SYNTHESIS, ANTICONVULSANT AND NEUROTOXICITY SCREENING OF SOME NOVEL 2, 5-DISUBSTITUTED - 1, 3, 4 – OXADIAZOLE DERIVATIVES
Abstract
A series of 2, 5-disubstituted - 1, 3, 4 – oxadiazoles (4a-o) were synthesized on refluxing hydrazine carbothioamides with iodine and potassium iodide in ethanolic sodium hydroxide solution starting from methyl-3-amino-4-hydroxy benzoate via synthesis of an intermediate methyl-2-substitutedaryl-1, 3-benzoxazole-5-carboxylates and 2-substitutedaryl-1, 3-benzoxazole-5-carbohydrazides. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H-NMR, MS) and elemental analysis. All these compounds were screened for anticonvulsant activity using Maximal Electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) method. Anticonvulsant activity was shown by majority of the synthesized compounds when given i.p. to mice. Among the tested compounds 4e, 4j and 4o were considered to have potent anticonvulsant activity comparable to that of standard drugs Phenytoin and Carbamazepine. Compounds 4e, 4g, 4h, 4i, 4k and 4m passed the rota rod test successfully without any sign of neurological deficit.
Keywords:
Anticonvulsant, Neurotoxicity, Lipophilicity, 1, 3, 4-Oxadiazoles.DOI
https://doi.org/10.25004/IJPSDR.2017.090104References
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6. Bell GS, Sander JW. The epidemiology of epilepsy: The size of the problem. Seizure. 2002; 11 (Suppl. A): 306-314.
7. Husain A, Siddiqui N, Sarafroz M, Khatoon Y, Rasid M, Ahmad N. Synthesis, anticonvulsant and neurotoxicity screening of some novel 1,2,4-trisubstituted-1H-imidazole derivatives. Acta Polo Pharm Drug Res. 2011; 68: 657-663.
8. Wlaz P, Loscher W. Weak anticonvulsant effects of two novel glycine B receptor antagonists in the amygdala-kindling model in rats. Eur J Pharmacol. 1998; 342: 39-46.
9. Scheurer ML, Pedley TA. The evaluation and treatment of seizures. N Engl J Med. 1990; 323: 1468-1474.
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12. Deckers CLP, Genton P, Sills GJ, Schmidt D. Current Limitations of Antiepileptic Drug Therapy: A Conference Review. Epilep Res. 2003; 53: 1-17.
13. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000; 342: 314-319.
14. Brazil CW, Pedly TA. Advances in the medical treatment of epilepsy. Ann Rev Med. 1998; 49: 135-162.
15. McCabe PH. New Anti-epileptic drugs for the 21st Century. Expert Opinion Pharmacother. 2000; 1: 633-674.
16. Lopes LJM. The new drugs and the strategies to manage epilepsy. Curr Pharmac Design. 2000; 6: 873-878.
17. Berk M, Segal J, Janet L, Vorster M. Emerging options in the treatment of bipolar disorders. Drugs. 2001; 61: 1407-1414.
18. Porter RJ, Rogawski MA. New antiepileptic drugs: from serendipity to rational discovery. Epilepsia. 1992; 33 Suppl 1: S1-6.
19. Bruno-Blanch L, Galvez J, Garcia-Domenech R. Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity. Bioorg Med Chem Lett. 2003; 13: 2749-2754.
20. Malawska B, Scatturium A. Application of Pharmacophore Models for the Design and Synthesis of New Anticonvulsant Drugs. Mini Rev Med Chem. 2003; 3: 341-348.
21. Lopes LJM. The new drugs and the strategies to manage epilepsy. Curr Pharmac Design. 2000; 6: 873-878.
22. Berk M, Segal J, Janet L, Vorster M. Emerging options in the treatment of bipolar disorders. Drugs. 2001; 61: 1407-1414.
