Skip to main content

Advertisement

SpringerLink
Log in

Imidazole as an anti-epileptic: an overview

  • Review Article
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Imidazole is incorporated into many important biological molecules. The major revolution in the field of imidazole derivatives with antiepileptic properties came with the synthesis of Denzimol and Nafimidone, which leads in its effectiveness among other molecules. The pharmacophore and substitution necessary to elevate the pharmacological effect of these derivatives in curing epilepsy are presented in this review, which can serve the medicinal chemist working on epileptic research to focus on this untouched class of molecules and enlarge its category and synthesize more active and potent anticonvulsant agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ahangar N, Ayati A, Alipour E, Pashapour A, Foroumadi A, Emami S (2011) 1-[(2-Arylthiazol-4-yl)methyl]azoles as a new class of anticonvulsants: design, synthesis, in vivo screening, and in silico drug-like properties. Chem Biol Drug Des 78:844–852

    Article  PubMed  CAS  Google Scholar 

  • Aktu Z, Kılıc F, Erol K, Pabuc V (2002) Synthesis and anticonvulsant activity of some ω-(1H–1-imidazolyl)-N-phenylalkanoic acid amide derivatives. IL Farmaco 57:201–206

    Article  Google Scholar 

  • Bertolote JM (1994) Epilepsy as a public health problem. Trop Geogr Med 46(3):28–30

    Google Scholar 

  • Chimirri A, Sarro AD, Sarro GD, Zappall M et al (1989) Synthesis and Anticonvulsant Properties of 2,3,3a,4-Tetrahydro-1H-pyrrolo[1,2-a Ibenzimidazol-1-ones. J Med Chem 32:93–95

    Article  PubMed  CAS  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  PubMed  CAS  Google Scholar 

  • Clark CR, Ching-Ming Lin, Norris GN et al (1985) Anticonvulsant activity of some 4-aminobenzanilides. J Med Chem 28:1259–1262

    Article  PubMed  CAS  Google Scholar 

  • Cortes S, Liao Zeng-Kun, Watson D, Kohn H (1985) Effect of structural modification of the hydantoin ring on anticonvulsant activity. J Med Chem 28:601–606

    Article  PubMed  CAS  Google Scholar 

  • Cruz I, Bossano F, Cruz ME (1991) Factores de riesgo para la epilepsia en una comunidad andina del Ecuador. In: Cruz ME (ed) Ed. Academia Ecuatoriana de Neurociencias. Control Comunitario de la Epilepsia, Quito, pp 21–26

    Google Scholar 

  • Curtis DR, Watkins JC (1960) The excitation and depression of spinal neurones by structurally related amino acids. J Neurochem 6:117–141

    Article  PubMed  CAS  Google Scholar 

  • Drislane FW (2000) Presentation, evaluation and treatment of nonconvulsive status epilepticus. Epilepsy Behav 1:301–314

    Article  PubMed  CAS  Google Scholar 

  • Emami S, Kebriaeezadeh A, Zamani MJ, Shafiee A (2006) Azolylchromans as a novel scaffold for anticonvulsant activity. Bio Med Chem Lett 16:1803–1806

    Article  CAS  Google Scholar 

  • Emami S, Kebriaeezadeh A, Ahangar N, Khorasani R (2011) Imidazolylchromanone oxime ethers as potential anticonvulsant agents: Anticonvulsive evaluation in PTZ-kindling model of epilepsy and SAR study. Bio Med Chem Lett 21:655–659

    Article  CAS  Google Scholar 

  • Fantini M, Rivara M, Zuliani V, Kalmar CL, Vacondio F et al (2009) 2,4(5)-Diarylimidazoles as inhibitors of hNaV1.2 sodium channels: pharmacological evaluation and structure–property relationships. Bio Med Chem 17:3642–3648

    Article  CAS  Google Scholar 

  • Flaherty PT, Greenwood TD, Manheim AL, Wolfe JF (1996) Synthesis and evaluation of N-(Phenylacetyl) trifluoromethane sulfonamides as anticonvulsant agents. J Med Chem 39:1509–1513

    Article  PubMed  CAS  Google Scholar 

  • Forsgren L, Johannessen SI, Gram L, Sillanpaa M, Thomson T (1995) Intractable epilepsy. Wrightson Biomedical Publishing, Petersfield, pp 25–40

    Google Scholar 

  • French JA (1999) Vigabatrin. Epilepsia 40:S11–S16

    Article  PubMed  CAS  Google Scholar 

  • Fuerst RH, Graves NM, Leppik IE, Brundage RC, Holmes GB, Remmel RP (1988) Felbamate increases phenytoin but decreases carbamazepine concentrations. Epilepsia 29:488–491

