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

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; Sergei   B.   Seredenin

doi:10.2174/1573406419666230908121759

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.

« Previous Next »

Graphical Abstract

[1]
WHO. Epilepsy.  Available from: https://www.who.int/news-room/fact-sheets/detail/epilepsy

[2]
Begley, C.E.; Durgin, T.L. The direct cost of epilepsy in the United States: A systematic review of estimates. Epilepsia,  2015, 56(9), 1376-1387.
 [http://dx.doi.org/10.1111/epi.13084] [PMID:  26216617]

[3]
Begley, C.; Wagner, R.G.; Abraham, A.; Beghi, E.; Newton, C.; Kwon, C.S.; Labiner, D.; Winkler, A.S. The global cost of epilepsy: A systematic review and extrapolation. Epilepsia,  2022, 63(4), 892-903.
 [http://dx.doi.org/10.1111/epi.17165] [PMID:  35195894]

[4]
Brandt, C.; Lahr, D.; May, T.W. Cognitive adverse events of topiramate in patients with epilepsy and intellectual disability. Epilepsy Behav.,  2015, 45, 261-264.
 [http://dx.doi.org/10.1016/j.yebeh.2014.12.043] [PMID:  25843340]

[5]
Fritz, N.; Glogau, S.; Hoffmann, J.; Rademacher, M.; Elger, C.E.; Helmstaedter, C. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav.,  2005, 6(3), 373-381.
 [http://dx.doi.org/10.1016/j.yebeh.2005.01.002] [PMID:  15820346]

[6]
White, J.R.; Walczak, T.S.; Marino, S.E.; Beniak, T.E.; Leppik, I.E.; Birnbaum, A.K. Zonisamide discontinuation due to psychiatric and cognitive adverse events: A case-control study. Neurology,  2010, 75(6), 513-518.
 [http://dx.doi.org/10.1212/WNL.0b013e3181eccfb5] [PMID:  20697103]

[7]
Mutanana, N.; Tsvere, M.; Chiweshe, M.K. General side effects and challenges associated with anti-epilepsy medication: A review of related literature. Afr. J. Prim. Health Care Fam. Med.,  2020, 12(1), e1-e5.
 [http://dx.doi.org/10.4102/phcfm.v12i1.2162] [PMID:  32634006]

[8]
Zhmurenko, L.A.; Voronina, T.A.; Litvinova, S.A.; Nerobkova, L.N.; Gaidukov, I.O.; Mokrov, G.V.; Gudasheva, T.A. Synthesis and anticonvulsive activity of 3- and 4-benzoylpyridine oxime derivatives. Pharm. Chem. J.,  2018, 52(1), 42-51.
 [http://dx.doi.org/10.1007/s11094-018-1763-z]

[9]
Mokrov, G.V.; Savel’ev, V.L.; Voronina, T.A.; Litvinova, S.A.; Kovalev, I.G.; Nerobkova, L.N.; Dmitrienko, A.O.; Gudasheva, T.A.; Seredenin, S.B. Synthesis and anticonvulsant activity of n-substituted 4-amino-3-nitrocoumarins. Pharm. Chem. J.,  2019, 53(2), 118-124.
 [http://dx.doi.org/10.1007/s11094-019-01964-7]

[10]
Mokrov, G.V.; Litvinova, S.A.; Voronina, T.A.; Nerobkova, L.N.; Kutepova, I.S.; Kovalev, I.G.; Gudasheva, T.A.; Durnev, A.D. Design, synthesis, and anticonvulsant evaluation of 4-GABA-3-nitrocoumarines, 1-thiocoumarines, quinolone-2-ones, and their derivatives. Med. Chem. Res.,  2019, 28(11), 1901-1911.
 [http://dx.doi.org/10.1007/s00044-019-02422-5]

[11]
Mokrov, G.V.; Voronina, T.A.; Litvinova, S.A.; Kovalev, I.G.; Nerobkova, L.N.; Durnev, A.D.; Gudasheva, T.A.; Seredenin, S.B. Synthesis and anticonvulsant activity of 4-amino-3-nitro-1-thiocoumarins and 4-amino-3-nitroquinolin-2-ones. Pharm. Chem. J.,  2019, 53(3), 194-200.
 [http://dx.doi.org/10.1007/s11094-019-01978-1]