23. Duncan JS. The promise of new antiepileptic drugs. Br J Clin Pharmacol. 2002; 53: 123-131.
24. Szelenyi I, Horvath K, Howes JF, Mazarati AM. The treatment of epilepsy: future possibilities. Drugs Fut. 2003; 28: 925-936.
25. Akhter M, Husain A, Azad B, Ajmal M. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur J Med Chem. 2009; 44: 2372-2378.
26. Amir M, Kumar S. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of ibuprofen derivatives. Acta Pharm. 2007; 57: 31-45.
27. Kumar H, Javed SA, Khan SA, Amir M. 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties. Eur J Med Chem. 2008; 43: 2688-2698.
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29. Kucukguzel SG, Kucukguzel I, Tatar E, Rollas S, Sahin F, Gulluce M, De Clercq E, Kabasakal L. Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents. Eur J Med Chem. 2007; 42: 893-901.
30. Padmavathi V, Reddy GS, Padmaja A, Kondaiah P, Shazia A. Synthesis, antimicrobial and cytotoxic activities of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Eur J Med Chem. 2009; 44: 2106-2112.
31. Karthikeyan MS, Prasad DJ, Mahalinga M, Holla BS, Kumari NS. Antimicrobial studies of 2,4-dichloro-5-fluorophenyl containing oxadiazoles. Eur J Med Chem. 2008; 43: 25-31.
32. Sahin G, Palaska E, Ekizoglu M, Ozalp M. Synthesis and antimicrobial activity of some 1, 3, 4-oxadiazole derivatives. I L Farmaco. 2002; 57: 539-542.
33. Chen CJ, Song BA, Yang S, Xu GF, Bhadury PS, Jin LH, Hu DY, Li QZ, Liu F, Xue W, Lu P, Chen Z. Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives. Bioorg Med Chem. 2007; 15: 3981-3989.
34. Zareef M, Iqbal R, De Dominguez NG, Rodrigues J, Zaidi JH, Arfan M, Supuran CT. Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties. J Enz Inhi Med Chem. 2007; 22: 301-308.
35. Aboraia AS, Abdel-Rahman HM, Mahfouz NM, EL-Gendy MA. Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: promising anticancer agents. Bioorg Med Chem. 2006; 14: 1236-1246.
36. Navarrete-Vazquez G, Molina-Salinas GM, Duarte-Fajardo ZV, Vargas-Villarreal J, Estrada-Soto S, Gonzalez-Salazar F, Hernandez-Nuneza E, Said-Fernandez S. Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. Bioorg Med Chem. 2007; 15: 5502-5508.
37. Kucukguzel SG, Oruc EE, Rollas S, Sahin F, Ozbek A. Synthesis, characterization and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur J Med Chem. 2002; 37: 197-206.
38. Mamolo MG, Zampieri D, Vio L, Fermeglia M, Ferrone M, Pricl M, Scialino G, Banfi E. Antimycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-1,3,4-oxadiazol-2-one and 2-thione derivatives. Preliminary molecular modeling investigations. Bioorg Med Chem. 2005; 13: 3797-3809.
39. Mazouz F, Lebreton L, Milcent R, Burstein C. 5-Aryl-1,3,4-Oxadiazol-2(3H)-one derivatives and sulfur analogues as new selective and competitive monoamine oxidase type B inhibitors. Eur J Med Chem. 1990; 25: 659-671.
40. Zarghi A, Faizi M, Shafaghi B, Ahadian A, Khojastehpoor HR, Zanganeh V, Tabatabai SA, Shafiee A. Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists. Bioorg Med Chem Lett. 2005; 15: 3126-3129.
41. Almasirad A, Tabatabai SA, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi A, Shafiee A. Synthesis and anticonvulsant activity of new 2-substituted-5- [2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett. 2004; 14: 6057-6059.
42. Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K, Bernoster K, Dost R, Egerland U, Rundfeldt C. New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med of Chem. 2007; 42: 873-879.
