Synthesis and Evaluation of Anticonvulsant Activities of 4-Phenylpiperidin- 2-one Derivatives

Shi-Ben       Wang; Hui       Liu; Guang-Yong       Li; Kang       Lei; Xiao-Jing       Li; Zhe-Shan       Quan; Xue-Kun       Wang

doi:10.2174/1570180816666190710142848

Abstract

Background: Although Antiepileptic Drugs (AEDs) acting on various targets have been applied in the clinic, the efficacy and tolerance of AEDs in the treatment of epilepsy have not significantly improved. Therefore, there is an urgent need to develop some novel chemical moieties with a better safety profile and greater efficacy. We designed and synthesized twenty-seven 4- phenylpiperidin-2-one derivatives. This study aimed to investigate the potential use of a series of 4- phenylpiperidin-2-one derivatives as anticonvulsant drugs.

Methods: Two experimental methods, Maximal Electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, neurotoxicity (NT) was tested using the rotarod test.

Results: Compound 7-[4-(trifluoromethyl)phenyl]-6,7-dihydrothieno[3,2-b]pyridin-5-(4H)-one (11; MES, ED50 = 23.7 mg/kg, PI > 33.7; PTZ, ED50 = 78.1 mg/kg, PI > 10.0) showed the best anticonvulsant activity. The results of in vivo γ-aminobutyric Acid (GABA) estimation showed that compound 11 may have an effect on the GABA system. Compound 11 showed significant interactions with residues at the benzodiazepine (BZD)-binding site on GABAA receptors. Most target compounds have favorable blood brain barrier (BBB) permeability and oral bioavailability in predictions using silico molecular properties.

Conclusion: According to the in vivo and in silico studies, compound 11 stand out as potential anticonvulsant agents for further studies.

Keywords: Synthesis, anticonvulsant, MES, scPTZ, GABA, molecular docking studies.

