Synthesis and Action of N-acylphenylacetamides and N-acyl-β-ketoamides on the Central Nervous System

Introduction. One of the most promising directions in the search for biologically active compounds is the molecular design of biologically active compounds containing a known pharmacoform fragment. In this article, phenylacetic acid derivatives are considered as a scaffold for the search for biologically active compounds. However, the phenylacetamide derivative is of particular interest, its fragment is included in the structure of the atenolol drug. Optimization of methods for the synthesis of N-acylphenylacetamides and N-acyl-β-ketoamides will expand the boundaries of molecular design and targeted synthesis of biologically active substances containing a phenylacetic acid fragment as a centroid.

Aim. Obtain N-acylphenylacetamides and N-acyl-β-ketoamides, optimize the synthesis and isolation methods, and establish the degree of manifestation of the psychotropic activity of the compounds.

Materials and methods. Obtaining the target N-acylphenylacetamides was carried out by the interaction of 2-phenylacetamide with carboxylic acid anhydrides under conditions of acid catalysis. The next stage of the synthesis was the preparation of N-acyl-β-ketoamides by the interaction of the synthesized N-acylphenylacetamides with carboxylic acid anhydrides in the proposed catalyst for boron trifluoride diacetate. The structure of the compounds was confirmed by IR, ¹H NMR spectrometry. The individuality and purity of the obtained compounds were monitored by thin layer chromatography. The study of the synthesized compounds on the central nervous system was carried out in the tests "Conditioned reflex of passive avoidance – CPAR", "Extrapolation escape (ETI)", "Morris water maze" and "Beam Walking".

Results and discussion. As a result of the research, N-acylphenylacetamides and N-acyl-β-ketoamides were synthesized. The essence of the optimization of the procedure for the synthesis of N-acylphenylacetamides is to replace chloric 65 % with concentrated sulfuric acid. The ¹H NMR spectra confirming the structures of the synthesized compounds revealed important characteristic features for N-acetyl-3-oxo-2- phenylpentanamide (VI) and N-acetyl-3-oxo-2-phenylhexanamide (VIII) containing a chiral center. The resulting substances have a pronounced effect on the central nervous system, their nootropic activity is to reduce the severity of sensorimotor disorders in animals. As a result of the study, the leading compounds were identified, superior to the effect of the reference drug piracetam.

Conclusion. The carried out research confirms the expediency of searching for highly effective and safe nootropic agents in the series of acylated derivatives of phenylacetic acid amide.

1. Mashkovskij M. D. Lekarstvennye sredstva [Medicinal products]. 15th ed. Moscow: LLC "Izdatel’stvo Novaja Volna"; 2005. 169 p. (In Russ.)

2. Vartanjan R. S. Sintez osnovnyh lekarstvennyh sredstv [Synthesis of basic medicines]. Moscow: Medicinskoe informacionnoe agenstvo; 2004. 233 p. (In Russ.)

3. Orlov V. D., Lipson V. V., Ivanov V. V. Medicinskaja himija [Medicinal chemistry]. Kharkov: Folio; 2005. 193 p. (In Russ.)

4. Voronkov A. V., Pozdnyakov D. I., Miroshnichenko K. A., Potapova A. A., Kodonidi I. P., Anenko D. S. Pyrimidine derivatives are promising correctors of metabolic and functional disorders of the brain in conditions of chronic traumatic encephalopathy. Vestnik Smolenskoy Gosudarstvennoy Medicinskoy Akademii. 2019;18(3):18–24. (In Russ.)

5. Kodonidi I. P., Anenko D. S., Terehov A. J., Sidorskaja S. J., Grigorjanc J. G. Synthesis of 2,6-dialkyl derivatives of pyrimidine-4 (1h)-one with an anti-inflammatory effect. Farmatsiya. 2021;70(1):11–17. (In Russ.) DOI: 10.29296/25419218-2021-01-02.

6. Kim K., Kim D., Lee H., Lee T. H., Kim K-Y., Kim H. New Pyrimidinone-Fused 1,4-Naphthoquinone Derivatives Inhibit the Growth of Drug Resistant Oral Bacteria. Biomedicines. 2020;8(6)160. DOI: 10.3390/biomedicines8060160.

7. Kelada M., Walsh J. M. D., Devine R. W., McArdle P., Stephens J. C. Synthesis of pyrazolopyrimidinones using a "one-pot" approach under microwave irradiation. Beilstein Journal of Organic Chemistry. 2018;14:1222–1228. DOI: 10.3762/bjoc.14.104.