    Article  PubMed  CAS  Google Scholar 

  • Godefroi EF, Platje JTJ (1971) DL-1-(α-methylbenzyl)-2-methylimidazole-5-carboxylate easters. Synthesis and pharmacological properties. J Med Chem 15:336–337

    Article  Google Scholar 

  • Grunwald C, Rundfeldt C, Lankau HJ, Arnold T, Hofgen N, Dost R, Egerland U, Hofmann HJ, Unverferth K (2006) Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors. J Med Chem 49:1855–1866

    Article  PubMed  CAS  Google Scholar 

  • Gupta A, Mishra P, Pandeya SN, Kashaw SK, Kashaw V, Stables JP (2009) Synthesis and anticonvulsant activity of some substituted 1,2,4-thiadiazoles. Eur J Med Chem 44:1100–1105

    Article  PubMed  CAS  Google Scholar 

  • Hack S, Wörlein B, Höfner G, Pabel J, Wanner KT (2011) Development of imidazole alkanoic acids as mGAT3 selective GABA uptake inhibitors. Eur J Med Chem 46:1483–1498

    Article  PubMed  CAS  Google Scholar 

  • Hauck FP, Demick J, Fan J (1967) Preparation and anticonvulsant activity of some aryldialkylsuccinimides. J Med Chem 10:611–614

    Article  PubMed  CAS  Google Scholar 

  • Husain A, Siddiqui N, Sarafroz M, Khatoon Y, Rasid M, Ahmad N (2011) Synthesis, anticonvulsant and neurotoxicity screening of some novel 1,2,4-trisubstituted-1H-imidazole derivatives. Acta Pol Pharm 68:657–663

    PubMed  CAS  Google Scholar 

  • Jeffrey SJ, Weaver DF (2003) Development of quantitative structure-activity relationships and classification models for anticonvulsant activity of hydantoin analogues. J Chem Inf Comput Sci 43:1028–1036

    Article  Google Scholar 

  • Johnson TB (1913) Hydantoin: the history of 2-thiohydantoin. J Am Chem Soc 35(6):780–784

    Article  CAS  Google Scholar 

  • Karakurt A, Ozalp M, Isik S, Stables JP, Dalkara S (2010) Synthesis, anticonvulsant and antimicrobial activities of some new 2-acetylnaphthalene derivatives. Bioorg Med Chem 18:2902–2911

    Article  PubMed  CAS  Google Scholar 

  • Karakurta A, Dalkaraa S, Zalpb MO, Kendic E, Stables JP (2001) 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 36:421–433

    Article  Google Scholar 

  • Keith DA (1978) Side effects of diphenylhydantoin: a review. J Oral Surg 36(3):206–209

    PubMed  CAS  Google Scholar 

  • Kmjevic K, Phillis JW (1963) Iontophoretic studies of neurones in the mammalian cerebral cortex. J Physiol 165:274–304

    Google Scholar 

  • Koller M, Lingenhoehl K, Schmutz M, Vranesic Ivan-Toma, Kallen J, Auberson YP, Carcache DA, Mattes H, Ofner S, Orain D, Urwyler S (2011) Quinazolinedione sulfonamides: a novel class of competitive AMPA receptor antagonists with oral activity. Bio Med Chem Lett 21:3358–3361

    Article  CAS  Google Scholar 

  • Kornet MJ, Crider AM, Magarian EO (1977) Potential long-acting anticonvulsants. 2. Synthesis and activity of succinimides containing an alkylating group on nitrogen or at the 3 position. J Med Chem 20(9):1210–1213

    Article  PubMed  CAS  Google Scholar 

  • Kubota M, Nishi-Nagase M, Sakakihara Y, Noma S, Nakamoto M, Kawaguchi H, Yanagisawa M (2000) Zonisamide-induced urinary lithiasis in patients with intractable epilepsy. Brain Dev 22:230–233

    Article  PubMed  CAS  Google Scholar 

  • Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K et al (2007) New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med Chem 42:873–879

    Article  PubMed  CAS  Google Scholar 

  • Łukawski K, Janowska A, Jakubus T, Gawda AT, Czuczwar SJ (2010) Angiotensin AT1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock. Eur J Pharmacol 640:172–177

    Article  PubMed  Google Scholar 

  • Macdonald RL, Meldrum BS (1995) Principles of antiepileptic drug action. In: Levy RH, Mattson RH, Meldrum BS (eds) Antiepileptic drugs, 4th edn. Raven Press, New York, pp 61–78

    Google Scholar 

  • Maggs JL, Naisbitt DJ, Tettey Justice NA, Pirmohamed M, Park BK (2000) Metabolism of lamotrigine to a reactive arene oxide intermediate. Chem Res Toxicol 13(11):1075–1081

