DESIGN, SYNTHESIS, IN SILICO STUDIES, AND PHARMACOLOGICAL EVALUATION OF 5-ARYL-4-(CHLOROACETYLAMINO)-3-MERCAPTO-1,2,4-TRIAZOLE DERIVATIVES AS ANTICONVULSANT AGENTS

RUPSHEE JAIN; PRABITHA P.; SUSHIL K. KASHAW; VIKAS JAIN; D. V. KOHLI

doi:10.22159/ijap.2024v16i6.52379

Authors

RUPSHEE JAIN Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar, India, 470003. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India, 570015 https://orcid.org/0000-0001-5863-3159
PRABITHA P. Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India, 570015 https://orcid.org/0000-0002-4642-8470
SUSHIL K. KASHAW Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar, India, 470003
VIKAS JAIN Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, Karnataka, India https://orcid.org/0000-0001-5863-3159
D. V. KOHLI Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar, India, 470003

DOI:

https://doi.org/10.22159/ijap.2024v16i6.52379

Keywords:

Anticonvulsants, 1,2,4-triazole, Molecular docking, BZD receptors, Maximal electroshock

Abstract

Objective: In this study, we reported the synthesis of a novel series of 5-aryl-4(chloroacetylamino)-3-mercapto-1, 2,4-triazoles.

Methods: These compounds were synthesized to screen for anticonvulsant effects in a Maximal Electroshock Seizure (MES) model and a Subcutaneous Pentylenetetrazole (sc‐PTZ) seizure model in rats. Furthermore, molecular docking studies with gamma-aminobutyric acid and in silico ADME prediction were carried out to determine interactions of these compounds with Benzodiazepine (BZD) receptors and their similarity with standard drugs. The rotarod test was used to evaluate neurotoxicity.

Results: 08 out of 40 compounds exhibited neurotoxicity at the maximum tested dose. Most of the compounds showed anti‐MES effects without any signs of neurological deficit. All the tested compounds significantly reduced seizures induced by PTZ compared to the control group. Carbamazepine and phenytoin were used as positive controls for anticonvulsant effects. Compounds 3d, 3h (a diphenylamine derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole), and 4a (a piperidinyl derivative of 5-aryl-4(chloroacetylamino)-3-mercapto-1,2,4-triazole) exhibited greater safety than phenytoin and carbamazepine in terms of neurotoxicity. The docking scores for the identified compounds 3d, 3h and 4a was 6.5133; 6.6558 and 5.6524, respectively. Nearly all the compounds (90%) demonstrated decreased locomotor activity.

Conclusion: It is gratifying that the compounds with higher hydrophobicity showed better performance in the seizure models. Many triazole derivatives holding a suitable aryl or alkyl group gave a better anticonvulsant activity in their analogs.

Downloads

Download data is not yet available.

References

Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS. Psychological distress comorbidities and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia. 2005 Jul;46(7):1133-9. doi: 10.1111/j.1528-1167.2005.01605.x, PMID 16026567.

Ashhar MU, Ahmad MZ, Jain V, Agarwal NB, Ahmad FJ, Jain GK. Intranasal pitavastatin attenuates seizures in different experimental models of epilepsy in mice. Epilepsy Behav. 2017 Oct 1;75:56-9. doi: 10.1016/j.yebeh.2017.07.004, PMID 28826009.

Soares DA Silva P, Pires N, Bonifacio MJ, Loureiro AI, Palma N, Wright LC. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015 Mar;3(2):e00124. doi: 10.1002/prp2.124, PMID 26038700.

Hanada T. The discovery and development of perampanel for the treatment of epilepsy. Expert Opin Drug Discov. 2014 Apr 1;9(4):449-58. doi: 10.1517/17460441.2014.891580, PMID 24559052.

Large CH, Sokal DM, Nehlig A, Gunthorpe MJ, Sankar R, Crean CS. The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use. Epilepsia. 2012 Mar;53(3):425-36. doi: 10.1111/j.1528-1167.2011.03364.x, PMID 22221318.