[12]
Zhmurenko, L.A.; Litvinova, S.A.; Mokrov, G.V.; Kovalev, I.G.; Voronina, T.A.; Nerobkova, L.N.; Gudasheva, T.A. Synthesis of 4-phenylpyrrolidone derivatives with anticonvulsant and nootropic activity. Pharm. Chem. J.,  2019, 53(5), 429-435.
 [http://dx.doi.org/10.1007/s11094-019-02015-x]

[13]
Zhmurenko, L.A.; Litvinova, S.A.; Kutepova, I.S.; Nerobkova, L.N.; Mokrov, G.V.; Rebeko, A.G.; Voronina, T.A.; Gudasheva, T.A. Synthesis of dibenzofuranone-oxime derivatives with anticonvulsant, antihypoxic, and anti-ischemic activity. Pharm. Chem. J.,  2020, 53(11), 997-1004.
 [http://dx.doi.org/10.1007/s11094-020-02112-2]

[14]
Zhmurenko, L.A.; Litvinova, S.A.; Mokrov, G.V.; Ivasheva, D.M.; Rebeko, A.G.; Voronina, T.A.; Gudasheva, T.A. Synthesis of aminoalkyl dibenzofuranone oxime derivatives possessing anticonvulsant activity. Pharm. Chem. J.,  2021, 54(10), 997-1002.
 [http://dx.doi.org/10.1007/s11094-021-02309-z]

[15]
Bagdy, G.; Kecskemeti, V.; Riba, P.; Jakus, R. Serotonin and epilepsy. J. Neurochem.,  2007, 100(4), 857-873.
 [http://dx.doi.org/10.1111/j.1471-4159.2006.04277.x] [PMID:  17212700]

[16]
Venzi, M.; David, F.; Bellet, J.; Cavaccini, A.; Bombardi, C.; Crunelli, V.; Di Giovanni, G. Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures. Neuropharmacology,  2016, 108, 292-304.
 [http://dx.doi.org/10.1016/j.neuropharm.2016.04.016] [PMID:  27085605]

[17]
Bryson, A.; Reid, C.; Petrou, S. Fundamental neurochemistry review: GABA A receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy. J. Neurochem.,  2023, 165(1), 6-28.
 [http://dx.doi.org/10.1111/jnc.15769] [PMID:  36681890]

[18]
Palma, E.; Ruffolo, G.; Cifelli, P.; Roseti, C.; Vliet, E.A.; Aronica, E. Modulation of GABAA Receptors in the treatment of epilepsy. Curr. Pharm. Des.,  2018, 23(37), 5563-5568.
 [http://dx.doi.org/10.2174/1381612823666170809100230] [PMID:  28799512]

[19]
Karakurt, A.; Alagöz, M.A.; Sayoğlu, B.; Çalış, Ü.; Dalkara, S. Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity. Eur. J. Med. Chem.,  2012, 57, 275-282.
 [http://dx.doi.org/10.1016/j.ejmech.2012.08.037] [PMID:  23085104]

[20]
Sari, S.; Kaynak, F.B.; Dalkara, S. Synthesis and anticonvulsant screening of 1,2,4-triazole derivatives. Pharmacol. Rep.,  2018, 70(6), 1116-1123.
 [http://dx.doi.org/10.1016/j.pharep.2018.06.007] [PMID:  30316046]

[21]
Yacovan, A.; Grynszpan, F.; Aizikovich, A.; Brody, M. S.; Bar-Joseph, A.; Meilin, S. Benzofuran derivatives with therapeutic activities. Patent WO 2006129318A2, 2006.

[22]
Hu, X.; Wang, M.; Yan, G.R.; Yu, M.H.; Wang, H.Y.; Hou, A.J. 2-Arylbenzofuran and tyrosinase inhibitory constituents of Morus notabilis. J. Asian Nat. Prod. Res.,  2012, 14(12), 1103-1108.
 [http://dx.doi.org/10.1080/10286020.2012.724400] [PMID:  23088613]

[23]
Chen, C.Y.; Wei, X.D.; Chen, C.R. 3,4,5-Trimethoxycinnamic acid, one of the constituents of Polygalae Radix exerts anti-seizure effects by modulating GABAAergic systems in mice. J. Pharmacol. Sci.,  2016, 131(1), 1-5.
 [http://dx.doi.org/10.1016/j.jphs.2015.07.021] [PMID:  26260747]

