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Medicinal Chemistry

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Research Article

Design, Synthesis and Anticonvulsant Activity of Cinnamoyl Derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one Oxime

Author(s): Grigory V. Mokrov*, Valentina E. Biryukova, Tatiana Y. Vorobieva, Andry S. Pantileev, Oksana S. Grigorkevich, Ludmila A. Zhmurenko, Alexey G. Rebeko, Felix S. Bayburtskiy, Svetlana A. Litvinova, Tatiana A. Voronina, Tatiana A. Gudasheva and Sergei B. Seredenin

Volume 20, Issue 1, 2024

Published on: 12 September, 2023

Page: [92 - 107] Pages: 16

DOI: 10.2174/1573406419666230908121759

Price: $65

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Abstract

Background: Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants.

Methods: New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test.

Results: Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[ b,d]furan-1(2Н)-one О-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg.

Conclusion: Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.

Keywords: Anticonvulsant, MES test, dibenzofuranes, oximes, docking studies, cinnamoyl derivatives.

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