Synthesis and anticonvulsant activity of substituted thiourea derivatives

Year 2011, Volume: 15 Issue: 2, 43 - 47, 07.03.2014

Ahmet Çelen Bedia Kaymakçıoğlu , Salih Gümrü Hale Toklu Feyza Arıcıoğlu

Abstract

ABSTRACT: Twelve new thiourea derivatives were prepared by the reacting of 4-aminophenylacetic
acide with substituted isothiocyanates. Their chemical structures were proved by
means of IR, 1H-NMR, mass spectroscopic and elemental analyses. These compounds were
tested at dose of 50 mg/kg for their anticonvulsant activity using by pentylenetetrazole induced
seizure (PTZ) and maximal electroshock seizure (MES) tests in mice. Compound 1b,
(4-{[(4-chlorophenyl)thiocarbamoyl]amino}phenyl)acetic acid, was found to be more active
than the other tested compounds. The compound 1b reduced convulsions in all types of
grades (from grade I to V), therefore it increased convulsive threshold. It also increased
onset time from 1.20 to 2.58 sec. and survival % from 50 to 95.
KEY WORDS: Synthesis, thiourea, anticonvulsant activity.

Keywords

-

Synthesis and anticonvulsant activity of substituted thiourea derivatives

Abstract

4-Aminofenilasetik asitin sübstitüe izotiyosiyanatlar ile reaksiyonu sonucu, on iki adet yeni tiyoüre bileşiği sentezlenmiştir. Bileşiklerin kimyasal yapıları IR, 1H-NMR, kütle spektroskopisi ve elementel analiz testleri ile aydınlatılmıştır. Tüm bileşiklerin antikonvulsan aktiviteleri 50mg/kg dozda farelerde pentilentetrazol (PTZ) ve maksimal elektroşok nöbet (MES) testleri kullanılarak tayin edilmiştir. Bileşik 1b’nin (4-{[(4-klorofenil)tiyokarbamoil]amino}fenil)asetik asit, diğer bileşiklere oranla daha aktif olduğu saptanmıştır. Tüm seviyelerde konvulsiyon oranını düşüren 1b bileşiği aynı zamanda nöbet eşiğini de yükseltmiştir. Ayrıca nöbet başlangıç süresini 1.20 saniyeden 2.58 saniyeye, hayatta kalma oranını ise %50’den %95’e yükseltmiştir