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[1] 
Siddall, T.L.; Ouse, D.G.; Benko, Z.L.; 
Garvin, G.M.; Jackson, J.L.; McQuiston, J.M.; Ricks, M.J.; Thibault, 
T.D.; Turner, J.A.; Vanheertum, J.C.; Weimer, M.R. Synthesis and 
herbicidal activity of phenyl-substituted benzoylpyrazoles. Pest Manag. Sci.,  2002, 58(12), 1175-1186.
[http://dx.doi.org/10.1002/ps.588] [PMID: 12476990] 
[2] 
Culbreath, A.K.; Brenneman, T.B.; Kemerait, 
R.C., Jr; Hammes, G.G. Effect of the new pyrazole carboxamide fungicide 
penthiopyrad on late leaf spot and stem rot of peanut. Pest Manag. Sci.,  2009, 65(1), 66-73.
[http://dx.doi.org/10.1002/ps.1646] [PMID: 18785218] 
[3] 
Penning, T.D.; Talley, J.J.; Bertenshaw, S.R.;
 Carter, J.S.; Collins, P.W.; Docter, S.; Graneto, M.J.; Lee, L.F.; 
Malecha, J.W.; Miyashiro, J.M.; Rogers, R.S.; Rogier, D.J.; Yu, S.S.; 
Anderson, G.D. Burton, E.G.; Cogburn, J.N.; Gregory, S.A.; Koboldt, 
C.M.; Perkins, W.E.; Seibert, K.; Veenhuizen, A.W.; Zhang, Y.Y.; 
Isakson, P.C. Synthesis and biological evaluation of the 
1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification 
of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-ze 
nesulfonamide (SC-58635, celecoxib). J. Med. Chem.,  1997, 40(9), 1347-1365.
[http://dx.doi.org/10.1021/jm960803q] [PMID: 9135032] 
[4] 
Guzman-Perez, A.; Wester, R.T.; Allen, M.C.; 
Brown, J.A.; Buchholz, A.R.; Cook, E.R.; Day, W.W.; Hamanaka, E.S.; 
Kennedy, S.P.; Knight, D.R.; Kowalczyk, P.J.; Marala, R.B.; Mularski, 
C.J.; Novomisle, W.A.; Ruggeri, R.B.; Tracey, W.R.; Hill, R.J. Discovery
 of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 
(NHE-1) inhibitor with high aqueous solubility. Bioorg. Med. Chem. Lett.,  2001, 11(6), 803-807.
[http://dx.doi.org/10.1016/S0960-894X(01)00059-2] [PMID: 11277524] 
[5] 
Marala, R.B.; Brown, J.A.; Kong, J.X.; Tracey,
 W.R.; Knight, D.R.; Wester, R.T.; Sun, D.; Kennedy, S.P.; Hamanaka, 
E.S.; Ruggeri, R.B.; Hill, R.J. Zoniporide: a potent and highly 
selective inhibitor of human Na(+)/H(+) exchanger-1. Eur. J. Pharmacol.,  2002, 451(1), 37-41.
[http://dx.doi.org/10.1016/S0014-2999(02)02193-3] [PMID: 12223226] 
[6] 
Anton, O.; Ernst, T.; Oskar, D.U.S. Patent No.1,898,431; U.S, Patent and Trademark Office 1933.
[7] 
Malinowska, K.; Lorenz, I.P.; Sadowska, B.; 
Mucha, P. Metal Ion Complexes with Pyrazoles, Aziridines and 
Diaziridines - Synthesis and Biological Activity. Curr. Med. Chem.,  2019, 26(4), 648-663.
[http://dx.doi.org/10.2174/0929867325666180221124447] [PMID: 29473492] 
[8] 
Porzelle, A.; Woodrow, M.D.; Tomkinson, N.C. Synthesis of benzoxazolones from nitroarenes or aryl halides. Org. Lett.,  2010, 12(4), 812-815.
[http://dx.doi.org/10.1021/ol902885j] [PMID: 20092263] 
[9] 
Kees, K.L.; Fitzgerald, J.J., Jr; Steiner, 
K.E.; Mattes, J.F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M.L. New 
potent antihyperglycemic agents in db/db mice: synthesis and 
structure-activity relationship studies of (4-substituted benzyl) 
(trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem.,  1996, 39(20), 3920-3928.
[http://dx.doi.org/10.1021/jm960444z] [PMID: 8831758] 
[10] 
Chuprun, S.S.; Kantin, G.; Krasavin, M. Synthesis and Medicinal Applications of N-Aryl-C-nitroazoles. Mini Rev. Med. Chem.,  2018, 18(20), 1733-1752.
[http://dx.doi.org/10.2174/1389557518666180831101841] [PMID: 30173645] 
[11] 
Hassan, G.S.; Abdel Rahman, D.E.; Abdelmajeed,
