Benzodiazepines have a various behavioral effects in addition to their anxiolytic action. There is every reason to believe that the BZ/GABA receptor complex is involved in these effects, since GABAmimetic manipulations modify the effect of BZ in tests of convulsive activity, motor function, and appetitive behavior. 1,5-Benzodiazepines are biologically important molecules and are extensively used clinically as analgesic, hypnotic, sedative, and antidepressive agents. Hence, 1,5-Benzodiazepines were synthesized by condensation of o-phenylenediamine and ketones, for example, cyclohexanone and acetone in presence of sulfated zirconia (catalyst). Mannich bases were synthesized with acetophenone, p-nitroacetophenone, p-chloroacetophenone, and formaldehyde. Schiff bases were synthesized using Mannich base of 1,5-benzodiazepines with p-chloroaniline and p-chlorophenylsemicarbazide in the presence of glacial acetic acid. All the synthesized compounds were characterized by 1H NMR and IR spectral analyses. All the synthesized derivatives were evaluated at the dose of 30？mg/kg b.w for anticonvulsant activity by isoniazid induced convulsion model, and the compounds NBZD-3 and NBZD-8 were found to be the most active among all compounds. Among all the synthesized derivatives, compounds NBZD-13 and NBZD-17 were found to be the most active among all compounds using thiosemicarbazide induced model. Although NBZD-8, NBZD-10, and NBZD-18 are the compounds which had shown good anticonvulsant activity and have an advantage over that, they were not sedative. 1. Introduction A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first benzodiazepine, chlordiazepoxide (Librium), discovered accidentally by Leo Sternbach in 1955 and made available in 1960 by Hoffmann La Roche, which has also marketed diazepam (Valium) since 1963 [1]. 1,5-Benzodiazepines constitute an important class of psychopharmaca [2], in particular as tranquilizers and also as potent Virucides and nonnucleoside inhibitors of HIV-1 reverse transcriptase [3]. Benzodiazepine has a traditional place in antiepileptic therapy. The clinical use of BZDs can be divided into two categories. First, in the acute treatment of seizures as drugs of choice in status epilepticus and also in some cases of febrile seizures. Second, the BZDs are utilized in long-term therapy of certain seizures types primarily in the pediatrics’ population [4]. There are some differences between the effects of 1,5- and 1,4-benzodiazepines. A greater therapeutic potential
References
[1]
C. Page, C. Michael, M. Sutter, M. Walker, and B. Hoffman, Integrated Pharmacology, Mosby, 2nd edition, 2005.
[2]
G. A. Archer and L. H. Sternbach, “The chemistry of benzodiazepines,” Chemical Reviews, vol. 68, no. 6, pp. 747–784, 1968.
[3]
R. H. Smith Jr., W. L. Jorgensen, J. Tirado-Rives et al., “Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method,” Journal of Medicinal Chemistry, vol. 41, no. 26, pp. 5272–5286, 1998.
[4]
M. A. Rogowaski and R. J. Porter, “Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds,” Pharmacological Reviews, vol. 42, no. 3, pp. 223–286, 1990.
[5]
R. Fisher and D. Blum, “Clobazam, oxcarbazepine, tiagabine, topiramate, and other new antiepileptic drugs,” Epilepsia, vol. 36, no. 2, pp. S105–S114, 1995.
[6]
L. Steru, R. Chermat, and B. Millet, “Comparative study in mice of ten 1,4-benzodiazepines and of clobazam: anticonvulsant, anxiolytic, sedative, and myorelaxant effects,” Epilepsia, vol. 27, no. 1, pp. S14–S17, 1986.
[7]
A. K. Shenoy, J. T. Miyahara, E. A. Swinyard, and H. J. Kuperberg, “Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats,” Epilepsia, vol. 23, no. 4, pp. 399–408, 1982.
