New derivatives of phosphorus-containing compounds with amino acid and triazolethione ­fragments are potential drugs that improve memory and cognitive functions

Background. Cognitive disorders are often the main symptom of neurological and mental diseases. Given the variety of mechanisms for the development of these changes, it is necessary to search for and develop new drugs.

Aim. An experimental study of the behavioral effects of new derivatives of phosphorus-containing compounds with amino acid and triazolethione fragments as potential agents that improve memory and cognitive functions.

Material and methods. A computer prediction of the activity of 43 compounds (the Prediction Activity Spectral of Substances and Pharma expert programs) and the selection of 5 active compounds were carried out. The compounds were studied on 140 outbred male mice (14 groups, n=10) and 100 male Wistar rats (10 groups, n=10) in the “T-maze” and “Morris water maze” behavioral tests when administered intraperitoneally in doses 1/100 and 1/50 LD50 for 14 days. A comparative analysis with memantine (10 mg/kg), piracetam (100 mg/kg) and the structural analogue of the 2-chloroethoxy-para-N-dimethylaminophenylphosphorylacetohydrazide compounds (10 mg/kg) was carried out. Statistical processing was performed using the GraphPad prism 8.0.1 program with the calculation of Student's t-test.

Results. The mnemotropic activity of N-substituted ammonium salts of arylphosphinic acids and phosphorylated derivatives of thiosemicarbazides was shown, the most effective representatives of which, 2-ethoxy-2-oxoethanammonium salt (2-ethoxy-2-oxotyl)(4-tolyl) of phosphinic acid (AH15) and 2-[(diphenyl phosphoryl)acetyl]-N-phenylhydrazine-1-carbothioamide (T8), reduced the time of searching for a feeder in the “T-maze” by 2.0 and 4.3 times, respectively (p <0.05). A similar effect was observed in the Morris Water Maze, where the use of substances T8 and 2-ethoxy-2-oxoethanammonium salt (2-ethoxy-2-oxotil)(4-chlorophenyl) of phosphinic acid (B3) on the 4th day of administration led to an increase in the time spent by rats in the platform area by 1.8 and 1.6 times (p <0.05), respectively, and on the 14th day — by 1.5 times (p <0.05). Memantine and piracetam were only effective after 14 days of administration.

Conclusion. Compounds of the series of N-substituted ammonium salts of arylphosphinic acids and phosphorylated derivatives of thiosemicarbazides improve memory and learning processes in experimental rodents with a single and 14-day application, showing significant advantages over memantine and piracetam.