    Article  PubMed  CAS  Google Scholar 

  • Malawska B (2005) New anticonvulsant agents. Curr Top Med Chem 5:69–85

    Article  PubMed  CAS  Google Scholar 

  • Mariappan G, Sutharson L, Srivastav TP, Kumar D, Patangia U (2012) Pharmacological and toxicological evaluation of some novel 2-substituted 4,5-diphenyl imidazole derivatives. Pharmacologia 3:258–266

    Article  Google Scholar 

  • Massey KM (1966) Teratogenic effects of diphenylhydantoin sodium. J Oral Ther Pharmacol 2:380–385

    PubMed  CAS  Google Scholar 

  • Matsumura N, Utsumi KK, Nakaki T (2008) Activities of 7-nitroindazole and 1-(2-(trifluoromethylphenyl)-imidazole independent of neuronal nitric-oxide synthase inhibition. J Pharmacol Exper Ther 325:357–362

    Article  CAS  Google Scholar 

  • McNamara JO (2001) Drugs effective in the therapy of the epilepsies. In: Hardman JG, Limbird LE, Gilman AG (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 10th edn. McGraw-Hills, New York, pp 521–548

    Google Scholar 

  • Merritt HH, Putnam TJ (1938) Sodium diphenyl hydantoinate in treatment of convulsive disorders. J Am Med Assoc 111:1068–1069

    Article  Google Scholar 

  • Monaghan DT, Bridges RJ, Cotman CW (1989) The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 29:365–402

    Article  PubMed  CAS  Google Scholar 

  • Nardi D, Tajana A, Leonardi A, Renzo P (1981) Synthesis and anticonvulsant activity of N-(Benzoylalky1)imidazoles and N-(ω-Phenyl-ω-hydroxyalky1)imidazoles. J Med Chem 24:721–731

    Article  Google Scholar 

  • Navidpour L, Shafaroodi H, Miri R, Dehpour AR, Shafiee A (2004) Lipophilic 4-imidazoly-1,4-dihydropyridines: synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure. IL Farmaco 59:261–269

    Article  PubMed  CAS  Google Scholar 

  • Nielsen EB, Suzdak PD, Andersen KE, Knutsen LJ, Sonnewald U, Braestrup C (1991) Characteristic of tiagabine(NO-328), a new potent and selective GABA uptake inhibitor. Eur J Pharmacol 196:257–266

    Article  PubMed  CAS  Google Scholar 

  • Ohmori J, Sakamoto S, Kubota H, Sasamata MS, Okada M et al (1994) 6-(1H-imidazol-l-y1)-7–nitro-2,3(1H, 4H) quinoxalinedione hydrochloride (YMSOK) and related compounds: structure-activity relationships for the AMPA-type non-NMDA receptor. J Med Chem 37:467–475

    Article  PubMed  CAS  Google Scholar 

  • Ohmori J, Kubota H, Sasamata MS, Okada M, Sakamoto S (1996) Novel α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonists: synthesis and structure-activity relationships of 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3b]pyrazinedione and related compounds. J Med Chem 39:1331–1338

    Article  PubMed  CAS  Google Scholar 

  • Ohmori J, Sasamata MS, Okada M et al (1997) 8-(1H-Imidazol-1-yl)-7-nitro-4(5H)-imidazo[1,2-a]quinoxalinone and related compounds: synthesis and structure–activity relationships for the AMPA-type non-NMDA receptor. J Med Chem 40:2053–2063

    Article  PubMed  CAS  Google Scholar 

  • Olney JW (1990) Excitotoxic amino acids and neuropsychiatric disorders. Annu Rev Pharmacol Toxicol 30:47–71

    Article  PubMed  CAS  Google Scholar 

  • Paruszewski R, Strupin′ska M, Rostafin′ska-Suchar G, Stables JP (2003) Anticonvulsant activity of benzylamides of some amino acids and heterocyclic acids. Prot Pept Lett 10:475–482

    Article  CAS  Google Scholar 

  • Perucca E (1996) The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol 42:531–543

    PubMed  CAS  Google Scholar 

  • Pevarello P, Bonsignori A, Dostert P, Heidempergher F, Pinciroli V, Colombo M, McArthur RA, Salvati P et al (1998) Synthesis and anticonvulsant activity of a new class of 2-[(Arylalkyl)amino]alkanamide derivatives. J Med Chem 41:579–590

    Article  PubMed  CAS  Google Scholar 

  • Polanski J, Bak A, Gieleciak R, Magdziarz T (2006) Modeling robust QSAR. J Chem Inf Model 46(6):2310–2318

    Article  PubMed  CAS  Google Scholar 

  • Puratchikody A, Doble M (2009) QSAR studies on antiepileptic and locomotor in vivo activities of 4,5-diphenyl-1H-imidazoles. Chem Biol Drug Des 74:173–182

