SYNTHESIS, INTRAMOLECULAR CYCLIZATION AND ANTINOCICEPTIVE ACTIVITY OF 4-(HET)ARYL-2-{[3-(ETHOXYCARBONYL)-4-(4-R-PHENYL)THIOPHEN-2-YL]AMINO}- 4-OXOBUT-2-ENOIC ACIDS
Abstract
In this work, new substituted 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids were studied. It was found that the intramolecular cyclisation of these acids under the action of a dehydrating agent leads to the formation of the corresponding substituted 3-(thiophen-2-yl)imino-3H-furan-2-ones, which are of great interest for further study. A content of several reaction centers in its structure allows to obtain products of heterocyclic and acyclic structure, which, at the same time, retain such important pharmacophore groups as the 2-aminothiophene fragment and 2,4-dioxobutanoic acid fragment. The studied 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids were obtained by a one-step method, providing high yields and involving the interaction of substituted 4-(het)aryl-2-hydroxy-4-oxobut-2-enoic acids with substituted ethyl 2-amino-4-(4-R-phenyl)thiophen-3-carboxylates. The structure of the isolated final compounds was confirmed by 1H and 13C NMR spectroscopy and elemental analysis. Substituted 4-(het)aryl-4-oxo-2-thienylaminobut-2-enoic acids were then screened in vivo to detect and evaluate their biological activity and acute toxicity. The antinociceptive activity was studied in white mice of both sexes by hot plate thermal irritation intraperitonally. Acute toxicity was studied according to Pershin's method, based on observation of mice condition during 10 days after intraperitoneal injection of tested compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the acute toxicity assessment indicates that they belong to the V class of practically non-toxic drugs. High values of antinociceptive activity in combination with low toxicity makes the considered 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids a highly promising class for further study in order to search and develop new biologically active compounds with analgesic action and low toxicity.
For citation:
Nikonov I.P., Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Gorbunova I.A. Synthesis, intramolecular cyclization and antinociceptive activity of 4-(het)aryl-2-{[3-(ethoxycarbonyl)-4-(4-R-phenyl)thiophen-2-yl]amino}-4-oxobut-2-enoic acids. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 11. P. 22-32. DOI: 10.6060/ivkkt.20246711.7055.
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