Kamboj VK, Verma PK, Dhanda A, Ranjan S. 1,2,4-triazole derivatives as a potential scaffold for anticonvulsant activity. Cent Nerv Syst Agents Med Chem. 2015 Apr 1;15(1):17-22. doi: 10.2174/1871524915666150209100533, PMID 25675400.

Ben Menachem E. Medical management of refractory epilepsy practical treatment with novel antiepileptic drugs. Epilepsia. 2014 Jan;55 Suppl 1:3-8. doi: 10.1111/epi.12494, PMID 24400690.

Luszczki JJ, Plech T, Wujec M. Effect of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock induced seizure model. Eur J Pharmacol. 2012 Sep 5;690(1-3):99-106. doi: 10.1016/j.ejphar.2012.06.023, PMID 22732650.

Loring DW, Meador KJ. Cognitive side effects of antiepileptic drugs in children. Neurology. 2004 Mar 23;62(6):872-7. doi: 10.1212/01.wnl.0000115653.82763.07, PMID 15037684.

Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017 Nov 1;76:24-31. doi: 10.1016/j.yebeh.2017.08.039, PMID 28931473.

Deka D, Chakravarty PI, Purkayastha AY. Evaluation of the anticonvulsant effect of aqueous extract of Centella asiatica in albino mice. Int J Pharm Pharm Sci. 2017;9(2):312-4. doi: 10.22159/ijpps.2017v9i2.15483.

Karakucuk Iyidogan A, Basaran E, Tatar Yilmaz G, Oruc Emre EE. Development of new chiral 1,2,4-triazole-3-thiones and 1,3,4-thiadiazoles with promising in vivo anticonvulsant activity targeting GABAergic system and voltage-gated sodium channels (VGSCs). Bioorg Chem. 2024 Oct 1;151:107662. doi: 10.1016/j.bioorg.2024.107662, PMID 39079390.

Rani S, Teotia S, Nain S. Recent advancements and biological activities of triazole derivatives: a short review. Pharm Chem J. 2024 Apr 15;57(12):1909-17. doi: 10.1007/s11094-024-03096-z.

Mula M. GABAergic drugs in the treatment of epilepsy: modern or outmoded? Future Med Chem. 2011 Feb;3(2):177-82. doi: 10.4155/fmc.10.296, PMID 21428812.

Froestl W. An historical perspective on GABAergic drugs. Future Med Chem. 2011 Feb;3(2):163-75. doi: 10.4155/fmc.10.285, PMID 21428811.

Plech T, Luszczki JJ, Wujec M, Flieger J, Pizon M. Synthesis characterization and preliminary anticonvulsant evaluation of some 4-alkyl-1,2,4-triazoles. Eur J Med Chem. 2013 Feb 1;60:208-15. doi: 10.1016/j.ejmech.2012.11.026, PMID 23291122.

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 Nov 1;15(21):6775-81. doi: 10.1016/j.bmc.2007.08.004, PMID 17761423.

Matin MM, Matin P, Rahman MR, Ben Hadda T, Almalki FA, Mahmud S. Triazoles and their derivatives: chemistry synthesis and therapeutic applications. Front Mol Biosci. 2022 Apr 25;9:864286. doi: 10.3389/fmolb.2022.864286, PMID 35547394, PMCID PMC9081720.

Zhang Y, Wang M, Ahmed M, HE L, JI M, QI Z. Synthesis fungicidal activity and SAR of 3,4-dichloroisothiazole based cycloalkyl sulfonamides. Bioorg Med Chem Lett. 2019 Jun 1;29(11):1345-9. doi: 10.1016/j.bmcl.2019.03.047, PMID 30956010.

Zhang Y, Wang M, Ahmed M, He L, JI M, QI Z. Synthesis fungicidal activity and SAR of 3,4-dichloroisothiazolebased cycloalkylsulfonamides. Bioorg Med Chem Lett. 2019;29(11):1345-49. doi: 10.1016/j.bmcl.2019.03.047, PMID 30956010.

Shalini K, Kumar N, Drabu S, Sharma PK. Advances in synthetic approach to and antifungal activity of triazoles. Beilstein J Org Chem. 2011 May 25;7(1):668-77. doi: 10.3762/bjoc.7.79, PMID 21804864.

