Synthesis, transformations and characterization of 8 aminomethyl substituted umbelliferones as probable anti-arrhythmic agents

Synthesis, transformations and characterization of 8 aminomethyl substituted umbelliferones as probable anti-arrhythmic agents Full article

Journal

Current Bioactive Compounds
ISSN: 1573-4072

Output data

Year: 2019, Volume: 15, Number: 1, Pages: 71-82 Pages count : 12 DOI: 10.2174/1573407213666171030152601

Tags

Anabasine; Anti-arrhythmic activity; Coumarin; Isoquinoline; Mannich reaction; Xanthine

Authors

Lipeeva A.V. ¹ , Brysgalov A.O. ² , Tolstikova T.G. ^2,3 , Shults E.E. ^1,3

Affiliations

1	(Scopus) Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, Novosibirsk, 630090, Russian Federation
2	(Scopus) Laboratory of Pharmacological Researches, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, Novosibirsk, 630090, Russian Federation
3	(Scopus) Novosibirsk State University, Pirogova Str. 2, Novosibirsk, 630090, Russian Federation

Background: Coumarin and modified nitrogen heterocyclic nuclei show biological activity. Combining these into a hybrid molecule could lead to new pharmacological agents. A series of hybrid compounds combining coumarin and piperidine, piperazine, purine or tetrahydroisoquinoline moieties were synthesized and evaluated for anti-arrhythmic activity. Methods: The Mannich reaction of coumarins (peurutenicin, peucenol and 6-cyanoumbelliferrone) with formaldehyde and various amines, including several alkaloids – anabasine, theophylline or tetrahydroisoquinolines, proceeds by heating under reflux in dioxane in the presence of 4-dimethylaminopyridine. The Suzuki reaction of 6,8-disubstituted umbelliferone triflate was used for the introduction of an aryl substituent in position 7 of the the coumarin framework. Results: Twenty two novel coumarin-based Mannich bases were synthesized via introduction of functional aminomethyl group at position 8 of 6 substituted 7-hydroxy-2H-chromen-2-ones by Mannich reaction. The results illustrated that the C-6 and C-8 substituents’ effect was obvious in our designed system and there was a relationship between the structures and the anti-arrhythmic activity of the 6,7,8-trisubstituted coumarins. 8-(6,7-dimethoxy-1-(3,4,5-trimethoxyphenyl)-tetrahydroisoquinolinylmethyl)-substituted peucenol derivatives shown in vivo a pronounced and selective anti-arrhythmic activity on epinephrine arrhythmias in comparison with natural coumarin peucenol. The moderate toxicity of the new compound encouraged further design of therapeutically relevant analogues based on this novel type of coumarin- tetrahydroisoquinoline hybrids. Conclusion: We have developed a mild reaction protocol to synthesize new mannich products on the basis of substituted coumarins. The anti-arrhythmic activity of coumarin-tetrahydroisoquinoline hybrids was revealed. We report for the first time that coumarin containing 8-(1-(3,4,5-trimethoxyphenyl) tetrahydroisoquinolinyl)methyl) substituent offer a suitable scaffold for the development of novel anti-arrhythmic agents. © 2019 Bentham Science Publishers.

Lipeeva A.V. , Brysgalov A.O. , Tolstikova T.G. , Shults E.E.
Synthesis, transformations and characterization of 8 aminomethyl substituted umbelliferones as probable anti-arrhythmic agents
Current Bioactive Compounds. 2019. V.15. N1. P.71-82. DOI: 10.2174/1573407213666171030152601 Scopus РИНЦ

Published print:

Feb 6, 2019

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