43. Gopalakrishna B, Ranghunandan N, Rao VJ, Bari S, Venkatesham A and Sarangapani M. Synthesis and anti-inflammatory activity of some new benzoxazole schiff bases. Ind Drug. 2005; 6: 369-374.
44. Husain A, Naseer MA, and Sarafroz M. Synthesis and anticonvulsant activity of some novel fused heterocyclic 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives. Acta Polo Pharm Drug Res. 2009; 66: 135-140.
45. Mavrova AT, Wesselinova D, Tsenov YA, Denkova P. Synthesis, cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. Eur J Med Chem. 2009; 44: 63-69.
46. Siddiqui AA, Arora A, Siddiqui N, Misra A. Synthesis of some 1,2,4-triazoles as potential antifungal agents. Ind J Chem. 2005; 44: 838-841.
47. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia. 1978; 19: 409-428.
48. Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B, White BG. Antiepileptic drug development program. Cleve Clin Q. 1984; 51: 293-305.
49. Swinyard EA, Woodhead JH, White HS, Franklin MR. General principles: experimental selection, quantification, and evaluation of anticonvulsants. In: Levy RH, Mattson RH, Melrum B, Penry JK, Dreifuss FE. Antiepileptic drugs. Edn 3, Raven-Press, New York, 1989, 85–102.
50. Chen J, Sun XY, Chai KY, Lee JS, Song MS, Quan ZS. Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Bioorg Med Chem. 2007; 15: 6775-6781.
51. Kucukguzel I, Kucukguzel SG, Rollas S, Sanis GO, Ozdemir O, Bayrak I, Altug T, Stables JP. 3-(aryl alkyl thio)-4-alkyl/aryl-5-(4-aminophenyl)-4h-1,2,4-triazole derivatives and their anticonvulsant activity. I L Farma. 2004; 59: 893-901.
52. Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit in rat and mice. J Am Pharm Asso Sci. 1957; 46: 208–209.
53. Kwan P, Brodie MJ. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia. 2005; 46: 224-35.
54. Lien EJ, Liuo RCH, Shinoucla HG. Quantitative structure-activity relationships and dipole moments of anticonvulsants and CNS depressants. J Pharm Sci. 1979; 68: 463-468.
55. Farrar VA, Ciechanowicz-Rutkowska M, Grochowski J, Serda P, Pilati T, Filippini G, Hinko CN, El-Assadi A, Moore JA, Edafiogho IO, Andrews CW, Cory M, Nicholson JM, Scott KR. Synthesis and CLOGP correlation of imidooxy anticonvulsants. J Med Chem. 1993; 36: 3517-3525.
56. Dimmock JR, Pandeya SN, Quail JW, Pugazhenthi U, Allen TM, Kao GY, Balzarini J, De Clercq E. Evaluation of the semicarbazones, thiosemicarbazones and biscarbohydrazones of some aryl alicyclic ketones for anticonvulsant and other biological properties. Eur J Med Chem. 1995; 30: 303-314.
57. White HS, Woodhead JH, Franklin MR, Mattson RH, Meldrum BS. Antiepileptic drugs. Edn 4, Raven Press, New York, 1995: 99.
2. Sharma AK, Khosla R, Mehta VL, Kela AK. Antiepileptic agents: newer generation. Ind J Pharmacol. 1996; 28: l-l0.
3. Kenda BM, Matagne AC, Talaga PE, Pasau PE, Differding E, Lallemand BI, Frycia AM, Moureau FG, Klitgaard HV, Gillard MR, Fuks B, Michel P. Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem. 2004; 47: 530-549.
4. Njamnshi AK, Bissek ACZK, Yepnjio FN, Tabah EN, Angwafor SA, Kuate CT, Dema F, Fonsah JY, Acho A, Kepeden MN, Azinwi YH, Kuwoh PB, Angwafor FF, Muna WF. A community survey of knowledge, perceptions, and practice with respect to epilepsy among traditional healers in the Batibo Health District, Cameroon. Epilep Behav. 2010; 17: 95-102.