 E.A.; Refaey, R.H.; Alaraby Salem, M.; Nissan, Y.M. New pyrazole 
derivatives: Synthesis, anti-inflammatory activity, cycloxygenase 
inhibition assay and evaluation of mPGES. Eur. J. Med. Chem.,  2019, 171, 332-342.
[http://dx.doi.org/10.1016/j.ejmech.2019.03.052] [PMID: 30928706] 
[12] 
Li, Y.R.; Li, C.; Liu, J.C.; Guo, M.; Zhang, 
T.Y.; Sun, L.P.; Zheng, C.J.; Piao, H.R. Synthesis and biological 
evaluation of 1,3-diaryl pyrazole derivatives as potential antibacterial
 and anti-inflammatory agents. Bioorg. Med. Chem. Lett.,  2015, 25(22), 5052-5057.
[http://dx.doi.org/10.1016/j.bmcl.2015.10.028] [PMID: 26490095] 
[13] 
Bildirici, I.; Cetin, A.; Menges, N.; Alan, Y.
 Synthesis and SAR studies of pyrazole-3-carboxamides and-3-carbonyl 
thioureides including chiral moiety: Novel candidates as antibacterial 
agents. J. Serb. Chem. Soc.,  2018, 83(7-8), 795-807.
[http://dx.doi.org/10.2298/JSC170313029B] 
[14] 
Saeed, S.; Rashid, N.; Jones, P.G.; Hussain, 
R.; Bhatti, M.H. Synthesis, spectroscopic characterization, crystal 
structure and antifungal activity of thiourea derivatives containing a 
thiazole moiety. Cent. Eur. J. Chem.,  2010, 8(3), 550-558.
[15] 
Anusionwu, C.G.; Aderibigbe, B.A.; Mbianda, 
X.Y. Hybrid Molecules Development: A Versatile Landscape for the Control
 of Antifungal Drug Resistance: A Review. Mini Rev. Med. Chem.,  2019, 19(6), 450-464.
[http://dx.doi.org/10.2174/1389557519666181210162003] [PMID: 30526457] 
[16] 
Turkan, F.; Cetin, A.; Taslimi, P.; Gulçin, İ.
 Some pyrazoles derivatives: Potent carbonic anhydrase, α-glycosidase, 
and cholinesterase enzymes inhibitors. Arch. Pharm. (Weinheim),  2018, 351(10)e1800200
[http://dx.doi.org/10.1002/ardp.201800200] [PMID: 30246264] 
[17] 
Cheng, L.; Zhao, W.; Shen, Z.H.; Xu, T.M.; Wu,
 H.K.; Peng, W.L.; Liu, X.H. Synthesis, Nematicidal Activity and Docking
 Study of Novel Pyrazole-4-Carboxamide Derivatives Against Meloidogyne 
incognita. Lett. Drug Des. Discov.,  2019, 16(1), 29-35.
[http://dx.doi.org/10.2174/1570180815666180326150827] 
[18] 
Alferez, F.; Pozo, L.; Burns, J.K. 
Physiological changes associated with senescence and abscission in 
mature citrus fruit induced by 5-chloro-3-methyl-4-nitro-1H-pyrazole and
 ethephon application. Physiol. Plant.,  2006, 127, 66-73.
[http://dx.doi.org/10.1111/j.1399-3054.2006.00642.x] 
[19] 
Kumar, N.; Ebel, R.C. Oxidative metabolism in 
‘Valencia’sweet orange [Citrus sinensis (L.) Osbeck] flavedo tissue 
treated with the abscission agent 5-chloro-3-methyl-4-nitro-1H-pyrazole 
(CMNP). J. Hortic. Sci. Biotechnol.,  2015, 90(4), 413-418.
[http://dx.doi.org/10.1080/14620316.2015.11513203] 
[20] 
Barot, K.P.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Antitubercular drug development: current status and research strategies. Mini Rev. Med. Chem.,  2013, 13(11), 1664-1684.
[http://dx.doi.org/10.2174/13895575113139990076] [PMID: 23895192] 
[21] 
Radi, S.; Salhi, S.; Radi, A. Synthesis and 
preliminary biological activity of some new pyrazole derivatives as 
acyclonucleoside analogues. Lett. Drug Des. Discov.,  2010, 7(1), 27-30.
[http://dx.doi.org/10.2174/157018010789869307] 
[22] 
Seibert, C.; Sakmar, T.P. Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs. Curr. Pharm. Des.,  2004, 10(17), 2041-2062.
[http://dx.doi.org/10.2174/1381612043384312] [PMID: 15279544] 
[23] 
Faria, J.V.; Vegi, P.F.; Miguita, A.G.C.; Dos 