Salma U, Ahmad S, Zafer Alam MZ, Khan SA. A review: synthetic approaches and biological applications of triazole derivatives. J Mol Struct. 2024;1301:137240. doi: 10.1016/j.molstruc.2023.137240.

Shivarama Holla BS, Veerendra B, Shivananda MK, Poojary B. Synthesis characterization and anticancer activity studies on some mannich bases derived from 1,2,4-triazoles. Eur J Med Chem. 2003 Jul 1;38(7-8):759-67. doi: 10.1016/s0223-5234(03)00128-4, PMID 12932907.

Turan Zitouni G, Sivaci M, Kilic FS, Erol K. Synthesis of some triazolyl-antipyrine derivatives and investigation of analgesic activity. Eur J Med Chem. 2001 Aug 1;36(7-8):685-9. doi: 10.1016/s0223-5234(01)01252-1, PMID 11600237.

Bekircan O, Kuxuk M, Kahveci B, Kolayli S. Convenient synthesis of fused heterocyclic 1,3,5-triazines from some N-acyl imidates and heterocyclic amines as anticancer and antioxidant agents. Arch Pharm Int. 2005 Aug;338(8):365-72. doi: 10.1002/ardp.200400964, PMID 16041836.

Wade PC, Vogt BR, Kissick TP, Simpkins LM, Palmer DM, Millonig RC. 1-Acyltriazoles as antiinflammatory agents. J Med Chem. 1982 Mar;25(3):331-3. doi: 10.1021/jm00345a021, PMID 6461764.

Mahdavi M, Akbarzadeh T, Sheibani V, Abbasi M, Firoozpour L, Tabatabai SA. Synthesis of two novel 3-amino-5-[4-chloro-2-phenoxyphenyl]-4H-1,2,4-triazoles with anticonvulsant activity. Iran J Pharm Res. 2010;9(3):265-9. PMID 24363736.

Modzelewska Banachiewicz B, Kalabun J. Synthesis and biological action of 5-oxo-1,2,4-triazine derivatives. Pharmazie. 1999 Jul 1;54(7):503-5. PMID 10445245.

Gupta D, Jain DK. Synthesis antifungal and antibacterial activity of novel 1,2,4-triazole derivatives. J Adv Pharm Technol Res. 2015 Jul 1;6(3):141-6. doi: 10.4103/2231-4040.161515, PMID 26317080.

Gao F, Wang T, Xiao J, Huang G. Antibacterial activity study of 1,2,4-triazole derivatives. Eur J Med Chem. 2019 Jul 1;173:274-81. doi: 10.1016/j.ejmech.2019.04.043, PMID 31009913.

Gulerman N, Rollas S, Kiraz M, Ekinci AC, Vidin A. Evaluation of antimycobacterial and anticonvulsant activities of new 1-(4-fluorobenzoyl)-4-substituted thiosemicarbazide and 5-(4-fluorophenyl)-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives. Farmaco. 1997 Nov 1;52(11):691-5. PMID 9550096.

Ikizler AA, Johansson CB, Bekircan O, Celik C. Drug synthesis. Acta Poloniae Pharnaceutica–Drug Research. 1999;56(4):283-8.

Shalini M, Yogeeswari P, Sriram D, Stables JP. Cyclization of the semicarbazone template of aryl semicarbazones: synthesis and anticonvulsant activity of 4,5-diphenyl-2H-1,2,4-triazol-3(4H) one. Biomed Pharmacother. 2009 Mar 1;63(3):187-93. doi: 10.1016/j.biopha.2006.04.002, PMID 19422088.

Siddiqui N, Ahsan W. Triazole incorporated thiazoles as a new class of anticonvulsants: design, synthesis and in vivo screening. Eur J Med Chem. 2010 Apr 1;45(4):1536-43. doi: 10.1016/j.ejmech.2009.12.062, PMID 20116140.

Almasirad A, Tabatabai SA, Faizi M, Kebriaeezadeh A, Mehrabi N, Dalvandi 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 Dec 20;14(24):6057-9. doi: 10.1016/j.bmcl.2004.09.072, PMID 15546729.