[24]
Cuan, Y.; He, X.; Zhao, Y.; Yang, J.; Bai, Y.; Sun, Y.; Zhang, Q.; Zhao, Z.; Wei, X.; Zheng, X. Anticonvulsant activity of halogen-substituted cinnamic acid derivatives and their effects on glycosylation of PTZ-induced chronic epilepsy in mice. Molecules,  2017, 23(1), 76.
 [http://dx.doi.org/10.3390/molecules23010076] [PMID:  29286347]

[25]
Gunia-Krzyżak, A.; Pańczyk, K.; Waszkielewicz, A.M.; Marona, H. Cinnamamide derivatives for central and peripheral nervous system disorders: A review of structure-activity relationships. ChemMedChem,  2015, 10(8), 1302-1325.
 [http://dx.doi.org/10.1002/cmdc.201500153] [PMID:  26083325]

[26]
Perucca, E.; French, J.; Bialer, M. Development of new antiepileptic drugs: Challenges, incentives, and recent advances. Lancet Neurol.,  2007, 6(9), 793-804.
 [http://dx.doi.org/10.1016/S1474-4422(07)70215-6] [PMID:  17706563]

[27]
Acar, M.F.; Sari, S.; Dalkara, S. Synthesis, in vivo anticonvulsant testing, and molecular modeling studies of new nafimidone derivatives. Drug Dev. Res.,  2019, 80(5), ddr.21538.
 [http://dx.doi.org/10.1002/ddr.21538] [PMID: 30973979]

[28]
Guiard, B.P.; Giovanni, G.D. Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: The missing link? Front. Pharmacol.,  2015, 6, 46.
 [http://dx.doi.org/10.3389/fphar.2015.00046] [PMID:  25852551]

[29]
Sourbron, J.; Lagae, L. Serotonin receptors in epilepsy: Novel treatment targets? Epilepsia Open,  2022, 7(2), 231-246.
 [http://dx.doi.org/10.1002/epi4.12580] [PMID:  35075810]

[30]
Braat, S.; Kooy, R.F. The GABAA receptor as a therapeutic target for neurodevelopmental disorders. Neuron,  2015, 86(5), 1119-1130.
 [http://dx.doi.org/10.1016/j.neuron.2015.03.042] [PMID:  26050032]

[31]
Peng, Y.; Luo, J.; Feng, Q.; Tang, Q. Understanding the scope of feist-bénary furan synthesis: Chemoselectivity and diastereoselectivity of the reaction between α-halo ketones and β-dicarbonyl compounds. Eur. J. Org. Chem.,  2016, 2016(30), 5169-5179.
 [http://dx.doi.org/10.1002/ejoc.201600975]

[32]
Kolb, K.E.; Field, K.W.; Schatz, P.F. A one-step synthesis of cinnamic acids using malonic acid: The verley-doebner modification of the knoevenagel condensation. J. Chem. Educ.,  1990, 67(12), A304.
 [http://dx.doi.org/10.1021/ed067pA304]

[33]
Voronina, T.A.; Nerobkova, L.N. In: Methodical instructions for the study of anticonvulsant activity of pharmacological substances. A guide to preclinical drug research. Metodicheskie ukazaniya po izucheniyu protivosudorozhnoi aktivnosti farmakologicheskikh veshchestv; , 2012, pp. 235-250.

[34]
Leitis, Z.; Lūsis, V. Conjugate addition of aryl nucleophiles to α,β-unsaturated cinnamic acid derivatives containing evans type chiral auxiliaries. Tetrahedron Asymmetry,  2016, 27(17-18), 843-851.
 [http://dx.doi.org/10.1016/j.tetasy.2016.07.003]

[35]
Chen, Y.; Luo, X.; Wang, Y.; Xing, Z.; Chen, J. Design and synthesis novel amide derivatives containing an 1,3,4‐oxadiazole moiety as potential antibacterial agents. J. Heterocycl. Chem.,  2022, 59(7), 1160-1168.
 [http://dx.doi.org/10.1002/jhet.4455]

[36]
Raffa, D.; Maggio, B.; Raimondi, M.V.; Cusimano, M.G.; Amico, G.; Carollo, A.; Conaldi, P.G.; Bai, R.; Hamel, E.; Daidone, G. 2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenyl propanamido)benzamides: Synthesis, antiproliferative activity, and mechanism of action. Eur. J. Med. Chem.,  2013, 65, 427-435.
 [http://dx.doi.org/10.1016/j.ejmech.2013.04.068] [PMID:  23747810]

