheslav V., Burganova, Tatyana I., Shaidoullina, Marina M., Batyeva, Elvira S., Cherkasov, Rafael A., Abdullin, Timur I.
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Cytotoxicity; Dithiophosphoric acids; Monoterpenes; MRSA; Nicotinamide; Nicotine; Pyridoxine; Quaternary ammonium salts; Wound infection
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.11.017

[Display omitted] The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(–)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(–)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10 µM (6 µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC50 = 48.6 and 57.6 µM, respectively, 72 h), encouraging their further investigation as potential antimicrobials against skin and wound infections.