Vaijanathappa J, Puttaswamygowda J, Bevanhalli R, Dixit S, Prabhakaran P. Molecular docking antiproliferative and anticonvulsant activities of swertiamarin isolated from Enicostemma axillare. Bioorg Chem. 2020 Jan 1;94:103428. doi: 10.1016/j.bioorg.2019.103428, PMID 31740047.

Siddiqui AA, Partap S, Khisal S, Yar MS, Mishra R. Synthesis anti-convulsant activity and molecular docking study of novel thiazole pyridazinone hybrid analogues. Bioorg Chem. 2020 Jun 1;99:103584. doi: 10.1016/j.bioorg.2020.103584, PMID 32229345.

White HS. Experimental selection quantification and evaluation of antiepileptic drugs. Antiepileptic. 1995:99-110.

Singh SP, Pandey BR, Kumar S, Parmar SS. Anticonvulsant activity and inhibition of respiration in rat brain homogenates by substituted trimethoxybenzamides. J Pharm Sci. 1978 Dec;67(12):1682-5. doi: 10.1002/jps.2600671212, PMID 722479.

Srivastava VK, Pandey BR, Gupta RC, Kishor K. New CNS-active 3-methyl-4-substituted methyl delta 2-isoxazolin-5-ones. Pharmazie. 1979 Oct 1;34(10):638-9. PMID 542475.

Mandhane SN, Aavula K, Rajamannar T. Timed pentylenetetrazol infusion test: a comparative analysis with S.C.PTZ and MES models of anticonvulsant screening in mice. Seizure. 2007 Oct 1;16(7):636-44. doi: 10.1016/j.seizure.2007.05.005, PMID 17570689.

Dandiya PC, Cullumbine H. Studies on acorus calamus (III); some pharmacological actions of the volatile oil. J Pharmacol Exp Ther. 1959 Apr 1;125(4):353-9. PMID 13642279.

Shannon HE, Eberle EL, Peters SC. Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neuropharmacology. 2005 Jun 1;48(7):1012-20. doi: 10.1016/j.neuropharm.2005.01.013, PMID 15857628.

Lokhande KB, Ballav S, Yadav RS, Swamy KV, Basu S. Probing intermolecular interactions and binding stability of kaempferol quercetin and resveratrol derivatives with PPAR-γ: docking molecular dynamics and MM/GBSA approach to reveal potent PPAR- γ agonist against cancer. J Biomol Struct Dyn. 2022 Feb 2;40(3):971-81. doi: 10.1080/07391102.2020.1820380, PMID 32954977.

Sravanthi B, Himavathi G, Robert AR, Karunakar P, Kiran KS, Maddila S. Design synthesis computational molecular docking studies of novel heterocyclics bearing 1, 2, 4–triazole, 1,3,4-oxadiazole conjugates as potent antibacterial and antitubercular agents. J Biomol Struct Dyn. 2024 Jul;42(10):5376-89. doi: 10.1080/07391102.2023.2226743.

Song M, Zhao W, Zhu Y, Liu W, Deng X, Huang Y. Design synthesis and evaluation of anticonvulsant activities of new triazolopyrimidine derivatives. Front Chem. 2022;10:925281. doi: 10.3389/fchem.2022.925281, PMID 35815216.

Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A. Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists. Bioorg Med Chem. 2003 Mar 6;11(5):769-73. doi: 10.1016/s0968-0896(02)00469-8, PMID 12538007.

Lipinski CA. Lead and drug like compounds: the rule of five revolution. Drug Discov Today Technol. 2004 Dec 1;1(4):337-41. doi: 10.1016/j.ddtec.2004.11.007, PMID 24981612.

Song MX, Deng XQ. Recent developments on triazole nucleus in anticonvulsant compounds: a review. J Enzyme Inhib Med Chem. 2018 Jan 1;33(1):453-78. doi: 10.1080/14756366.2017.1423068, PMID 29383949.

Deng XQ, Song MX, Zheng Y, Quan ZS. Design synthesis and evaluation of the antidepressant and anticonvulsant activities of triazole containing quinolinones. Eur J Med Chem. 2014 Feb 12;73:217-24. doi: 10.1016/j.ejmech.2013.12.014, PMID 24412497.