A variety of 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethines and 1,3-dihydro-2H-1,4-benzodiazepin-2-one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin-induced seizure model. The prepared 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7-{(E)-[(4-nitrophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-{(E)-[(4-bromo-2,6-difluorophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 7-[(E)-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

Department of Chemistry College of Science King Saud University Riyadh 11451 Saudi Arabia

Department of Chemistry S S G M College Kopargaon Dist Ahmednagar Maharashtra 423601 India

Department of Pharmacology Poona College of Pharmacy Bharati Vidyapeeth Erandwane Pune Maharashtra 411038 India

Institute of Chemical Technology Mumbai Marathwada Campus Jalna Maharashtra 431203 India

Regional Center of Advanced Technologies and Materials Faculty of Science Palacký University Šlechtitelů 27 78371 Olomouc Czech Republic

Syngenta Biosciences Pvt Ltd Santa Monica Works Corlim Ilhas Goa 403110 India

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W. Löscher, ‘New visions in the pharmacology of anticonvulsion’, Eur. J. Pharmacol. 1998, 342, 1-13.

C. C. Kuo, ‘A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels’, Mol. Pharmacol. 1998, 54, 712-721.

J. Wang, Y. Chen, Q. Wang, G. van Luijtelaar, M. Sun, ‘The effects of lamotrigine and ethosuximide on seizure frequency, neuronal loss, and astrogliosis in a model of temporal-lobe epilepsy’, Brain Res. 2019, 1712, 1-6.

U. Rudolph, F. Knoflach, ‘Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes’, Nat. Rev. Drug Discovery 2011, 10, 685-697.

K. Staley, ‘Enhancement of the excitatory actions of GABA by barbiturates and benzodiazepines’, Neurosci. Lett. 1992, 146, 105-107.

M. A. Rogawski, W. Löscher, J. M. Rho, ‘Mechanisms of action of antiseizure drugs and the ketogenic diet’, Cold Spring Harbor Perspect. Med. 2016, 6, 1-28.

S. B. Wang, P. Jin, F. N. Li, Z. S. Quan, ‘Synthesis and anticonvulsant activity of novel purine derivatives’, Eur. J. Med. Chem. 2014, 84, 574-583.

B. Chen, H. Choi, L. J. Hirsch, A. Katz, A. Legge, R. Buchsbaum, K. Detyniecki, ‘Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy’, Epilepsy Behavior 2017, 76, 24-31.

H. N. Khan, S. Kulsoom, H. Rashid, ‘Ligand based pharmacophore model development for the identification of novel antiepileptic compound’, Epilepsy Res. 2012, 98, 62-71.

C. J. Landmark, S. I. Johannessen, ‘Modifications of antiepileptic drugs for improved tolerability and efficacy’, Perspect. Med. Chem. 2008, 2, 21-39.

A. W. Sobańska, G. Żydek, P. Włodno, E. Brzezińska, ‘Comparative (Q)SAR analysis of benzodiazepine derivatives with different biological activity’, Eur. J. Med. Chem. 2015, 89, 147-155.

J. Y. Wick, ‘The history of benzodiazepines’, Consultant Pharmacist 2013, 28, 538-548.

B. Narayana, K. K. V. Raj, B. V. Ashalatha, N. S. Kumari, ‘Synthesis of some new substituted triazolo[4,3-a][1,4]benzodiazepine derivatives as potent anticonvulsants’, Eur. J. Med. Chem. 2006, 41, 417-422.

R. I. Shader, D. J. Greenblatt, ‘Use of benzodiazepines in anxiety disorders’, N. Engl. J. Med. 1993, 328, 1398-1405.

A. Y. Chweh, Y. B. Lin, E. A. Swinyard, ‘Hypnotic action of benzodiazepines: A possible mechanism’, Life Sci. 1984, 34, 1763-1768.

M. J. Kukla, H. J. Breslin, R. Pauwels, C. L. Fedde, M. Miranda, M. K. Scott, R. G. Sherrill, A. Raeymaekers, J. V. Gelder, K. Andries, M. A. C. Janssen, E. D. Clerq, P. A. J. Janssen, ‘Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives’, J. Med. Chem. 1991, 34, 746-751.