Santos, M.S.; Boechat, N.; Bernardino, A.M.R. Recently reported 
biological activities of pyrazole compounds. Bioorg. Med. Chem.,  2017, 25(21), 5891-5903.
[http://dx.doi.org/10.1016/j.bmc.2017.09.035] [PMID: 28988624] 
[24] 
Kasımoğulları, R.; Arslan, B.S. Synthesis and 
characterization of some pyrazole derivatives of 
1,5-diphenyl-1H-pyrazole-3,4-dicarboxylic acid. J. Het. Chem.,  2010, 47(5), 1040-1048.
[http://dx.doi.org/10.1002/jhet.416] 
[25] 
Cetin, A.; Korkmaz, A.; Bildirici, I. A novel 
oligo-pyrazole-based thin film: synthesis, characterization, optical and
 morphological properties. Colloid Polym. Sci.,  2018, 296(7), 1249-1257.
[http://dx.doi.org/10.1007/s00396-018-4342-7] [PMID: 29983478] 
[26] 
Bekhit, A.A.; Abdel-Aziem, T. Design, 
synthesis and biological evaluation of some pyrazole derivatives as 
anti-inflammatory-antimicrobial agents. Bioorg. Med. Chem.,  2004, 12(8), 1935-1945.
[http://dx.doi.org/10.1016/j.bmc.2004.01.037] [PMID: 15051061] 
[27] 
Korkusuz, E.; Yildirim, I. Reactions of 
4-benzoyl-1, 5-diphenyl-1H-pyrazole-3-carboxylic acid chloride with 
various hydroxylamines and carbazates. Turk. J. Chem.,  2010, 34(6), 859-868.
[28] 
Cetin, A.; Bildirici, İ. A study on synthesis and antimicrobial activity of 4-acyl-pyrazoles. J Saud. Chem. Soc.,  2018, 22(3), 279-296.
[29] 
Abdel-Hafez, S.M.; Abuo-Rahma, Gel-D.; 
Abdel-Aziz, M.; Radwan, M.F.; Farag, H.H. Design, synthesis and 
biological investigation of certain pyrazole-3-carboxylic acid 
derivatives as novel carriers for nitric oxide. Bioorg. Med. Chem.,  2009, 17(11), 3829-3837.
[http://dx.doi.org/10.1016/j.bmc.2009.04.037] [PMID: 19419878] 
[30] 
Turkan, F.; Cetin, A.; Taslimi, P.; Karaman, 
M.; Gulçin, İ. Synthesis, biological evaluation and molecular docking of
 novel pyrazole derivatives as potent carbonic anhydrase and 
acetylcholinesterase inhibitors. Bioorg. Chem.,  2019, 86, 420-427.
[http://dx.doi.org/10.1016/j.bioorg.2019.02.013] [PMID: 30769267] 
[31] 
Cetin, A.; Gündüz, B.; Menges, N.; Bildirici, 
I. Unsymmetrical pyrazole-based new semiconductor oligomer: synthesis 
and optical properties. Polym. Bull.,  2017, 74(7), 2593-2604.
[http://dx.doi.org/10.1007/s00289-016-1846-5] 
[32] 
Kandile, N.G.; Mohamed, M.I.; Zaky, H.; 
Mohamed, H.M. Novel pyridazine derivatives: Synthesis and antimicrobial 
activity evaluation. Eur. J. Med. Chem.,  2009, 44(5), 1989-1996.
[http://dx.doi.org/10.1016/j.ejmech.2008.09.047] [PMID: 19013692] 
[33] 
Schrödinger, L.L.C. Small-Molecule Drug Discovery Suite 2017-4; Schrödinger, LLC: New York, NY, 2017. 
[34] 
Akcamur, Y.; Sener, A.; Ipekoglu, A.M.; 
Kollenz, G. Functionalization and cyclization reactions of 4-benzoyl-1, 
5-diphenyl-1H-pyrazole-3-carboxylic acid. J. Het. Chem.,  1997, 34(1), 221-224.
[http://dx.doi.org/10.1002/jhet.5570340133] 
[35] 
Schmidt, A.; Dreger, A. Recent advances in the chemistry of pyrazoles. Properties, biological activities, and syntheses. Curr. Org. Chem.,  2011, 15(9), 1423-1463.
[http://dx.doi.org/10.2174/138527211795378263] 

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DOI https://dx.doi.org/10.2174/1570180816666190710142848	Print ISSN 1570-1808
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Synthesis and Evaluation of Anticonvulsant Activities of 4-Phenylpiperidin- 2-one Derivatives

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