Similar articles

Abstract: Objective: To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. Methods: A series of twenty-six compounds of N⁴-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Results: Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electroshock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. Conclusion: The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.

[1] Boisser, J.R., Simon, P., 1965. Amoxapine in experimental psychopharmacology: a neuroleptic or an antidepressant? Arch. Int. Pharmacodyn. Ther., 158:212-218.

[2] Chen, L.L., Yad, J.B., Yang, J.B., Yang, J., 2005. Predicting MDCK cell permeation coefficients of organic molecules using membrane-interaction QSAR analysis. Acta Pharm. Sin., 26(11):1322-1328.

[3] Dewar, J.S.M., Walter, T., 1977. The MNDO method: approximations and parameters. J. Am. Chem. Soc., 99(15):4899-4907.

[4] Dichter, M.A., 1998. Mechanisms of action of new antiepileptic drugs. Adv. Neurol., 76:1-8.

[5] Dimmock, J.R., Sidhu, K.K., Tumber, S.D., Basran, S.K., Chen, M., Quail, J.W., Yang, J., Rozas, I., Weaver, D.F., 1995. Some aryl semicarbazones possessing anticonvulsants activities. Eur. J. Med. Chem., 30(4):287-295.

[6] Kadaba, P.K., 1984. Triazolines XΙΙΙ: Δ²-1,2,3-triazolines, anew class of anticonvulsants. J. Pharm. Sci., 73(6):850-856.

[7] Krall, R.I., Penry, J.K., White, B.G., Kupferberg, H.J., Swinyard, E.A., 1978. Antiepileptic drug development: II. anticonvulsant drug screening. Epilepsia, 19(4):409-415.

[8] Kupferberg, H.J., 1989. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia, 30(Suppl. 1):S51-S56.

[9] Pandeya, S.N., Yogeeswari, P., Stables, J.P., 2000. Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones. Eur. J. Med. Chem., 35(10):879-885.

[10] Porsolt, R.D., Anton, G., Blanet, N., Jalfre, M., 1978. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur. J. Pharmacol., 47(4):379-486.

[11] Porter, R.J., Cereghino, J.J., Gladding, G.D., Hessie, B.J., Kupferberg, H.J., Scoville, B., 1984. Antiepileptic drug development program. Cleve. Clin. Q., 51(2):293-299.

[12] Roberts, E., 1962. Methods in Enzymology. Academic Press, New York, Vol. 4, p.612.

[13] Thirumurugan, R., Sriram, D., Saxena, A., Stables, J., Yogeeswari, P., 2006. 2,4-dimethoxyphenylsemicarbazones with anticonvulsant activity against three animal models of seizures: synthesis and pharmacological evaluation. Bioorg. Med. Chem., 14(9):3106-3112.

[14] Willmore, L.J., 2005. Antiepileptic drugs and neuroprotection: current status and future roles. Epilepsy Behav., 7(Suppl. 3):25-28.

[15] Yogeeswari, P., Sriram, D., Brahmandam, A., Sridharan, I., Thirumurugan, R., Stables, J.P., 2003. Synthesis of novel aryl semicarbazones as anticonvulsants with GABA-mediated mechanism. Med. Chem. Res., 12(2):57-68.

[16] Yogeeswari, P., Thirumurugan, R., Kavya, R., Samuel, J.S., Stables, J.P., Sriram, D., 2004a. 3-chloro-2-methyl-phenyl-substituted semicarbazones: synthesis and anticonvulsant activity. Eur. J. Med. Chem., 39(8):729-736.

[17] Yogeeswari, P., Sriram, D., Pandeya, S.N., Stables, J.P., 2004b. 4-sulphamoylphenyl semicarbazones with anticonvulsant activity. Farmaco, 59(8):609-616.

[18] Yogeeswari, P., Sriram, D., Veena, V., Kavya, R., Rakhra, K., Mehta, S., Ragavendran, J.V., Thirumurugan, R., Stables, J.P., 2005a. Synthesis of aryl semicarbazones as potential anticonvulsant agents. Biomed. Pharmacother., 59(1-2):51-57.

[19] Yogeeswari, P., Sriram, D., Thirumurugan, R., Ragavendran, J.V., Sudhan, K., Kuamr, R., Stables, J.P., 2005b. Discovery of N-(2,6-dimethylphenyl)-substituted semicarbazones as anticonvulsants: hybrid pharmacophore-based design. J. Med. Chem., 48(20):6202-6206.

[20] Yogeeswari, P., Ragavendran, J.V., Thirumurugan, R., Induja, S., Sriram, D., Stables, J.P., 2006. Synthesis and structure-activity relationship on anticonvulsant aryl semicarbazones. Med. Chem., 2(1):55-62.

[21] Zerner, M.C., 1991. Hartree-Fock Self-Consistent Field Method. In: Lipkowtz, K.B., Boyd, D.B. (Eds.), Reviews in Computational Chemistry, 2nd Ed. VCH Publishers Inc., Weinheim, p.313.