Keywords

ANAHTAR KELİMELER: Sentez, tiyoüre, antikonvulsan aktivite

References

• Bell FW, Cantrell AS, Högberg M, Jaskunas SR, Johans- son NG, Jordan CL, Kinnick MD, Lind P, Morin JM, Noreen R, Öberg B, Palkowitz JA, Parrish CA, Pranc P, Sahlberg C, Ternansky RJ, Vasileff RT, Vrong L, West SJ, Zhang H, Zhou XX. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1.Synthesis and basic structure-activity re- lationship studies of PETT analogs. J Med Chem 1995; 38(25): 4929-4936.
• Uçkun FM, Pendergrass S, Maher D, Zhu D, Tuel-Ahl- gren L, Mao C, Venkatachalam TK. N’-[2-(2-thiophene) ethyl]-N’-[2-(5-bromopyridyl)] thio-urea as a potent in- hibitor of NNI-resistant and multidrug-resistant HIV-1. Bioorg Med Chem Lett 1999; 9(24): 3411-3416.
• Küçükgüzel İ, Tatar E, Küçükgüzel ŞG, Rollas S, De Clercq E. Synthesis of some novel thiourea derivatives obtai ned from 5-[(4-aminophenoxy)methyl]-4-alkyl/ aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evalua- tion as antiviral/ anti-HIV and anti-tuberculosis agents. Eur J Med Chem 2008; 43(2):381-392.
• Todoulou OG, Papadaki-Valiraki AE, Filippatos EC, Ike- da, S, De Clercq E. Synthesis and anti-myxovirus activity of some novel N,N′-disubstituted thioureas. Eur J Med Chem 1994; 29(2): 127-131.
• Sriram D, Yogeeswari P, Madhu K. Synthesis and in vitro antitubercular activity of some 1-[(4-sub)phenyl]- 3-(4-{1-[(pyridine-4-carbonyl) hydrazono] ethyl}phenyl) thiourea. Bioorg Med Chem Lett 2006; 16: 876–878.
• Dixit PP, Patil VJ, Nair PS, Jain S, Sinha N, Arora SK. Synthesis of 1-[3-(4-benzotriazol-1/2-yl-3-fluorophenyl)- 2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea derivatives as antituberculosis agents. Eur J Med Chem 2006; 41: 423–428.
• Küçükgüzel İ, Küçükgüzel ŞG, Rollas S, Kiraz M. Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials. Bioorg Med Chem Lett 2001; 11: 1703-1707.
• Saeed A, Shaheen U, Hameed A, Haider Naqvi SZ. Syn- thesis, characterization and antimicrobial activity of some new 1-(fluorobenzoyl)-3-(fluorophenyl) thioureas. J of Fluor Chem 2009; 130(11): 1028-1034.
• Chung J, Kim SY, Lim J, Choi H, Kang S, Yoon H, Ryu H, Kang DW, Lee J, Kang B, Choi S, Toth A, Pearce LV, Pav- lyukovets VA, Lundberg DJ, Blumberg PM. a-Substitut- ed N-(4-tert-butylbenzyl)-N’-[4-(methylsulfonylam ino)- b enzyl]thiourea analogues as potent and stereospecific TRPV1 antagonists. Bioorg Med Chem 2007; 15: 6043– 6053.
• Dos Santos L, Lima LA, Cechinel-Filho V, Corrêa R, Buz- zi FC, Nunes RJ. Synthesis of new 1-phenyl-3-{4-[(2E)-3- phenylprop-2-enoyl]phenyl}-thiourea and urea deriva- tives with anti-nociceptive activity. Bioorg Med Chem 2008; 16: 8526–8534.
• Mahajan A, Yeh S, Nell M, Van Rensburg CJ, Chibale K. Synthesis of new 7-chloroquinolinyl thioureas and their biological investigation as potential antimalarial and an- ticancer agents. Bioorg Med Chem Lett 2007; 17: 5683– 5685.
• Karakuş S, Küçükgüzel ŞG, Küçükgüzel İ, De Clercq E, Pannecouque C, Andrei G, Snoeck R, Ş ahin F, Bayrak Ö F. S ynthesis, ant iviral and anticancer activity of s ome novel thioureas derived from N-(4-nitro-2-phenox yphenyl)- methanesulfonamide. Eur J Med Chem 2009; 44(9): 3591- 3595.
• Liu J, Song B, Fan H, Bhadury PS, Wan W, Yang S, Xu W, Wu J, Jin L, Wei X, Hu D, Zeng S. Synthesis and in vitro study of pseudo-peptide thioureas containing α-aminophosphonate moiety as potential antitumor agents. Eur J Med Chem 2010; 45(11): 5108-5112.
• Heinisch G, Matuszczak B, Rakowitz D, Tantisina B. Synthesis of N-aryl-N’-heteroaryl-substituted urea and thiourea derivatives and evaluation of their anticonvul- sant activity. Arch Pharm (Weinheim) 1997; 330(7): 207- 210.
• Masereel B, Lambert DM, Dogne JM, Poupaert JH, De- large J. Anticonvulsant activity of 3-pyrid-3-yl-sulfonyl ureas and thioureas. Epilepsia 1997; 38(3): 334-337.
• Pandeya SN, Manjula H, Stables JP. Design of semicarba- zones and their bioisosteric analoques as potential anti- convulsants. Pharmazie 2001; 56(2): 121-124.
• Perucca E, French J, Bialer M. Development of new an- tiepileptic drugs: challenges, incentives, and recent ad- vances. Lancet Neurol 2007; 6: 793–804.
• Koçyiğit-Kaymakçıoğlu B, Rollas S, Korcegez E, Ari- cioglu F. Synthesis and biological evaluation of new N-substituted-N’-(3,5-di/1,3,5-trimethylpyrazole-4-yl) thiourea/urea derivatives. Eur J Pharm Sci 2005; 26(1): 97-103.
• Karakuş S, Koçyiğit-Kaymakçıoğlu B, Toklu HZ, Arıcıoğlu F, Rollas S. Synthesis And Anticonvulsant Activity of New N-(Alkyl/Substitutedaryl) - N’-[4- (5-Cyclohexylamino)-1,3,4-Thiadiazole-2-yl) Phenyl] Thioureas. Archive der Pharmazie 2009; 342(1): 48-53.
• Pandeya SN, Mishra V, Sign PN, Rupainwar DC. An- ticonvulsant activity of thioureido derivatives of ac- etophenone semicarbazone. Pharmacol Res 1999; 37(1): 17-22.
• Litchfield JT, Wilcoxon FA. A simplified method of eval- uating dose-effect experiments. J Pharmacol Exp Ther 1949; 96: 99-113.
• Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-294.
• Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Anticonvulsant drug development: Anticonvulsant drug screening. Epilepsia 1978; 19: 409-428.