Bis-methylamides of 1,2-dialkyl substituted imidazole-4,5-dicarboxylic acids: preparation and antinociceptive activity

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Abstract

BACKGROUND: Searching for substances with high analgesic activity is one of the main problems of modern medicine. N-methyl-D-aspartate receptors present in all areas of the central nervous system responsible for reaction on pain stimulation. Moreover, peripheral glutamate receptors may be directly involved in the genesis of pain reactions. Therefore, it is of interest to search for new analgesics among N-methyl-D-aspartate receptor ligands.

AIM: To develop a preparative method of synthesis and to investigate the antinociceptive activity of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-methylamides on the example of 2-propyl-1-ethylimidazole-4,5-dicarboxylic acid bis-methylamide.

MATHERIALS AND METHODS: 1-Ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide was obtained using methods of organic synthesis. The Gaffner test of mechanical irritation of the base of the tail and the hot water tail-flick test in mice were selected to study the antinociceptive activity.

RESULTS: It was shown that the amidation of 2-substituted imidazole-4,5-dicarboxylic acids dimethyl ether followed by the alkylation of the resulting 2-substituted imidazole-4,5-dicarboxylic acids bis-amide is а preferable method of the two alternative for obtaining of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-amides. It was shown that 1-ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide exhibits pronounced antinociceptive activity exceeding the activity of the comparative drugs analgin and ketorolac.

CONCLUSIONS: A preparative method for the synthesis of 1,2-dialkylimidazole-4,5-dicarboxylic acids bis-amides is proposed. The dose-dependent antinociceptive activity of 1-ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide was shown. 1-Ethyl-2-propylimidazole-4,5-dicarboxylic acids bis-methylamide exhibits antinociceptive activity exceeding the activity of analgin and ketorolac.

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About the authors

Polina P. Kropacheva

Saint-Petersburg State Institute of Technology (Technical University); Institute of Experimental Medicine

Author for correspondence.
Email: p.kropacheva99@mail.ru
ORCID iD: 0009-0005-1625-1108

student, student assistant

Russian Federation, Saint Petersburg; Saint Petersburg

Larisa G. Kubarskaya

Institute of Experimental Medicine; Golikov Research Clinical Center of Toxicology under the Federal Medical Biological Agency

Email: larkub@yandex.ru
ORCID iD: 0000-0001-7622-0390

Cand. Sci. (Biology), engineer, Senior Research Associate

Russian Federation, Saint Petersburg; Saint Petersburg

Mariia A. Brusina

Institute of Experimental Medicine

Email: mashasemen@gmail.com
ORCID iD: 0000-0001-8433-120X

Cand. Sci. (Chemistry), Research Associate

Russian Federation, Saint Petersburg

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2. Figure. Practically possible ways to obtain bis-methylamides 1,2-dialkyl-4,5-IDC on the example of the preparation of 2-propyl-1-ethyl-4,5-dicarboxylic acids bis-methylamide (6)

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