An Important Potential Anti-Epileptic/Anticonvulsant Active Group: A Review of 1,2,4-Triazole Groups and Their Action

Abstract

Epilepsy is one of the most common encountered neurological disorders. Many individuals continue to have seizures despite medical and surgical treatments, suggesting new antiepileptic/anticonvulsant drugs are required. Triazole compounds are widely used in pharmaceuticals and have gained significant importance in medicinal chemistry. This article is an attempt to systematically review the research of triazole derivatives in the design and development of anticonvulsant agents during the past two decades through extensive literature research. The results show that triazole occupy a distinct niche in heterocyclic chemistry and represent a key motif in medicinal chemistry because of their capability to exhibit an array of properties and bioactivities, Therefore, 1,2,4-triazole seems to be an important pharmacophore, especially in the field of antiepileptic, which is of great explored potentiality and utilized value. Through in-depth research on this type of structure, it is believed that more 1,2,4-triazole compounds will be developed as anti-epileptic drugs for clinical use.

Key words

Antiepileptic Drugs - Behavioural Pharmacology - Drug Research - GABA - Chemistry

• References

• 1 GBD 2016 Epilepsy Collaborators Global, regional, and national burden of epilepsy, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. The Lancet. Neurology 2019; 18: 357-375
• 2 Fisher RS, Acevedo C, Arzimanoglou A. et al ILAE official report: A practical clinical definition of epilepsy. Epilepsia 2014; 55: 475-482
• 3 Kalilani L, Sun X, Pelgrims B. et al The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis. Epilepsia 2018; 59: 2179-2193
• 4 Taylor AP, Robinson RP, Fobian YM. et al Modern advances in heterocyclic chemistry in drug discovery. Organic & biomolecular chemistry 2016; 14: 6611-6637
• 5 Song MX, Huang YS, Zhou QG. et al Synthesis of ring-opened derivatives of triazole-containing quinolinones and their antidepressant and anticonvulsant activities. Bioorganic chemistry 2021; 106: 104505
• 6 Song MX, Deng XQ. Recent developments on triazole nucleus in anticonvulsant compounds: a review. Journal of enzyme inhibition and medicinal chemistry 2018; 33: 453-478
• 7 Aggarwal R, Sumran G. An insight on medicinal attributes of 1,2,4-triazoles. European journal of medicinal chemistry 2020; 205: 112652
• 8 Kaproń B, Łuszczki JJ, Płazińska A. et al Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies. European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 2019; 129: 42-57
• 9 Shahzad SA, Yar M, Khan ZA. et al Identification of 1,2,4-triazoles as new thymidine phosphorylase inhibitors: Future anti-tumor drugs. Bioorganic chemistry 2019; 85: 209-220
• 10 El-Sherief HAM, Youssif BGM, Abbas Bukhari SN. et al Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors. European journal of medicinal chemistry 2018; 156: 774-789
• 11 Wittine K, Stipković Babić M, Makuc D. et al Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations. Bioorganic & medicinal chemistry 2012; 20: 3675-3685
• 12 Küçükgüzel I, Tatar E, Küçükgüzel SG. et al Synthesis of some novel thiourea derivatives obtained from 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIV and anti-tuberculosis agents. European journal of medicinal chemistry 2008; 43: 381-392
• 13 Zhang S, Xu Z, Gao C. et al Triazole derivatives and their anti-tubercular activity. European journal of medicinal chemistry 2017; 138: 501-513
• 14 Barbieri KP, Ercolin LDR, Louat T. et al Synthesis and Immunosuppressive Activity of New Mycophenolic Acid Derivatives. Medicinal chemistry (Shariqah (United Arab Emirates)) 2017; 13: 159-167
• 15 Jin RY, Zeng CY, Liang XH. et al Design, synthesis, biological activities and DFT calculation of novel 1,2,4-triazole Schiff base derivatives. Bioorganic chemistry 2018; 80: 253-260
• 16 Xu J, Cao Y, Zhang J. Design, synthesis and antifungal activities of novel 1,2,4-triazole derivatives. European journal of medicinal chemistry 2011; 46: 3142-3148
• 17 Eswaran S, Adhikari AV, Shetty NS. Synthesis and antimicrobial activities of novel quinoline derivatives carrying 1,2,4-triazole moiety. European journal of medicinal chemistry 2009; 44: 4637-4647
• 18 Kahveci B, Yılmaz F, Menteşe E. et al Design, Synthesis, and Biological Evaluation of Coumarin-Triazole Hybrid Molecules as Potential Antitumor and Pancreatic Lipase Agents. Archiv der Pharmazie 2017; 350: 10
• 19 Meunier B. Hybrid molecules with a dual mode of action: dream or reality?. Accounts of chemical research 2008; 41: 69-77
• 20 Shaveta Mishra S, Singh P. Hybrid molecules: The privileged scaffolds for various pharmaceuticals. European journal of medicinal chemistry 2016; 124: 500-536
