Abstract
Background: Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs.
Methods: A series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test. Results: Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results. Conclusion: Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.Keywords: Thioxothiazolidindione derivatives, synthesis, anticonvulsant, NaV1.1 channel, stiripentol, patch-clamp.
[1]
Malawska B. New anticonvulsant agents. Curr Top Med Chem 2005; 5(1): 69-85.
[http://dx.doi.org/10.2174/1568026053386944] [PMID: 15638779]
[http://dx.doi.org/10.2174/1568026053386944] [PMID: 15638779]
[2]
French JA. Refractory epilepsy: Clinical overview. Epilepsia 2007; 48(Suppl. 1): 3-7.
[http://dx.doi.org/10.1111/j.1528-1167.2007.00992.x] [PMID: 17316406]
[http://dx.doi.org/10.1111/j.1528-1167.2007.00992.x] [PMID: 17316406]
[3]
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342(5): 314-9.
[http://dx.doi.org/10.1056/NEJM200002033420503] [PMID: 10660394]
[http://dx.doi.org/10.1056/NEJM200002033420503] [PMID: 10660394]
[4]
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]
[http://dx.doi.org/10.1016/S1474-4422(07)70215-6] [PMID: 17706563]
[5]
Wagner ML. Felbamate: A new antiepileptic drug. Am J Hosp Pharm 1994; 51(13): 1657-66.
[PMID: 7942890]
[PMID: 7942890]
[6]
Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007; 48(7): 1223-44.
[http://dx.doi.org/10.1111/j.1528-1167.2007.01041.x] [PMID: 17386054]
[http://dx.doi.org/10.1111/j.1528-1167.2007.01041.x] [PMID: 17386054]
[7]
Lin Z, Kadaba PK. Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents. Med Res Rev 1997; 17(6): 537-72.
[http://dx.doi.org/10.1002/(SICI)1098-1128(199711)17:6<537: AID-MED3>3.0.CO;2-2] [PMID: 9359082]
[http://dx.doi.org/10.1002/(SICI)1098-1128(199711)17:6<537: AID-MED3>3.0.CO;2-2] [PMID: 9359082]
[8]
Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: A summary of the Tenth Eilat Conference (EILAT X). Epilepsy Res 2010; 92(2-3): 89-124.
[http://dx.doi.org/10.1016/j.eplepsyres.2010.09.001] [PMID: 20970964]
[http://dx.doi.org/10.1016/j.eplepsyres.2010.09.001] [PMID: 20970964]
[9]
Bialer M, Yagen B. Valproic Acid: Second generation. Neurotherapeutics 2007; 4(1): 130-7.
[http://dx.doi.org/10.1016/j.nurt.2006.11.007] [PMID: 17199028]
[http://dx.doi.org/10.1016/j.nurt.2006.11.007] [PMID: 17199028]
[10]
Nau H, Löscher W. Pharmacologic evaluation of various metabolites and analogs of valproic acid: Teratogenic potencies in mice. Fundam Appl Toxicol 1986; 6(4): 669-76.
[http://dx.doi.org/10.1016/0272-0590(86)90180-6] [PMID: 3086174]
[http://dx.doi.org/10.1016/0272-0590(86)90180-6] [PMID: 3086174]
[11]
Huang X, Chen T, Han RB, Piao FY. Synthesis and anticonvulsant activity of 3-(alkylamino, alkoxy)-1,3,4,5- tetrahydro-2H-benzo [b] azepine-2-one derivatives. CNS Neurol Disord Drug Targets 2018; 17(6): 448-57.
[http://dx.doi.org/10.2174/1871527317666180704101332] [PMID: 29972104]
[http://dx.doi.org/10.2174/1871527317666180704101332] [PMID: 29972104]
[12]
Witkin JM, Schober DA, Gleason SD, et al. Targeted blockade of TARP-γ8-associated AMPA receptors: Anticonvulsant activity with the selective antagonist LY3130481 (CERC-611). CNS Neurol Disord Drug Targets 2017; 16(10): 1099-110.
[http://dx.doi.org/10.2174/1871527316666171101132047] [PMID: 29090671]
[http://dx.doi.org/10.2174/1871527316666171101132047] [PMID: 29090671]
[13]
Shiha AA, de la Rosa RF, Delgado M, Pozo MA, García-García L. Subacute fluoxetine reduces signs of hippocampal damage induced by a single convulsant dose of 4-Aminopyridine in Rats. CNS Neurol Disord Drug Targets 2017; 16(6): 694-704.
[http://dx.doi.org/10.2174/1871527315666160720121723] [PMID: 27989232]
[http://dx.doi.org/10.2174/1871527315666160720121723] [PMID: 27989232]
[14]
Song MX, Rao BQ, Cheng BB, et al. Design, synthesis and evaluation of the antidepressant and anticonvulsant activities of triazole-containing benzo[d]oxazoles. CNS Neurol Disord Drug Targets 2017; 16(2): 187-98.