5. Blum DE. New drugs for persons with epilepsy. Adv Neurol. 1998; 76: 57-87.
6. Bell GS, Sander JW. The epidemiology of epilepsy: The size of the problem. Seizure. 2002; 11 (Suppl. A): 306-314.
7. Husain A, Siddiqui N, Sarafroz M, Khatoon Y, Rasid M, Ahmad N. Synthesis, anticonvulsant and neurotoxicity screening of some novel 1,2,4-trisubstituted-1H-imidazole derivatives. Acta Polo Pharm Drug Res. 2011; 68: 657-663.
8. Wlaz P, Loscher W. Weak anticonvulsant effects of two novel glycine B receptor antagonists in the amygdala-kindling model in rats. Eur J Pharmacol. 1998; 342: 39-46.
9. Scheurer ML, Pedley TA. The evaluation and treatment of seizures. N Engl J Med. 1990; 323: 1468-1474.
10. Husain A, Naseer MA, Sarafroz M. Synthesis and anticonvulsant activity of some novel fused heterocyclic 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives. Acta Polo Pharm Drug Res. 2009; 66: 135-140.
11. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med. 1996; 334: 168-175.
12. Deckers CLP, Genton P, Sills GJ, Schmidt D. Current Limitations of Antiepileptic Drug Therapy: A Conference Review. Epilep Res. 2003; 53: 1-17.
13. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000; 342: 314-319.
14. Brazil CW, Pedly TA. Advances in the medical treatment of epilepsy. Ann Rev Med. 1998; 49: 135-162.
15. McCabe PH. New Anti-epileptic drugs for the 21st Century. Expert Opinion Pharmacother. 2000; 1: 633-674.
16. Lopes LJM. The new drugs and the strategies to manage epilepsy. Curr Pharmac Design. 2000; 6: 873-878.
17. Berk M, Segal J, Janet L, Vorster M. Emerging options in the treatment of bipolar disorders. Drugs. 2001; 61: 1407-1414.
18. Porter RJ, Rogawski MA. New antiepileptic drugs: from serendipity to rational discovery. Epilepsia. 1992; 33 Suppl 1: S1-6.
19. Bruno-Blanch L, Galvez J, Garcia-Domenech R. Topological virtual screening: a way to find new anticonvulsant drugs from chemical diversity. Bioorg Med Chem Lett. 2003; 13: 2749-2754.
20. Malawska B, Scatturium A. Application of Pharmacophore Models for the Design and Synthesis of New Anticonvulsant Drugs. Mini Rev Med Chem. 2003; 3: 341-348.
21. Lopes LJM. The new drugs and the strategies to manage epilepsy. Curr Pharmac Design. 2000; 6: 873-878.
22. Berk M, Segal J, Janet L, Vorster M. Emerging options in the treatment of bipolar disorders. Drugs. 2001; 61: 1407-1414.
23. Duncan JS. The promise of new antiepileptic drugs. Br J Clin Pharmacol. 2002; 53: 123-131.
24. Szelenyi I, Horvath K, Howes JF, Mazarati AM. The treatment of epilepsy: future possibilities. Drugs Fut. 2003; 28: 925-936.
25. Akhter M, Husain A, Azad B, Ajmal M. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur J Med Chem. 2009; 44: 2372-2378.
26. Amir M, Kumar S. Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of ibuprofen derivatives. Acta Pharm. 2007; 57: 31-45.
27. Kumar H, Javed SA, Khan SA, Amir M. 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxy acetic acid: synthesis and preliminary evaluation of biological properties. Eur J Med Chem. 2008; 43: 2688-2698.
28. Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ. Design, synthesis and evaluation of anti-inflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid derivatives. Bioorg Med Chem. 2008; 16: 1822-1831.