    Article  PubMed  CAS  Google Scholar 

  • Reddy PA, Hsiang BCH, Latifi TN, Hill MW, Woodward KE, Rothman SM, Ferrendelli JA, Covey DF (1996) 3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: a new class of anticonvulsant agents. J Med Chem 39:1898–1906

    Article  PubMed  CAS  Google Scholar 

  • Rivara M, Baheti AR, Fantini M, Cocconcelli G, Ghiron C et al (2008) 2,4(5)-Diarylimidazoles: synthesis and biological evaluation of a new class of sodium channel blockers against hNav1.2. Bio Med Chem Lett 18:5460–5462

    Article  CAS  Google Scholar 

  • Rivas FM, Stables JP, Lauren M et al (2009) Antiseizure activity of novel γ-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models. J Med Chem 52:1795–1798

    Article  PubMed  CAS  Google Scholar 

  • Robertson DW, Krushinski JH, Beedle EE, Leander JD, Wong DT, Rathbun RC (1986) Structure-activity relationships of (Arylalky1)imidazole anticonvulsants: comparison of the (Fluorenylalky1)imidazoles with Nafimidone and Denzimol. J Med Chem 29:1577–1586

    Article  PubMed  CAS  Google Scholar 

  • Robertson DW, Beedle EE, Lawson R, Leander JD (1987) Imidazole anticonvulsants: structure-activity relationships of [(Biphenylyloxy)alkyl] imidazoles. J Med Chem 30:939–943

    Article  PubMed  CAS  Google Scholar 

  • Schoenberg BS (1987) Recent studies of the epidemiology of epilepsy in developing countries: a coordinated program for prevention and control. Epilepsia 28(6):721–722

    Article  PubMed  CAS  Google Scholar 

  • Scott KR (2003) Anticonvulsants. In: Abraham DJ (ed) Burger’s medicinal chemistry and drug discovery, 6th edn. Wiley, Virginia, pp 264–328

    Google Scholar 

  • Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE (2000) An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41:S3–S9

    Article  PubMed  CAS  Google Scholar 

  • Soyer Z, Kilic FS, Erol K, Pabuçcuoglu V (2003) Synthesis and anticonvulsant activity of some ω-(1H-imidazol-1-yl)-N-phenylacetamide and propionamide derivatives. IL Farmaco 59:595–600

    Article  Google Scholar 

  • Sun Xian-Yu, Zhang Lei, Wei Cheng-Xi, Piao Hu-Ri, Quan Zhe-Shan (2009) Design, synthesis of 8-alkoxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-1-ones with anticonvulsant activity. Eur J Med Chem 44:1265–1270

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi A, Takeuchi N (1964) The effect on crayfish muscle of iontophoretically applied glutamate. J Physiol 170:296–317

    PubMed  CAS  Google Scholar 

  • Treiman DM (2001) GABAergic mechanisms in epilepsy. Epilepsia 42:8–12

    Article  PubMed  Google Scholar 

  • Walker KAM, Marshall B, Wallach MB, Hirschfeld DR (1981) 1-(Naphthylalky1)-1H imidazole derivatives, a new class of anticonvulsant agents. J Med Chem 24:67–74

    Article  PubMed  CAS  Google Scholar 

  • Weinhardt K, Beard CC, Dvorak C, Marx M, Patterson J, Roszkowski A, Schuler M, Unger SH, Wagner PJ, Wallach MB (1984) Synthesis and Central Nervous System Properties of 2-[(Alkoxycarbonyl)amino]-4( 5)-phenyl-2-imidazolin. J Med Chem 27: 616–627

    Article  PubMed  CAS  Google Scholar 

  • WHO Information Fact Sheets (2001) Epilepsy: epidemiology, etiology and prognosis. Fact Sheet No. 165, February 2001

  • Wolfgang L (1998) New visions in the pharmacology of anticonvulsion. Eur J Pharmacol 342:1–13

    Article  Google Scholar 

  • Wulfsohn M (1972) Carbamazepine (Tegretol) in the long-term treatment of grand mal epilepsy. S Afr Med J 46:1091–1092

    PubMed  CAS  Google Scholar 

  • Zuliani V, Fantini M, Nigam A, Stables JP, Patel MK, Rivara M (2010) Anticonvulsant activity of 2,4(1H)-diarylimidazoles in mice and rats acute seizure models. Bioorg Med Chem 18:7957–7965

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful for the financial aid in the form of a Fellowship by the All India Council for Technical Education, New Delhi, India.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Science, Birla Institute of Technology, Mesra, Ranchi, 835215, Jharkhand, India

    Rahul Mishra & Swastika Ganguly

Authors
  1. Rahul Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Swastika Ganguly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rahul Mishra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mishra, R., Ganguly, S. Imidazole as an anti-epileptic: an overview. Med Chem Res 21, 3929–3939 (2012). https://doi.org/10.1007/s00044-012-9972-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-012-9972-6

Keywords

Search

Navigation