Romanian Society of Pharmaceutical Sciences
 

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SYNTHESIS, MOLECULAR DOCKING, AND PHARMACOLOGICAL EVALUATION OF NOVEL AMIDES OF 2-(3-(1-BENZYL-5-OXOPYRROLIDIN-3-YL)-5-THIOXO-4,5-DIHYDRO-1H-1,2,4-TRIAZOL-4-YL)ACETIC ACID AS POTENTIAL NOOTROPIC AGENTS

LINA PEREKHODA 1, RUSTAM SULEIMAN 1, ANTON SEMENETS 2, SERGII SHTRYGOL 3, MARHARYTA SULEIMAN 1*, NATALIIA KOBZAR 1, VITALIY YAREMENKO 1, VICTORIYA GEORGIYANTS 1, SERGIY M. KOVALENKO ⁴

¹ Department of Pharmaceutical Chemistry, National University of Pharmacy, 61002, Kharkiv, Ukraine
2 Bayer Limited Liability Company, 0407, Kyiv, Ukraine
3 Department of Pharmacology and Clinical Pharmacy, National University of Pharmacy, 61002, Kharkiv, Ukraine
4 Department of Organic Chemistry and Molecular Materials, V.N.Karazin Kharkiv National University, 61077, Kharkiv,
Ukraine

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Pyrrolidone derivatives are promising substances for supporting and restoring cognitive functions in various etiological forms and disorders. The search for active molecules in this class of substances is becoming increasingly relevant, particularly in connection with the prevalence of post-COVID-19 cognitive deficits, neurodegenerative diseases, and traumatic brain injuries. In order to obtain new potential nootropics, a chemical modification of the synthetic framework we previously obtained, 1- benzyl-4-(5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-one, was carried out by introducing an acetate group and subsequent amidation with the corresponding amines. The structure and purity of the obtained amides were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy, and LC/MS. The effectiveness of the performed chemical modification was confirmed by molecular docking to the nootropic biomolecules, the α-amino-3-hydroxy-5-methyl-4-isoxa- zolepropionic acid (AMPA) receptor and the muscarinic (M1) acetylcholine receptor, as well as by pharmacological studies of antiamnesic activity. In the passive avoidance test in mice, the most promising compound, 1-benzyl-4-{4-[2-oxo-2-(piperidin- 1-yl)ethyl]-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl}pyrrolidine-2-one 9d, was found, which eliminated the amnesic effect of scopolamine: 100% of the animals that had reached the learning criterion, and the antiamnesic activity was 106.4%.