Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Pyrrolopyridine and Isoindole as Potential Anticonvulsant Agents: Design, Synthesis, and Pharmacological Evaluation

Author(s): Sepideh Taghizad, Khadijeh Behbahaninia, Mahsa Hadipour Jahromy and Asghar Davood*

Volume 18, Issue 3, 2022

Published on: 15 June, 2022

Page: [159 - 167] Pages: 9

DOI: 10.2174/1573409918666220512000247

Price: $65

Abstract

Background and Objective: Phthalimide, as the rigid form of ameltolide, exhibits a phenytoin-like profile of drug-receptor interaction and is active in the MES model and inactive in the PTZ model as an anti-epileptic agent. In this research, based on the isosteric replacement, we reported the design, preparation, and antiepileptic activity of 13 new analogs of pyrrolopyridine and isoindole.

Methods: The designed compounds were prepared by condensing 3, 4-pyridine dicarboxylic anhydride, or 4-fluorophthalic anhydride with different aryl amines. MES and PTZ-induced seizure models were utilized to evaluate the antiepileptic effect of the prepared ligands.

Results: It was found that the prepared ligands have significantly affected both tonic and clonic seizures. In tonic seizures, the prepared compounds decreased mortality to a significant extent, and in clonic seizures, they significantly showed better frequency and latency. Compounds 9, 12, and 13 were the most potent ligands than phenytoin.

Conclusion: It is concluded that the best distance between two aryl parts is two bonds, and the substitution of the nitro group at the meta position of the phenyl ring is better than the para position. Our research group has investigated this concept for designing newer compounds with better anticonvulsant activity.

Keywords: Pyrrolopyridine, isoindole, anticonvulsant, docking, sodium channel blockers, MES, PTZ.