29. Kucukguzel SG, Kucukguzel I, Tatar E, Rollas S, Sahin F, Gulluce M, De Clercq E, Kabasakal L. Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents. Eur J Med Chem. 2007; 42: 893-901.
30. Padmavathi V, Reddy GS, Padmaja A, Kondaiah P, Shazia A. Synthesis, antimicrobial and cytotoxic activities of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Eur J Med Chem. 2009; 44: 2106-2112.
31. Karthikeyan MS, Prasad DJ, Mahalinga M, Holla BS, Kumari NS. Antimicrobial studies of 2,4-dichloro-5-fluorophenyl containing oxadiazoles. Eur J Med Chem. 2008; 43: 25-31.
32. Sahin G, Palaska E, Ekizoglu M, Ozalp M. Synthesis and antimicrobial activity of some 1, 3, 4-oxadiazole derivatives. I L Farmaco. 2002; 57: 539-542.
33. Chen CJ, Song BA, Yang S, Xu GF, Bhadury PS, Jin LH, Hu DY, Li QZ, Liu F, Xue W, Lu P, Chen Z. Synthesis and antifungal activities of 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-thiadiazole and 5-(3,4,5-trimethoxyphenyl)-2-sulfonyl-1,3,4-oxadiazole derivatives. Bioorg Med Chem. 2007; 15: 3981-3989.
34. Zareef M, Iqbal R, De Dominguez NG, Rodrigues J, Zaidi JH, Arfan M, Supuran CT. Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties. J Enz Inhi Med Chem. 2007; 22: 301-308.
35. Aboraia AS, Abdel-Rahman HM, Mahfouz NM, EL-Gendy MA. Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: promising anticancer agents. Bioorg Med Chem. 2006; 14: 1236-1246.
36. Navarrete-Vazquez G, Molina-Salinas GM, Duarte-Fajardo ZV, Vargas-Villarreal J, Estrada-Soto S, Gonzalez-Salazar F, Hernandez-Nuneza E, Said-Fernandez S. Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. Bioorg Med Chem. 2007; 15: 5502-5508.
37. Kucukguzel SG, Oruc EE, Rollas S, Sahin F, Ozbek A. Synthesis, characterization and biological activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur J Med Chem. 2002; 37: 197-206.
38. Mamolo MG, Zampieri D, Vio L, Fermeglia M, Ferrone M, Pricl M, Scialino G, Banfi E. Antimycobacterial activity of new 3-substituted 5-(pyridin-4-yl)-3H-1,3,4-oxadiazol-2-one and 2-thione derivatives. Preliminary molecular modeling investigations. Bioorg Med Chem. 2005; 13: 3797-3809.
39. Mazouz F, Lebreton L, Milcent R, Burstein C. 5-Aryl-1,3,4-Oxadiazol-2(3H)-one derivatives and sulfur analogues as new selective and competitive monoamine oxidase type B inhibitors. Eur J Med Chem. 1990; 25: 659-671.
40. Zarghi A, Faizi M, Shafaghi B, Ahadian A, Khojastehpoor HR, Zanganeh V, Tabatabai SA, Shafiee A. Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists. Bioorg Med Chem Lett. 2005; 15: 3126-3129.
41. Almasirad A, Tabatabai SA, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi A, Shafiee A. Synthesis and anticonvulsant activity of new 2-substituted-5- [2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazoles and 1,2,4-triazoles. Bioorg Med Chem Lett. 2004; 14: 6057-6059.
42. Lankau HJ, Unverferth K, Grunwald C, Hartenhauer H, Heinecke K, Bernoster K, Dost R, Egerland U, Rundfeldt C. New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med of Chem. 2007; 42: 873-879.
43. Gopalakrishna B, Ranghunandan N, Rao VJ, Bari S, Venkatesham A and Sarangapani M. Synthesis and anti-inflammatory activity of some new benzoxazole schiff bases. Ind Drug. 2005; 6: 369-374.