[http://dx.doi.org/10.2174/1871527315666160822112501] [PMID: 27549143]
[http://dx.doi.org/10.2174/1871527315666160822112501] [PMID: 27549143]
[15]
Nabbout R, Chiron C. Stiripentol: An example of antiepileptic drug development in childhood epilepsies. Eur J Paediatr Neurol 2012; 16(Suppl. 1): S13-7.
[http://dx.doi.org/10.1016/j.ejpn.2012.04.009] [PMID: 22695038]
[http://dx.doi.org/10.1016/j.ejpn.2012.04.009] [PMID: 22695038]
[16]
Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel antiepileptic drug. Pharmacol Rep 2005; 57(2): 154-60.
[PMID: 15886413]
[PMID: 15886413]
[17]
Poisson M, Huguet F, Savattier A, Bakri-Logeais F, Narcisse G. A new type of anticonvulsant, stiripentol. Pharmacological profile and neurochemical study. Arzneimittelforschung 1984; 34(2): 199-204.
[PMID: 6326778]
[PMID: 6326778]
[18]
Aboul-Enein MN, El-Azzouny AA, Attia MI, et al. Design and synthesis of novel stiripentol analogues as potential anticonvulsants. Eur J Med Chem 2012; 47(1): 360-9.
[http://dx.doi.org/10.1016/j.ejmech.2011.11.004] [PMID: 22118828]
[http://dx.doi.org/10.1016/j.ejmech.2011.11.004] [PMID: 22118828]
[19]
Wang T, Dong S, Chen X, et al. Design, synthesis, biological evaluation, homology modeling and docking studies of (E)-3-(benzo[d][1,3]dioxol-5-ylmethylene) pyrrolidin-2-one derivatives as potent anticonvulsant agents. Bioorg Med Chem Lett 2018; 28(8): 1324-9.
[http://dx.doi.org/10.1016/j.bmcl.2018.03.015] [PMID: 29548572]
[http://dx.doi.org/10.1016/j.bmcl.2018.03.015] [PMID: 29548572]
[20]
Dong S, Wang T, Hu C, Chen X, Jin Y, Wang Z. Design and synthesis of 5-substituted benzo[d][1,3]dioxole derivatives as potent anticonvulsant agents. Arch Pharm (Weinheim) 2017; 350(2)e1600274
[http://dx.doi.org/10.1002/ardp.201600274] [PMID: 28092111]
[http://dx.doi.org/10.1002/ardp.201600274] [PMID: 28092111]
[21]
Braga FG, Coimbra ES, de Oliveira Matos M, Lino Carmo AM, Cancio MD, da Silva AD. Synthesis and biological evaluation of some 6-substituted purines. Eur J Med Chem 2007; 42(4): 530-7.
[http://dx.doi.org/10.1016/j.ejmech.2006.10.014] [PMID: 17156894]
[http://dx.doi.org/10.1016/j.ejmech.2006.10.014] [PMID: 17156894]
[22]
Piao ZT, Guan LP, Zhao LM, Piao HR, Quan ZS. Synthesis of novel 7-benzylamino-2H-1,4-benzoxazin-3(4H)-ones as anticonvulsant agents. Eur J Med Chem 2008; 43(6): 1216-21.
[http://dx.doi.org/10.1016/j.ejmech.2007.08.006] [PMID: 17950496]
[http://dx.doi.org/10.1016/j.ejmech.2007.08.006] [PMID: 17950496]
[23]
Xie ZF, Chai KY, Piao HR, Kwak KC, Quan ZS. Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines. Bioorg Med Chem Lett 2005; 15(21): 4803-5.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.051] [PMID: 16139502]
[http://dx.doi.org/10.1016/j.bmcl.2005.07.051] [PMID: 16139502]
[24]
Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 1978; 19(4): 409-28.
[http://dx.doi.org/10.1111/j.1528-1157.1978.tb04507.x] [PMID: 699894]
[http://dx.doi.org/10.1111/j.1528-1157.1978.tb04507.x] [PMID: 699894]
[25]
Porter RJ, Cereghino JJ, Gladding GD, et al. Antiepileptic drug development program. Cleve Clin Q 1984; 51(2): 293-305.
[http://dx.doi.org/10.3949/ccjm.51.2.293] [PMID: 6380818]
[http://dx.doi.org/10.3949/ccjm.51.2.293] [PMID: 6380818]
[26]
Kupferberg HJ. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia 1989; 30(Suppl. 1): S51-6.
[http://dx.doi.org/10.1111/j.1528-1157.1989.tb05815.x] [PMID: 2776711]
[http://dx.doi.org/10.1111/j.1528-1157.1989.tb05815.x] [PMID: 2776711]
[27]
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 1981; 391(2): 85-100.
[http://dx.doi.org/10.1007/BF00656997] [PMID: 6270629]
[http://dx.doi.org/10.1007/BF00656997] [PMID: 6270629]
[28]
Ucar H, Cacciaguerra S, Spampinato S, et al. Van derpoorten K. Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives. J Med Chem 1998; 41(16): 3102.
[http://dx.doi.org/10.1021/jm980259g] [PMID: 9685250]
[http://dx.doi.org/10.1021/jm980259g] [PMID: 9685250]
[29]
Deng X, Xie Y, Chen Y. Effect of neuroinflammation on ABC transporters: Possible contribution to refractory epilepsy. CNS Neurol Disord Drug Targets 2018; 17(10): 728-35.
