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

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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.

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About the authors

Anastasiya V. Nikitina

Kazan State Medical University

ORCID iD: 0000-0001-6219-6246

Assistant, Depart. of Pharmacology

Russian Federation, Kazan, Russia

Irina I. Semina

Kazan State Medical University

ORCID iD: 0000-0003-3515-0845

M.D., D. Sci. (Med.), Prof., Depart. of Pharmacology, Head, Central Research Laboratory

Russian Federation, Kazan, Russia

Afrida Z. Baychurina

Kazan State Medical University

Author for correspondence.
ORCID iD: 0000-0002-7779-6583

M.D., D. Sci. (Med.), Prof., Depart. of Pharmacology

Russian Federation, Kazan, Russia

Anastasia A. Vivolaneс

Kazan State Medical University

ORCID iD: 0000-0001-6793-7939


Russian Federation, Kazan, Russia

Diana V. Akhmedieva

Kazan State Medical University

ORCID iD: 0000-0002-7666-0326


Russian Federation, Kazan, Russia


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Supplementary files

Supplementary Files
1. Рис. 1. Структурные формулы исследуемых соединений

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2. Рис. 2. Общий план — дизайн исследования

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3. Рис. 3. Влияние производных N-замещённых аммонийных солей арилфосфиновых кислот и фосфорилированных производных тиосемикарбазидов на время подхода к кормушке мышей в тесте «Т-образный лабиринт»; К — контроль; П — пирацетам (100 мг/кг); М —мемантин (10 мг/кг); * р <0,05 в сравнении с контролем.

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4. Рис. 4. Влияние производных N-замещённых аммонийных солей арилфосфиновых кислот и фосфорилированных производных тиосемикарбазидов при 4-дневном (А) и 14-дневном (Б) введении на показатели обучаемости и памяти крыс в тесте «Водный лабиринт Морриса»; К — показатели группы контрольных животных; П — показатели группы животных, которым вводили пирацетам (100 мг/кг); М — показатели группы животных, которым вводили мемантин (10 мг/кг); *статистически значимые различия между контрольной и опытной группами (р <0,05).

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