Synthesis and evaluation of anticonvulsant activity of (Z)-4-(2-oxoindolin-3-ylideneamino)-N-phenylbenzamide derivatives in mice

Marzieh Rahmani Khajouei, Ahmad Mohammadi-Farani, Aref Moradi, Alireza Aliabadi

Abstract


Due to resistance of some epileptic patients to the current medications and the general incidence of severe side effects of these drugs, development and discovery of novel antiepileptic drugs is crucial. Isatin-based derivatives are promising compounds as antiepileptic agents. In this study a new series of isatin-containing derivatives were synthesized via the imine formation between isatin and p-aminobenzoic acid. Subsequently, the obtained acidic compound was utilized to prepare the final amidic derivatives (4a-4l) through the reaction with various aniline derivatives. Then, their anti-seizure activity was investigated using maximal electroshock seizure (MES) as well as pentylenetetrazole (PTZ) models in mice. Neurotoxicity of target compounds was also determined by rotarod test. Tested isatin-based derivatives exhibited a favorable protection in both MES and PTZ procedures with high safety levels in neurotoxicity test. The introduced derivatives have demonstrated remarkable activity in mice and could be suggested as potential anticonvulsant lead compounds. All methoxylated derivatives (4j, 4k, 4l) showed a significant anti-seizure activity in MES model. Compounds 4j (2-OCH3) and 4l (4-OCH3) also demonstrated a potent anti-seizure activity against PTZ. Compound 4k (m-OCH3) did not induce protection towards PTZ-induced convulsion. 


Keywords


Synthesis; Isatin; Anticonvulsant; PTZ; MES.

Full Text:

PDF

References


Prakash CR, Raja S. Design, synthesis and antiepileptic properties of novel 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl)urea derivatives. Eur J Med Chem. 2011;46(12):6057-6065.

Verma M, Pandeya SN, Singh KN, Stables JP. Anticonvulsant activity of Schiff bases of isatin derivatives. Acta Pharm. 2004;54:49-56.

Aliabadi A, Gholamine B, Karimi T. Synthesis and antiseizure evaluation of isoindoline-1,3-dionederivatives in mice. Med Chem Res. 2014;23(6):2736-2743.

Rajak H, Deshmukh R, Aggarwal N, Kashaw S, Kharya MD, Mishra P. Synthesis of novel 2,5-disubstituted 1,3,4-thiadiazoles for their potential anticonvulsant activity: pharmacophoric model studies. Arch Pharm (Weinheim). 2009;342(8):453-461.

Deng XQ, Dong ZQ, Song MX, Shu B, Wang SB, Qua ZS. Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives. Arch Pharm (Weinheim). 2012;345(7):565-573.

Kwan P, Brodie MJ. Early identification of refractory epilepsy. New Engl J Med. 2000;342(5):314-319.

Kwan P, Brodie MJ. Drug treatment of epilepsy: when does it fail and how to optimize its use? CNS Spectr. 2004;9(2):110-119.

Leppik IE. Antiepileptic drugs in development: prospects for the near future. Epilepsia. 1994;35(suppl 4):S29‐S40.

Meldrum BS, Rogawski MA. Molecular targets for antiepileptic drug development. Neurotherapeutics. 2007;4(1):18-61.

Medvedev AE, Clow A, Sandler M, Glover V. Isatin: a link between natriuretic peptides and monoamines? Biochem Pharmacol. 1996;52(3): 385-391.

Han K, Zhou Y, Liu F, Guo Q, Wang P, Yang Y, et al. Design, synthesis and in vitro cytotoxicity evaluation of 5-(2-carboxyethenyl)isatin derivatives as anticancer agents. Bioorg Med Chem Lett. 2014;24(2):591-594.

Lashgari N, Mohammadi Ziarani G. Synthesis of heterocyclic compounds based on isatin through 1,3-dipolar cycloaddition reactions. Arkivoc. 2012;2012:277-320.