[8]
K. P. Jadhav and D. B. Ingled, “Synthis of 2,4-diary1-2,3-dihyrdo-1,5-benzothiazeoines and thier 1,1-dioxides as antibacterial agents,” Indian Journal of Chemistry, vol. B22, p. 180, 1983.
[9]
R. J. Reddy, D. Ashok, and P. N. Sharma, “Synthesis of 4.6-bis(2′-substitutcri-2-3′-dihydro-1.5- benzothiazepin-4′-yl)resorcinols as potential antifeedants,” Indian Journal of Chemistry B, vol. 32, pp. 404–406, 1993.
[10]
K. Satyanarayana and M. N. A. Rao, “Synthesis of 3-[4-[2t 3-dihydro-2-(substituted aryl)-1,5- benzothiazcpin-4-yl]phcnyl]sydnones as potential antiinflammatory agents,” Indian Journal of Pharmaceutical Sciences, vol. 55, pp. 230–233, 1993.
[11]
G. Dessarro, A. Chimirri, A. Dessaro, and R. Gitto, Chemical Abstracts, vol. 106, p. 11222g, 1995.
[12]
J. K. Landquist, “Application as pharmaceuticals,” in Comprehensive Heterocyclic Chemistry, A. R. Kalritzky and C. W. Rees, Eds., vol. 1, pp. 143–183, Peramon, Oxford, UK, 1984.
[13]
L. H. Sternbach, “The benzodiazepine story,” Journal of Medicinal Chemistry, vol. 22, no. 1, pp. 1–7, 1979.
[14]
P. Danneberg and K. H. Weber, “Chemical structure and biological activity of the diazepines,” British Journal of Clinical Pharmacology, vol. 16, no. 2, pp. 231S–243S, 1983.
[15]
A. Walser and R. I. Fryer, Chemical Abstracts, vol. 89, p. 59906, 1978.
[16]
T. Hashiyama, H. Inoue, M. Takeda, S. Murtates, and T. Nagao, “Reactions of 3-phenylglycidic esters. V. Reaction of methyl 3-(4-methoxyphenyl) glycidate with 2-nitroaniline and synthesis of 1,5-benzodiazepine derivatives,” Chemical & Pharmaceutical Bulletin, vol. 33, pp. 2348–2358, 1985.
[17]
J. K. Chakrabarti, L. Horsman, T. M. Hotten, I. A. Pullar, D. E. Tupper, and F. C. Wright, “4-Piperazinyl-10H-thieno[2,3-b][1,5]benzodiazepines as potential neuroleptics,” Journal of Medicinal Chemistry, vol. 23, no. 8, pp. 878–884, 1980.
[18]
S. Caccia, G. Grossi, C. Fracasso et al., “Acid-catalysed hydrolysis and benzodiazepine-like properties of 5-(dialkylamino)- and 5-(alkylthio)-substituted 8-chloro-6-phenyl-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines in mice,” Journal of Pharmacy and Pharmacology, vol. 50, no. 7, pp. 723–728, 1998.
[19]
A. Bauer, K. H. Weber, and P. Danneberg, Chemical Abstracts, vol. 82, p. 4331, 1975.
[20]
R. Unny, P. Joshi, M. P. Dobhal, and Y. C. Joshi, “Synthesis of 1,3-diketone and its reaction with different N-nucleophiles (part II),” Heterocyclic Communications, vol. 9, no. 2, pp. 171–174, 2003.
[21]
N. Fokialakis, P. Magiatis, I. Chinou, S. Mitaku, and F. Tillequin, “Megistoquinones I and II, two quinoline alkaloids with antibacterial activity from the bark of Sarcomelicope megistophylla,” Chemical and Pharmaceutical Bulletin, vol. 50, no. 3, pp. 413–414, 2002.
[22]
R. Pili, Proceedings of the American Association for Cancer Research, vol. 43, p. 5363, 2002.
[23]
N. K. Raju, T. S. Seniappan, S. Thangaraju, and S. M. Palathurai, Heterocycles, vol. 52, no. 2, p. 357, 2000.