[37]
Mikroyannidis, J.A.; Spiliopoulos, I.K.; Kasimis, T.S.; Kulkarni, A.P.; Jenekhe, S.A. Synthesis, photophysics, and electroluminescence of conjugated poly(p -phenylenevinylene) derivatives with 1,3,4-oxadiazoles in the backbone. Macromolecules,  2003, 36(25), 9295-9302.
 [http://dx.doi.org/10.1021/ma034793w]

[38]
Novácek, L.; Nováková, O.; Polásek, L.; Danĕk, J. Preparation of derivatives of 3-(3,4-dimethoxyphenyl)propanic acid and a study of its biological activity. Cesk. Farm.,  1990, 39(3), 109-112.
 [PMID:  2401012]

[39]
Kim, T.H.; Huh, C.; Lee, B.S.; Lee, I. Nucleophilic substitution reactions of cinnamoyl chlorides with anilines in acetonitrile and acetonitrile–methanol mixtures. J. Chem. Soc., Perkin Trans. 2,  1995, (12), 2257-2261.
 [http://dx.doi.org/10.1039/P29950002257]

[40]
Norman, M.H.; Heathcock, C.H. Novel transformations leading to 3-benzylindolizidin-2-ones. J. Org. Chem.,  1987, 52(2), 226-235.
 [http://dx.doi.org/10.1021/jo00378a012]

[41]
Nardi, A.; Grunnet, M.; Demnitz, J.; Jensen, T.D.; Christophersen, P.; Jones, D.S.; Nielsen, E.O.; Strøbæk, D.; Madsen, L.S. Novel cinnamic amide derivatives useful as ion channel modulators. WO 2008074755A22007, 

[42]
Gakhar, H.K.; Kaur, R.; Gupta, S.B. [1,3]Dioxolo[5,6][1] benzothieno[2,3-c]-quinolin-6(5H)-ones. Monatsh. Chem.,  1995, 126(11), 1253-1256.
 [http://dx.doi.org/10.1007/BF00824304]

[43]
Rasschaert, A.; Janssens, W.; Slootmaekers, P.J. A re-examination of the selectivity in the Friedel-crafts chalcone synthesis. Bull. Soc. Chim. Belg.,  1966, 75, 449-455.
 [http://dx.doi.org/10.1002/bscb.19660750703]

[44]
Robinson, E.R.T.; Frost, A.B.; Elías-Rodríguez, P.; Smith, A.D. Enantioselective isothiourea-catalysed michael–michael–lactonisation cascade reaction for the synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes. Synthesis,  2017, 49, 409-423.

[45]
Sharma, M.L.; Kaur, S. Synthesis of quaternary salts of ammonia from cinnamic acids and their plant growth retardant activity. J. Indian Chem. Soc.,  2007, 84, 612-614.

[46]
Wu, Z.; Minhas, G.S.; Wen, D.; Jiang, H.; Chen, K.; Zimniak, P.; Zheng, J. Design, synthesis, and structure-activity relationships of haloenol lactones: Site-directed and isozyme-selective glutathione S-transferase inhibitors. J. Med. Chem.,  2004, 47(12), 3282-3294.
 [http://dx.doi.org/10.1021/jm0499615] [PMID:  15163208]

[47]
Coutrot, P.; Snoussi, M.; Savignac, P. An improvement in the wittig-horner synthesis of 2-alkenoic acids. Synthesis,  1978, 1978(2), 133-134.
 [http://dx.doi.org/10.1055/s-1978-24686]

[48]
Jiménez, V.; Alderete, J.B. The role of charge transfer interactions in the inclusion complexation of anionic guests with α-cyclodextrin. Tetrahedron,  2005, 61(23), 5449-5456.
 [http://dx.doi.org/10.1016/j.tet.2005.04.001]

[49]
Zhang, Y.M.; Zhou, Z.M.; Jiang, F. Synthesis of new phenols 1. derivatives of 8 hydroxy indolizine. J. Chem. Res. Synopses,  1981, 366-367.

[50]
Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Copper(I)-catalyzed carboxylation of aryl- and alkenylboronic esters. Org. Lett.,  2008, 10(13), 2697-2700.
 [http://dx.doi.org/10.1021/ol800829q] [PMID:  18507391]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1573406419666230908121759	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638

Medicinal Chemistry

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

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract