Download PDF
Arzneimittelforschung 2011; 61(6): 327-334
DOI: 10.1055/s-0031-1296206
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

Ünsal Çaliş
1   Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey
,
Septioğlu SeptioğluEbubekir
1   Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey
,
Mutlu Dilsiz Aytemir
1   Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
27 November 2011 (online)

    Permissions and Reprints

Abstract

A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substi-tuted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarba-zides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicar-bazone compounds were compared at different doses, 2-(1H-imidazole-1-yl)-1-(2-naphthyl)ethane-1-one N-(3-chloro-phenyl)thiosemicarbazone (3) and 2-(1H-imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl)thiosemicarba-zone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1-(1-biphenyl)ethane-1-one N-(4-methylphe-nyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4-dichloro-phenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemi-carbazone compounds showed neurotoxicity at higher doses

Key words

Anticonvulsant activity - Arylalkylimidazole - Semicarbazone - Synthesis - Thiosemicarbazone
 

  • References

  • 1 Shindikar AV, Khan F, Viswanathan CL. Design, synthesis and in vivo anticonvulsant screening in mice of Novel phe-nylacetamides. Eur J Med Chem. 2006; 41 (6) 786-92
    CrossrefPubMedGoogle Scholar
  • 2 Siddiqui N, Arshad MF, Khan SA. Synthesis of Some new coumarin incorporated thiazolyl semicarbazones as anticonvulsants. Acta Pol Pharm. 2009; 66 (2) 161-7
    PubMedGoogle Scholar
  • 3 Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B et al. Antiepileptic Drug Development Program. Cleveland Clin Q. 1984; 51 (2) 293-305
    PubMedGoogle Scholar
  • 4 Zhang L, Guan LP, Sun XY, Wei CX, Chai KY, Quan ZS. Synthesis and anticonvulsant activity of 6-alkoxy-[1,2,4]-triazolo[3,4-a]phthalazines. Chem Biol Drug Des. 2009; 73 (3) 313-9
    CrossrefPubMedGoogle Scholar
  • 5 Brodie MJ. Do we need any more new antiepileptic drugs?. Epilepsy Res. 2001; 45 (1–3) 3-6
    CrossrefPubMedGoogle Scholar
  • 6 Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E. Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI). Epilepsy Res. 2002; 51 (1–2) 31-71
    CrossrefPubMedGoogle Scholar
  • 7 Siddiqui N, Rana A, Khan SA, Bhat MA, Haque SE. Synthesis of benzothiazole semicarbazones as novel anticonvul-sants-the role of hydrophobic domain. Bioorg Med Chem Lett. 2007; 17 (15) 4178-82
    CrossrefPubMedGoogle Scholar
  • 8 Shalini M, Yogeeswari P, Sriram D, Stables JP. Cyclization of the semicarbazone template of aryl semicarbazones: synthesis and anticonvulsant activity of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one. Biomed Pharmacother. 2009; 63 (3) 187-93
    CrossrefPubMedGoogle Scholar
  • 9 Thirumurugan R, Sriram D, Saxena A, Stables J, Yogeeswari P. 2,4-dimethoxyphenylsemicarbazones with anticonvulsant activity against three animal models of seizures: synthesis and pharmacological evaluation. Bioorgan Med Chem. 2006; 14 (9) 3106-12
    CrossrefPubMedGoogle Scholar
  • 10 Karakurt A, Dalkara S, Ozalp M, Ozbey S, Kendi E, Stables JP. Synthesis of some 1-(2-naphthyl)-2-(imidazole-1-yl)-ethanone oxime and oxime ether derivatives and their anticonvulsant and antimicrobial activities. Eur J Med Chem. 2001; 36 (5) 421-33
    CrossrefPubMedGoogle Scholar
  • 11 Shafiee A, Rineh A, Kebriaeezadeh A, Foroumadi A, Sheibani V, Afarinesh M. Synthesis and anticonvulsant activity of 4-(2-phenoxyphenyl)semicarbazones. Med Chem Res. 2009; 18 (9) 758-69
    CrossrefPubMedGoogle Scholar
  • 12 Kshirsagar A, Toraskar MP, Kulkarni VM, Dhanashire S, Kadam V. microwave assisted synthesis of potential anti infective and anticonvulsant thiosemicarbazones. Int J ChemTech Res. 2009; 1 (3) 696-701
    PubMedGoogle Scholar
  • 13 Rajak H, Veerasamy R, Singour P, Kharya MD, Mishra P. anticonvulsant activity of a novel series of 2,5-disubsti-tuted 1,3,4-oxadiazoles: semicarbazones based pharmaco-phoric model studies. Lett Drug Des Discov. 2009; 6 (6) 456-63
    CrossrefPubMedGoogle Scholar
  • 14 Pandeya SN, Raja AS, Stables JR. Synthesis of isatin semicarbazones as novel anticonvulsants-role of hydrogen bonding. J Pharm Pharm Sci. 2002; 5 (3) 266-71
    PubMedGoogle Scholar
  • 15 Aggarwal N, Mishra P. Synthesis and evaluation of 4-sub-stituted semicarbazones of levulinic acid for anticonvulsant activity. J Zhejiang Univ Sci B. 2005; 6 (7) 617-621
    PubMedGoogle Scholar
  • 16 Walker KAM, Wallach MB, Hirschfeld DR. 1-(Naphthylal-kyl)- 1H-imidazole derivatives, a new class of anticonvulsant agents. J Med Chem. 1981; 24 (1) 67-74
    CrossrefPubMedGoogle Scholar
  • 17 Nardi D, Tajana A, Leonardi A, Pennini R, Portioli F, Magistretti MJ et al Synthesis and anticonvulsant activity of N-(benzoylalkyl)imidazoles and N-(omega-phenyl-omega-hydroxyalkyl)imidazoles. J Med Chem. 1981; 24 (6) 727-31
    CrossrefPubMedGoogle Scholar
  • 18 Pandeya SN, Aggarwal N, Jain JS. Evaluation of semicarbazones for anticonvulsant and sedative-hypnotic properties. Pharmazie. 1999; 54 (4) 300-2
    PubMedGoogle Scholar
  • 19 Pandeya SN, Kohli S, Siddique N, Stables JP. Synthesis and anticonvulsant activities of 4-N-substituted arylsemicarba-zones. Pol J Pharmacol. 2003; 55 (4) 565-71
    PubMedGoogle Scholar
  • 20 Yogeeswari P, Sriram D, Pandeya SN, Stables JP. 4-Sulpha-moylphenyl semicarbazones with anticonvulsant activity. Farmaco. 2004; 59 (8) 609-13
    CrossrefPubMedGoogle Scholar
  • 21 Yogeeswari P, Sriram D, Mehta S, Nigam D, Kumar MM, Murugesan S et al Anticonvulsant and neurotoxicity evaluation of some 6-substituted benzothiazolyl-2-thiosemi-carbazones. Farmaco. 2005; 60 (1) 1-5
    CrossrefPubMedGoogle Scholar
  • 22 Aggarwal N, Aggarwal R, Mishra P, Jain JS, Bansal SK, Jha KK. Design and evaluation of semicarbazones and thiosemicarbazones as novel anticonvulsants. Curr Med Chem. 2008; 8: 26-–8
    PubMedGoogle Scholar
  • 23 Siddiqui N, Pandeya SN, Khan SA, Stables J, Rana A, Alam M et al Synthesis and anticonvulsant activity of sulfonamide derivatives-hydrophobic domain. Bioorg Med Chem Lett. 2007; 17 (1) 255-9
    CrossrefPubMedGoogle Scholar
  • 24 Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development. 2. Anticonvulsant drug screening. Epilepsia 1978; 19 (4) 409-28
    CrossrefPubMedGoogle Scholar
  • 25 Septioglu E, Aytemir MD, Calis U. Synthesis and anticonvulsant activity of some new hexahydropyrimidine-2,4-dione derivatives. Arzneimittelforschung 2005; 55 (5) 259-64