44. Husain A, Naseer MA, and Sarafroz M. Synthesis and anticonvulsant activity of some novel fused heterocyclic 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole derivatives. Acta Polo Pharm Drug Res. 2009; 66: 135-140.
45. Mavrova AT, Wesselinova D, Tsenov YA, Denkova P. Synthesis, cytotoxicity and effects of some 1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. Eur J Med Chem. 2009; 44: 63-69.
46. Siddiqui AA, Arora A, Siddiqui N, Misra A. Synthesis of some 1,2,4-triazoles as potential antifungal agents. Ind J Chem. 2005; 44: 838-841.
47. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia. 1978; 19: 409-428.
48. Porter RJ, Cereghino JJ, Gladding GD, Hessie BJ, Kupferberg HJ, Scoville B, White BG. Antiepileptic drug development program. Cleve Clin Q. 1984; 51: 293-305.
49. Swinyard EA, Woodhead JH, White HS, Franklin MR. General principles: experimental selection, quantification, and evaluation of anticonvulsants. In: Levy RH, Mattson RH, Melrum B, Penry JK, Dreifuss FE. Antiepileptic drugs. Edn 3, Raven-Press, New York, 1989, 85–102.
50. Chen J, Sun XY, Chai KY, Lee JS, Song MS, Quan ZS. Synthesis and anticonvulsant evaluation of 4-(4-alkoxylphenyl)-3-ethyl-4H-1,2,4-triazoles as open-chain analogues of 7-alkoxyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolines. Bioorg Med Chem. 2007; 15: 6775-6781.
51. Kucukguzel I, Kucukguzel SG, Rollas S, Sanis GO, Ozdemir O, Bayrak I, Altug T, Stables JP. 3-(aryl alkyl thio)-4-alkyl/aryl-5-(4-aminophenyl)-4h-1,2,4-triazole derivatives and their anticonvulsant activity. I L Farma. 2004; 59: 893-901.
52. Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit in rat and mice. J Am Pharm Asso Sci. 1957; 46: 208–209.
53. Kwan P, Brodie MJ. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia. 2005; 46: 224-35.
54. Lien EJ, Liuo RCH, Shinoucla HG. Quantitative structure-activity relationships and dipole moments of anticonvulsants and CNS depressants. J Pharm Sci. 1979; 68: 463-468.
55. Farrar VA, Ciechanowicz-Rutkowska M, Grochowski J, Serda P, Pilati T, Filippini G, Hinko CN, El-Assadi A, Moore JA, Edafiogho IO, Andrews CW, Cory M, Nicholson JM, Scott KR. Synthesis and CLOGP correlation of imidooxy anticonvulsants. J Med Chem. 1993; 36: 3517-3525.
56. Dimmock JR, Pandeya SN, Quail JW, Pugazhenthi U, Allen TM, Kao GY, Balzarini J, De Clercq E. Evaluation of the semicarbazones, thiosemicarbazones and biscarbohydrazones of some aryl alicyclic ketones for anticonvulsant and other biological properties. Eur J Med Chem. 1995; 30: 303-314.
57. White HS, Woodhead JH, Franklin MR, Mattson RH, Meldrum BS. Antiepileptic drugs. Edn 4, Raven Press, New York, 1995: 99.
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“SYNTHESIS, ANTICONVULSANT AND NEUROTOXICITY SCREENING OF SOME NOVEL 2, 5-DISUBSTITUTED - 1, 3, 4 – OXADIAZOLE DERIVATIVES”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 9, no. 1, Jan. 2017, pp. 22-29, https://doi.org/10.25004/IJPSDR.2017.090104.
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Research Article
How to Cite
“SYNTHESIS, ANTICONVULSANT AND NEUROTOXICITY SCREENING OF SOME NOVEL 2, 5-DISUBSTITUTED - 1, 3, 4 – OXADIAZOLE DERIVATIVES”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 9, no. 1, Jan. 2017, pp. 22-29, https://doi.org/10.25004/IJPSDR.2017.090104.