8. MacDonald J. A., Sutherland C., Carlson D. A., Bhaidani S., Al-Ghabkari A., Sward K., Haystead T. A. J., Walsh M. P. A Small Molecule Pyrazolo[3,4-d]Pyrimidinone Inhibitor of Zipper-Interacting Protein Kinase Suppresses Calcium Sensitization of Vascular Smooth Muscle. Molecular Pharmacology. 2016;89(1):105–117. DOI: 10.1124/mol.115.100529.

9. Elsharif A. M. Synthesis of New Pyrimidinone Derivatives and Their Respective Biological Structure Assessment. Orient Journal of Chemistry. 2019;35(2):658–667. DOI: 10.13005/ojc/350221.

10. Bederson J. B., Pitts L. H., Tsuji M., Nishimura M. C., Davis R. L., Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17:472–476.

11. Cohen P. A., Zakharevich I., Gerona R. Presence of Piracetam in Cognitive Enhancement Dietary Supplements. JAMA Internal Medicine. 2019;180(3):458–459. DOI: 10.1001/jamainternmed.2019.5507.

12. Keil U., Scherping I., Hauptmann S., Schuessel K., Eckert A., Müller W. E. Piracetam improves mitochondrial dysfunction following oxidative stress. British Journal of Pharmacology. 2005;147(2):199–208. DOI:10.1038/sj.bjp.0706459.

13. Mironov A. N., editor. Rukovodstvo po provedeniyu doklinicheskikh issledovaniy lekarstvennykh sredstv [Guidelines for conducting preclinical studies of drugs]. Part One. Moscow: Grif i K; 2012. 944 p. (In Russ.)

14. Fleming S. M, Ekhator O. R., Ghisays V. Assessment of Sensorimotor Function in Mouse Models of Parkinson’s Disease. Journal of Visualized Experiments. 2013;76:50303. DOI: 10.3791/50303.

15. Plotnikova E. Y., Gracheva T. Y., Sinkov M. A., Sukhikh A. S. Error analysis in comparative studies of clinical and economic efficiency using the ursodeoxycholic acid generics example. RMJ. 2019;27(5):3–7. (In Russ.)

16. Hayashi M., Bachman S., Hashimoto S., Eichman C. C., Stoltz B. M. Ni-Catalysed Enantioselective C-Acylation of α-substituted Lactams. Journal of the American Chemical Society. 2016;138(29):8997–9000. DOI: 10.1021/jacs.6b02120.

17. Moradian M., Amini A., Naeimi H. Zncl2@MWCNTs nanocomposite as an efficient and reusable catalyst for direct regioselective ortho C-acylation of phenolic compounds under solvent-free and microwave conditions. Green Chemistry Letters and Reviews. 2017;10(4):228–234. DOI: 10.1080/17518253.2017.1349194.

18. Lee J., Hong M., Jung Y., Cho E., Rhee H. Synthesis of 1,3,5-trisubstituted-1,2,4-triazoles by microwave-assisted N-acylation of amide derivatives and the consecutive reaction with hydrazine hydrochlorides. Tetrahedron. 2012;68(8):2045–2051.

19. Li W., Zheng Y., Qu E., Bai J. β-Keto Amides: A Jack-of-All-Trades Building Block in Organic Chemistry. European Journal of Organic Chemistry. 2021;37:5151–5192. DOI: 10.1002/ejoc.202100692.

20. Ospanov M. A., Turmuhanova M. Z., Murzagulova K. B., Abilov Z. A. Stereochemical features of unsaturated aminodiesters – intermediates in the synthesis of Richlocaine. Vestnik KazNU. Seriya khimicheskaya = Chemical Bulletin of Kazakh National University. Serija himicheskaja. 2014;3(75):361–368. (In Russ.) DOI: 10.15328/chemb_2014_361-68.

21. Terney A. L. Sovremennaya organicheskaya khimiya [Modern organic chemistry]. In 2 volumes. 2 volume. Moscow: Mir; 1981. 559–561 p. (In Russ.)

22. Pakal’nis V. V., Zerova I. V., Jakimovich S. I. Interaction of aroyland heteroaroyltrifluoroacetones with acylhydrazines: regional orientation and tautomerism of condensation products. Zhurnal organicheskoj himii. 2007;77:1665–1676. (In Russ.)

23. Meshcheryakova S. A. Sintez, svojstva, struktura i biologicheskaja aktivnost’ novyh S i N-proizvodnyh pirimidina [Synthesis, properties, structure and biological activity of new S and N-pyrimidine derivatives] [dissertation]. Ufa; 2015. 205 p. Available at: https://www.dissercat.com/content/sintez-svoistva-strukturai-biologicheskaya-aktivnost-novykh-s-i-n-proizvodnykhpirimidina. Accessed: 29.12.2021. (In Russ.)