Разработка и регистрация лекарственных средств (Feb 2022)
Synthesis and Action of N-acylphenylacetamides and N-acyl-β-ketoamides on the Central Nervous System
Abstract
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.
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