Sridhar SK, Pandeya SN, Stables JP, Ramesh A. Anticonvulsant activity of hydrazones, Schiff and Mannich bases of isatin derivatives. Eur J Pharm Sci. 2002;16:129-132.

Rahmani-Khajouei M, Mohammadi-Farani A, Ghorbani H, Aliabadi A. Synthesis and acetylcholinesterase inhibitory assessment of 3-(2-(4-benzoylpiperazin-1-yl)ethylimino)indolin-2-one with potential anti-Alzheimer effects. J Rep Pharm Sci. 2015;4(2):148-157.

Bhrigu B, Pathak D, Siddiqui N, Alam MS, Ahsan W, Search for biological active isatins: a short review. Int J Pharm Sci Drug Res. 2010;2(4):229-235.

Smitha S, Pandeya SN, Stables JP, Ganapathy S. Anticonvulsant and sedative-hypnotic activities of N-acetyl/methyl isatin derivatives. Sci Pharm. 2008;76(4):621-636.

Pandeya SN, Raja AS. Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants-role of hydrogen bonding. J Pharm Pharm Sci. 2002;5(3):266-271.

Eggadi V, Kulandaivelu U, Sharvanabhava BS, Jupally VR. Screening of the anticonvulsant activity of some isatin derivatives in experimental seizure models and its effect on brain GABA levels in mice. Am J Pharmacol Sci. 2013;1(3):42-46.

Rahmani-Khajouei M, Mohammadi-Farani A, Mirzaei D, Aliabadi A. Isatin-based anticonvulsant agents: Synthesis and antiseizure evaluation in mice. J Rep Pharm Sci. 2017;6:13-22.

Siddiqui N, Alam MS, Stables JP. Synthesis and anticonvulsant properties of 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl)urea derivatives. Eur J Med Chem. 2011;46(6):2236-2242.

Mohammadi-Farani A, Heidarian N, Aliabadi A. N-(5-Mercapto-1,3,4-thiadiazol-2-yl)-2-phenylacetamide derivatives: Synthesis and in vitro cytotoxcity evaluation as potential anticancer agents. Iran J Pharm Res. 2014;13(2):487-492.

Mohammadi-Farani A, Foroumadi A, Rezvani Kashani M, Aliabadi A. N-Phenyl-2-p-tolylthiazole-4-carboxamide derivatives: Synthesis and cytotoxicity evaluation as anticancer agents. Iran J Basic Med Sci. 2014;17(7):502-508.

Aliabadi A, Hasanvand Z, Kiani A, Mirabdali SS. Synthesis and in vitro cytotoxicity assessment of N-(5-(Benzylthio)-1,3,4-thiadiazol-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide with potential anticancer activity. Iran J Pharm Res. 2013;12(4):687-693.

Aliabadi A, Andisheh S, Tyarani-Najaran Z, Tayarani-Najaran M. 2-(4-Fluorophenyl)-N-phenylacetamide derivatives as anticancer agents: synthesis and in vitro cytotoxicity evaluation. Iran J Pharm Res. 2013;12(3):267-271.

Nazaritarhan H, Hosseinzadeh L, Aliabadi A, Babak Gholamine, Foroumadi A. Cytotoxic and apoptogenic properties of 2-phenylthiazole-4-carboxamide derivatives in human carcinoma cell lines. Res Pharm Sci. 2012;7(5):S129.

Agamennone M, Campestre C, Preziuso S, Consalvi V, Crucianelli M, Mazza F, et al. Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2. Eur J Med Chem. 2005;40(3):271-279.

Porter RJ, Cereghino JJ, Gladding GD, Hessei BJ, Kupferberg HJ, Scoville B. Antiepileptic drug development program. Cleve Clin Q. 1984;51(2):293-305.

Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949;96(2):99-113.


Refbacks

  • There are currently no refbacks.


Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.