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Aytemir MD, Septioglu E, Calis U. Synthesis and anticonvulsant activity of new kojic acid derivatives. Arzneimittelforschung 2010; 60 (1) 22-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Aytemir MD, Calis U. Anticonvulsant and neurotoxicity evaluation of some novel Kojic acids and allomaltol derivatives. Arch Pharm (Weinheim) 2010; 343 (3) 173-81
    CrossrefPubMedGoogle Scholar
  • 28 Buuhoi MNP, Xuong MND, Nam MNH. Potential antiviral thiourea derivatives. J Chem Soc. 1956; Jul 2160-5
    CrossrefPubMedGoogle Scholar
  • 29 Lieber E, Ramachandran J. Isomeric 5-(substituted)ami-nothiatriazole and 1-substituted-tetrazolinethiones. Can J Chem. 1959; 37 (1) 101-9
    CrossrefPubMedGoogle Scholar
  • 30 Niederschulte U, Ballschmiter K. Analytische Anwendung der Di-(4-phenyl)thiosemicarbazone von 1,2-Diketonen. Fresen J Anal Chem. 1972; 261 (3) 191-7 [German]
    PubMedGoogle Scholar
  • 31 Klayman DL, Bartosevich JF, Griffin TS, Mason CJ, Scovill JP. 2-Acetylpyridine thiosemicarbazones. 1. New class of potential anti-malarial agents. J Med Chem. 1979; 22 (7) 855-62
    CrossrefPubMedGoogle Scholar
  • 32 Fromm E, Soffner M, Frey M. Die Einwirkung von S?urechloriden auf Semicarbazide. Liebig?s Ann Chem. 1923; 434 (1) 285-295 German
    PubMedGoogle Scholar
  • 33 Yogeeswari P, Sriram D, Veena V, Kavya R, Rakhra K, Ragavendran JV et al Synthesis of aryl semicarbazones as potential anticonvulsant agents. Biomed Pharmacother. Jan–Feb 2005; 59 (1–2) 51-55
    CrossrefPubMedGoogle Scholar
  • 34 Beukers MW, Wanner MJ, Kunzel JKV, Klaasse EC, IJzerman AP, Koomen GJ. N-6-cyclopentyl-2-(3-phenylamino-carbonyltriazene-1-yl) adenosine (TCPA), a very selective agonist with high affinity for the human adenosine A(1) receptor. J Med Chem. 2003; 46 (8) 1492-503
    CrossrefPubMedGoogle Scholar
  • 35 Karali N. Synthesis and primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives. Eur J Med Chem. 2002; 37 (11) 909-18
    CrossrefPubMedGoogle Scholar
  • 36 Pandeya SN, Yogeeswari P, Stables JP. Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones. Eur J Med Chem. 2000; 35 (10) 879-86
    CrossrefPubMedGoogle Scholar
  • 37 Smitha S, Pandeya SN, Stables JP, Ganapathy S. Anticonvulsant and sedative-hypnotic activities of N-acetyl/methyl isatin derivatives. Sci Pharm. 2008; 76 (4) 621-36
    CrossrefPubMedGoogle Scholar
  • 38 Sriram D, Yogeeswari P, Thirumurugan R. Antituberculous activity of some aryl semicarbazone derivatives. Bioorg Med Chem Lett. 2004; 14 (15) 3923-4
    CrossrefPubMedGoogle Scholar
  • 39 Yogeeswari P, Sriram D, Saraswat V, Ragavendran JV, Kumar MM, Murugesan S et al Synthesis and anticonvulsant and neurotoxicity evaluation of N-4-phthalimido phenyl(thio)-semicarbazides. Eur J Pharm Sci. 2003; 20 (3) 341-6
    CrossrefPubMedGoogle Scholar
  • 40 Verma K, Pandeya SN, Singh UK, Gupta S, Prashant P An-urag et al Synthesis and pharmacological activity of some substituted menthone semicarbazone and thiosemicarba-zone derivatives. Int J Pharm Sci Nanotechnol. 2009; 1 (4) 357-62
    PubMedGoogle Scholar
  • 41 Hadjipavlou-Litina D. Review, reevaluation, and new results in quantitative structure-activity studies of anticonvulsants. Med Res Rev. 1998; 18 (2) 91-119
    CrossrefPubMedGoogle Scholar