W. Ho, M. J. Kukla, H. J. Breslin, D. W. Ludovici, P. P. Grous, C. J. Diamond, M. Miranda, J. D. Rodgers, C. Y. Ho, E. D. Clercq, R. Pauwels, K. Andries, M. A. C. Janssen, P. A. J. Janssen, ‘Synthesis and Anti-HIV-1 Activity of 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TlBO) Derivatives’, J. Med. Chem. 1995, 38, 794-802.

H. J. Breslin, M. J. Kukla, T. Kromis, H. Cullis, F. D. Knaep, R. Pauwels, K. Andries, E. D. Clercq, M. A. C. Janssen, P. A. J. Janssen, ‘Synthesis and anti-HIV activity of 1,3,4,5-Tetrahydro-2H-1,4-benzodiazepin-2-one (TBO) derivatives. Truncated 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-ones (TIBO) Analogs’, Bioorg. Med. Chem. 1999, 7, 2427-2436.

J. W. Butcher, N. J. Liverton, D. A. Claremon, R. M. Freidinger, N. K. Jurkiewicz, J. J. Lynch, J. J. Salata, J. Wang, C. M. Dieckhaus, D. E. Slaughter, K. Vyas, ‘Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones as potent and selective IKs-blocking class III antiarrhythmic agents’, Bioorg. Med. Chem. Lett. 2003, 13, 1165-1168.

G. Seebohm, J. Chen, N. Strutz, C. Culberson, C. Lerche, M. C. Sanguinetti, ‘Molecular determinants of KCNQ1 channel block by a benzodiazepine’, Mol. Pharmacol. 2003, 64, 70-77.

J. Dourlat, W. Q. Liu, N. Gresh, C. Garbay, ‘Novel 1,4-benzodiazepine derivatives with antiproliferative properties on tumor cell lines’, Bioorg. Med. Chem. Lett. 2007, 17, 2527-2530.

G. Hsiao, M. Y. Shen, D. S. Chou, Y. Chang, L. W. Lee, C. H. Lin, J. R. Sheu, ‘Mechanisms of antiplatelet and antithrombotic activity of midazolam in in vitro and in vivo studies’, Eur. J. Pharmacol. 2004, 487, 159-166.

Y. Ohtake, A. Naito, H. Hasegawa, D. M. Kawano, M. Taniguchi, Y. Tanaka, H. Matsukawa, K. Naito, T. Oguma, Y. Ezure, Y. Tsuriya, ‘Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives’, Bioorg. Med. Chem. 1999, 7, 1247-1254.

C. M. Sandra, C. C. Eduardo, H. O. Simon, R. A. Teresa, N. C. Antonio, I. V. Lijanova, M. G. Marcos, ‘Anticancer activity and anti-inflammatory studies of 5-aryl-1,4-benzodiazepine derivatives’, Anti-Cancer Agents Med. Chem. 2012, 12, 611-618.

L. H. Sternbach, ‘1,4-Benzodiazepines. Chemistry and some aspects of the structure-activity relationship’, Angew. Chem. 1971, 10, 34-43.

C. M. S. Menezes, G. Rivera, M. A. Alves, D. N. Amaral, J. P. B. Thibaut, F. Noel, E. J. Barreiro, L. M. Lima, ‘Synthesis, Biological Evaluation, and Structure−activity Relationship of Clonazepam, Meclonazepam, and 1,4-Benzodiazepine Compounds with Schistosomicidal Activity’, Chem. Biol. Drug Des. 2012, 79, 943-949.

M. Rudrapal, B. De, ‘Chemistry and biological importance of heterocyclic Schiff's bases’, Int. Res. J. Pure Appl. Chem. 2013, 3, 232-249.

P. Anand, V. M. Patil, V. K. Sharma, R. L. Khosa, N. Masand, ‘Schiff bases: A review on biological insights’, Int. J. Drug Des. Discov. 2012, 3, 851-868.

A. Kajal, S. Bala, S. Kamboj, N. Sharma, V. Saini, ‘Schiff bases: a versatile pharmacophore’, J. Catal. 2013, 201, 1-14.

Z. I. Zhilina, A. V. Bogat-skii, S. A. Andronati, N. I. Danilina, ‘1,4-benzodiazepines and their cyclic homologs and analogs’, Chem. Heterocycl. Compd. 1979, 15, 447-451.