Next »
Graphical Abstract

[1]
López González, F.J.; Rodríguez Osorio, X.; Gil-Nagel Rein, A.; Carreño Martínez, M.; Serratosa Fernández, J.; Villanueva Haba, V.; Donaire Pedraza, A.J.; Mercadé Cerdá, J.M. Drug-resistant epilepsy: definition and treatment alternatives. Neurologia, 2015, 30(7), 439-446.
[PMID: 24975343]
[2]
Brodie, M.J.; Besag, F.; Ettinger, A.B.; Mula, M.; Gobbi, G.; Comai, S.; Aldenkamp, A.P.; Steinhoff, B.J. Epilepsy, antiepileptic drugs, and aggression: an evidence-based review. Pharmacol. Rev., 2016, 68(3), 563-602.
[http://dx.doi.org/10.1124/pr.115.012021] [PMID: 27255267]
[3]
Stefan, H.; Feuerstein, T.J. Novel anticonvulsant drugs. Pharmacol. Ther., 2007, 113(1), 165-183.
[http://dx.doi.org/10.1016/j.pharmthera.2006.07.005] [PMID: 17030393]
[4]
Goldenberg, M.M. Overview of drugs used for epilepsy and seizures: etiology, diagnosis, and treatment. P&T, 2010, 35(7), 392-415.
[PMID: 20689626]
[5]
Phenytoin, package insert. 2009. Available from: http://media.pfizer.com/files/products/uspi_dilantin.pdf
[6]
Johannessen, S.I.; Landmark, C.J. Antiepileptic drug interactions - principles and clinical implications. Curr. Neuropharmacol., 2010, 8(3), 254-267.
[http://dx.doi.org/10.2174/157015910792246254] [PMID: 21358975]
[7]
Kuo, C.C.; Bean, B.P. Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol. Pharmacol., 1994, 46(4), 716-725.
[PMID: 7969051]
[8]
Wiecek, M.; Kieć-Kononowicz, K. Synthesis and anticonvulsant evaluation of some N-substituted phthalimides. Acta Pol. Pharm., 2009, 66(3), 249-257.
[PMID: 19645325]
[9]
Davood, A.; Shafaroodi, H.; Amini, M.; Nematollahi, A.; Shirazi, M.; Iman, M. Design, synthesis and protection against pentylene-tetrazole-induced seizure of N-aryl derivatives of the phthalimide pharmacophore. Med. Chem., 2012, 8(5), 953-963.
[http://dx.doi.org/10.2174/157340612802084289] [PMID: 22741781]
[10]
Davood, A.; Amini, M.; Azimdoost, L.; Rahmatpour, S.; Nikbakht, A.; Iman, M.; Shafaroodi, H.; Ansari, A. Docking, synthesis and pharmacological evaluation of isoindoline derivatives as anticonvulsant agents. Med. Chem. Res., 2013, 22(7), 3177-3184.
[http://dx.doi.org/10.1007/s00044-012-0256-y]
[11]
Davood, A.; Azimdoost, L.; Shafaroodi, H.; Amini, M.; Iman, M.; Ansari, A.; Nikbakht, A.; Rahmatpour, S.; Nematollahi, A.R. Docking and synthesis of 2-arylisoindoline-1,3-dione derivatives as anticonvulsant agents. Pharm. Chem. J., 2014, 48(3), 175-180.
[http://dx.doi.org/10.1007/s11094-014-1073-z]
[12]
Iman, M.; Saadabadi, A.; Davood, A. Molecular docking analysis and molecular dynamics simulation study of ameltolide analogous as a sodium channel blocker. Turk. J. Chem., 2015, 39, 306-316.
[http://dx.doi.org/10.3906/kim-1402-37]
[13]
Vamecq, J.; Bac, P.; Herrenknecht, C.; Maurois, P.; Delcourt, P.; Stables, J.P. Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore. J. Med. Chem., 2000, 43(7), 1311-1319.
[http://dx.doi.org/10.1021/jm990068t] [PMID: 10753468]
[14]
Brown, N. Weinheim: Bioisosteres in Medicinal Chemistry; Wiley-VCH, 2012, p. 54.
[http://dx.doi.org/10.1002/9783527654307]
[15]
Ujváry, I.; Hayward, J. Weinheim: BIOSTER: A Database of Bioisosteres and Bioanalogues. Bioisosteres in Medicinal Chemistry; Wiley-VCH, 2012, 54, pp. 55-74.
[16]
Iman, M.; Saadabadi, A.; Davood, A. Docking studies of phthalimide pharmacophore as a sodium channel blocker. Iran. J. Basic Med. Sci., 2013, 16(9), 1016-1021.
[PMID: 24171082]
[17]
Saadabadi, A.; Kohen, B.; Irandoust, M.; Shafaroodi, H.; Mohammadpour, T.; Rezayat, M.; Davood, A 2,5-disubstituted phthalimides: Design, Synthesis and Aniconvulsant activity in scPTZ and MES models. Current computer-aided drug design (CCADD), 2018, 14, 310-321.
[18]
Davood, A.; Iman, M.; Pouriaiee, H.; Shafaroodi, H.; Akhbari, S.; Azimidoost, L.; Imani, E.; Rahmatpour, S. Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models. Iran. J. Basic Med. Sci., 2017, 20(4), 430-437.
[PMID: 28804613]
[19]
Iman, M.; Saadabadi, A.; Davood, A.; Shafaroodi, H.; Nikbakht, A.; Ansari, A.; Abedini, M. Docking, synthesis and anticonvulsant activi-ty of N-substituted isoindoline-1, 3-dione. Iran. J. Pharm. Res., 2017, 16(2), 586-595.
[PMID: 29721024]
[20]
Iman, M.; Fakhari, S.; Jahanpanah, M.; Naderi, N.; Davood, A. Design and Synthesis of 4-flurophthalimides as potential anticonvulsant agents. Iran. J. Pharm. Res., 2018, 17(3), 896-905.
[PMID: 30127813]
[21]
Lipkind, G.M.; Fozzard, H.A. Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels. Mol. Pharmacol., 2005, 68(6), 1611-1622.
[http://dx.doi.org/10.1124/mol.105.014803] [PMID: 16174788]
[22]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Auto-mated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[23]
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng., 1995, 8(2), 127-134.
[http://dx.doi.org/10.1093/protein/8.2.127] [PMID: 7630882]

Rights & Permissions Print Cite
Article Metrics
7
© 2024 Bentham Science Publishers | Privacy Policy