[http://dx.doi.org/10.2174/1871527317666180828121820] [PMID: 30152292]
[http://dx.doi.org/10.2174/1871527317666180828121820] [PMID: 30152292]
[30]
Jiang XW, Lu HY, Xu Z, et al. In Silico analyses for key genes and molecular genetic mechanism in epilepsy and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17(8): 608-17.
[http://dx.doi.org/10.2174/1871527317666180724150839] [PMID: 30047339]
[http://dx.doi.org/10.2174/1871527317666180724150839] [PMID: 30047339]
[31]
Zang K, Zhang Y, Hu J, Wang Y. The large conductance calcium- and voltage-activated potassium channel (BK) and epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 248-54.
[http://dx.doi.org/10.2174/1871527317666180404104055] [PMID: 29623857]
[http://dx.doi.org/10.2174/1871527317666180404104055] [PMID: 29623857]
[32]
Zhu Y, Zhang S, Feng Y, Xiao Q, Cheng J, Tao J. The Yin and Yang of BK channels in epilepsy. CNS Neurol Disord Drug Targets 2018; 17(4): 272-9.
[http://dx.doi.org/10.2174/1871527317666180213142403] [PMID: 29437015]
[http://dx.doi.org/10.2174/1871527317666180213142403] [PMID: 29437015]
[33]
Cordero-Arreola J, West RM, Mendoza-Torreblanca J, et al. The role of innate immune system receptors in epilepsy research. CNS Neurol Disord Drug Targets 2017; 16(7): 749-62.
[http://dx.doi.org/10.2174/1871527316666170725145549] [PMID: 28745241]
[http://dx.doi.org/10.2174/1871527316666170725145549] [PMID: 28745241]
[34]
Leo A, Citraro R, Marra R, et al. The sphingosine 1-phosphate signaling pathway in epilepsy: A possible role for the immunomodulator drug fingolimod in epilepsy treatment. CNS Neurol Disord Drug Targets 2017; 16(3): 311-25.
[http://dx.doi.org/10.2174/1871527315666161104163031] [PMID: 27823573]
[http://dx.doi.org/10.2174/1871527315666161104163031] [PMID: 27823573]
[35]
Naseer MI, Rasool M, Chaudhary AG, et al. Chromosomal micro-aberration in a Saudi family with juvenile myoclonic epilepsy. CNS Neurol Disord Drug Targets 2017; 16(9): 1010-7.
[PMID: 28758580]
[PMID: 28758580]
[36]
Pevarello P, Bonsignori A, Caccia C, et al. Sodium channel activity and sigma binding of 2-aminopropanamide anticonvulsants. Bioorg Med Chem Lett 1999; 9(17): 2521-4.
[http://dx.doi.org/10.1016/S0960-894X(99)00415-1] [PMID: 10498200]
[http://dx.doi.org/10.1016/S0960-894X(99)00415-1] [PMID: 10498200]
[37]
Obniska J, Byrtus H, Kamiński K, Pawłowski M, Szczesio M, Karolak-Wojciechowska J. Design, synthesis, and anticonvulsant activity of new N-Mannich bases derived from spirosuccinimides and spirohydantoins. Bioorg Med Chem 2010; 18(16): 6134-42.
[http://dx.doi.org/10.1016/j.bmc.2010.06.064] [PMID: 20638856]
[http://dx.doi.org/10.1016/j.bmc.2010.06.064] [PMID: 20638856]
[38]
Zuliani V, Fantini M, Nigam A, Stables JP, Patel MK, Rivara M. Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models. Bioorg Med Chem 2010; 18(22): 7957-65.
[http://dx.doi.org/10.1016/j.bmc.2010.09.029] [PMID: 20943396]
[http://dx.doi.org/10.1016/j.bmc.2010.09.029] [PMID: 20943396]
[39]
Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol 2010; 588(Pt 11): 1849-59.
[http://dx.doi.org/10.1113/jphysiol.2010.187484] [PMID: 20194124]
[http://dx.doi.org/10.1113/jphysiol.2010.187484] [PMID: 20194124]
[40]
Volkers L, Kahlig KM, Verbeek NE, et al. Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome. Eur J Neurosci 2011; 34(8): 1268-75.
[http://dx.doi.org/10.1111/j.1460-9568.2011.07826.x] [PMID: 21864321]
[http://dx.doi.org/10.1111/j.1460-9568.2011.07826.x] [PMID: 21864321]
[41]
Courtney KR, Kendig JJ, Cohen EN. The rates of interaction of local anesthetics with sodium channels in nerve. J Pharmacol Exp Ther 1978; 207(2): 594-604.
[PMID: 712641]
[PMID: 712641]
[42]
Chernoff DM. Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine. Biophys J 1990; 58(1): 53-68.
[http://dx.doi.org/10.1016/S0006-3495(90)82353-5] [PMID: 2166601]
[http://dx.doi.org/10.1016/S0006-3495(90)82353-5] [PMID: 2166601]