M. Altenkämper, B. Bechem, J. Perruchon, S. Heinrich, A. Madel, R. Ortmann, H. M. Dahse, E. Freunscht, Y. Wang, J. Rath, A. Stich, M. Hitzler, P. Chiba, M. Lanzer, M. Schlitzer, ‘Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone’, Bioorg. Med. Chem. 2009, 17, 7690-7697.

I. Cepanec, M. Litvić, I. Pogorelić, ‘Efficient synthesis of 3-hydroxy-1,4-benzodiazepines oxazepam and lorazepam by new acetoxylation reaction of 3-position of 1,4-benzodiazepine ring’, Org. Process Res. Dev. 2006, 10, 1192-1198.

J. Feely, P. V. Kavanagh, S. M. McNamara, J. E. O'Brien, ‘Simple preparation of the major urinary metabolites of flunitrazepam and nitrazepam’, Ir. J. Med. Sci. 1999, 168, 8-9.

T. P. Gosavi, A. D. Kandhare, P. Ghosh, S. L. Bodhankar, ‘Anticonvulsant activity of Argentum metallicum, a homeopathic preparation’, Pharm. Lett. 2012, 4, 626-637.

E. N. Bum, M. Schmutz, C. Meyer, A. Rakotonirina, M. Bopelet, C. Portet, A. Jeker, S. V. Rakotonirina, H. R. Olpe, P. Herrling, ‘Anticonvulsant properties of the methanolic extract of Cyperus articulatus (Cyperaceae)’, J. Ethnopharmacol. 2001, 76, 145-150.

L. Mackenzie, A. Medvedev, J. J. Hiscock, K. J. Pope, J. O. Willoughby, ‘Picrotoxin-induced generalised convulsive seizure in rat: changes in regional distribution and frequency of the power of electroencephalogram rhythms’, Clin. Neurophysiol. 2002, 113, 586-596.

M. Mohammadi-Khanaposhtani, M. Shabani, M. Faizi, I. Aghaei, R. Jahani, Z. Sharafi, N. S. Zafarghandi, M. Mahdavi, T. Akbarzadeh, S. Emami, A. Shafiee, A. Foroumadi, ‘Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1,2,4-oxadiazoles as potential anticonvulsant agents’, Eur. J. Med. Chem. 2016, 112, 91-98.

R. Jarapula, K. Gangarapu, S. Manda, S. Rekulapally, ‘Synthesis, in vivo anti-inflammatory activity, and molecular docking studies of new isatin derivatives’, Int. J. Med. Chem. 2016, 2016, 1-9.

L. Richter, C. Graaf, W. Sieghart, Z. Varagic, M. Morzinger, I. J. P. Esch, G. F. Ecker, M. Ernst, ‘Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands’, Nat. Chem. Biol. 2012, 8, 455-464.

S. X. Sun, X. B. Li, W. B. Liu, Y. Ma, R. L. Wang, X. C. Cheng, S. Q. Wang, W. Liu, ‘Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2’, Int. J. Mol. Sci. 2013, 14, 12661-12674.

Z. Dolatkhah, S. Javanshir, A. S. Sadr, J. Hosseini, S. Sardari, ‘Synthesis, Molecular Docking, Molecular Dynamics Studies, and Biological Evaluation of 4H-Chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate Derivatives as Potential Antileukemic Agents’, J. Chem. Inf. Model. 2017, 57, 1246-1257.

A. Javidan, M. J. Taghizadeh, S. A. Hosseini, M. Iman, R. Jafari, ‘Docking, Molecular Dynamics Simulation and Synthesis of New Fenobam Analogs as mGlu5 Receptor Antagonists’, Comb. Chem. High Throughput Screening 2016, 19, 764-770.

B. C. Variya, S. J. Modi, J. Savjani, S. Patel, ‘In silico molecular docking and pharmacokinetic prediction of gallic acid derivatives as PPAR-γ Agonists’, Int. J. Pharm. Pharm. Sci. 2016, 9, 102-107.