• 21 Walker KA, Wallach MB, Hirschfeld DR. 1-(Naphthylalkyl)-1H-imidazole derivatives, a new class of anticonvulsant agents. Journal of medicinal chemistry 1981; 24: 67-74
• 22 Wauquier A, Fransen J, Melis W. et al Loreclezole (R 72 063): an anticonvulsant chemically unrelated to prototype antiepileptic drugs. Drug Dev Res 1990; 19: 375-392
• 23 Karakurt A, Aytemir MD, Stables JP. et al Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities. Archiv der Pharmazie 2006; 339: 513-520
• 24 Lankau HJ, Unverferth K, Grunwald C. et al New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. European journal of medicinal chemistry 2007; 42: 873-879
• 25 Wang SB, Deng XQ, Song MX. et al Synthesis and anticonvulsant activity evaluation of some 1-alkoxy-4-(1H-1,2,4-triazol-1-yl)phthalazines. Letters in Drug Design & Discovery 2012; 9: 409-414
• 26 Wang SB, Deng XQ, Zheng Y. et al Synthesis and anticonvulsant activity evaluation of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinoline derivatives. Archives of pharmacal research 2013; 36: 32-40
• 27 Wang SB, Jin P, Li FN. et al Synthesis and anticonvulsant activity of novel purine derivatives. European journal of medicinal chemistry 2014; 84: 574-583
• 28 Wang SB, Piao GC, Zhang HJ. et al Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities. Molecules (Basel, Switzerland) 2015; 20: 6827-6843
• 29 Yuan YP, Wang SB, Gong GH. et al Synthesis and Studies on Anticonvulsant and Antibacterial Activities of 1-Alkyl-4-(4H-1,2,4- triazol-4-yl)piperidine Derivatives. Lett Drug Des Discov 2014; 11: 1070-1078
• 30 Deng XQ, Song MX, Zheng Y. et al Design, synthesis and evaluation of the antidepressant and anticonvulsant activities of triazole-containing quinolinones. European journal of medicinal chemistry 2014; 73: 217-224
• 31 Fang YQ, Sun CL, Liu DC. et al Synthesis and Anticonvulsant Activity Evaluation of 3-alkoxy-4-(4-(hexyloxy/heptyloxy)phenyl)-4H-1,2,4 -triazole. Iranian journal of pharmaceutical research : IJPR 2015; 14: 77-87
• 32 Song MX, Rao BQ, Cheng BB. et al Design, Synthesis and Evaluation of the Antidepressant and Anticonvulsant Activities of Triazole-Containing Benzo[d]oxazoles. CNS & neurological disorders drug targets 2017; 16: 187-198
• 33 Dehestani L, Ahangar N, Hashemi SM. et al Design, synthesis, in vivo and in silico evaluation of phenacyl triazole hydrazones as new anticonvulsant agents. Bioorganic chemistry 2018; 78: 119-129
• 34 Song M, Yan R, Zhang Y. et al Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H₃ receptor antagonists/inverse agonists containing triazole moiety. Journal of enzyme inhibition and medicinal chemistry 2020; 35: 1310-1321
• 35 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 poloniae pharmaceutica 2009; 66: 135-140
• 36 Guan LP, Sui X, Deng XQ. et al Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine. European journal of medicinal chemistry 2010; 45: 1746-1752
• 37 Deng XQ, Quan LN, Song MX. et al Synthesis and anticonvulsant activity of 7-phenyl-6,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones and their derivatives. European journal of medicinal chemistry 2011; 46: 2955-2963
• 38 Song MX, Zhang CB, Deng XQ. et al Synthesis and anticonvulsant activity evaluation of 6-phenyl-7H-[1,2,4]triazolo[3,4-b][1, 3,4]thiadiazines. Lett Drug Des Discov 2011; 8: 769-773
• 39 Deng XQ, Dong ZQ, Song MX. et al Synthesis and Anticonvulsant Activities of Some Triazolothiadiazole Derivatives. Arch Pharm Chem Life Sci 2012; 345: 565-573
• 40 Deng XQ, Song MX, Gong GH. et al Synthesis and Anticonvulsant Evaluation of some New 6-(Substituted-phenyl)thiazolo[3,2-b][1,2,4]triazole Derivatives in Mice. Iranian journal of pharmaceutical research : IJPR 2014; 13: 459-469
• 41 Jiang N, Deng XQ, Li FN. et al Synthesis of novel 7-substituted-5- phenyl-[1,2,4] triazolo [1,5-a] pyrimidines with anticonvulsant activity.. Iranian Journal of Pharmaceutical Research 2012; 11: 799-806
• 42 Guan LP, Sui X, Chang Y. et al Design, synthesis and anticonvulsant activity evaluation of 7-substituted-[1,2,4]-triazolo[4,3-f]pyrimidine derivatives. Medicinal chemistry (Shariqah (United Arab Emirates)) 2012; 8: 1076-1083
• 43 Guan LP, Zhang RP, Sun Y. et al. Synthesis and studies on the anticonvulsant activity of 5-alkoxy-[1,2,4] triazolo [4, 3-a] pyridine derivatives. Original Article 2012; 62: 372-377
• 44 Huang LJ, Tian Y, Teng DW. et al. (2016). A class of [1,2,4]-triazole[1,5-a]pyrimidone hetero cyclic compounds, their preparation methods and uses: CN201611115587. 6[P].
• 45 Ding J, Cao FD, Geng YR. et al Synthesis and in vitro anti-epileptic activities of novel [1,2,4]-triazolo[1,5-a]pyrimidin-7(4H)-one derivatives. Journal of Asian natural products research 2019; 21: 1190-1204
• 46 Huang L, Ding J, Li M. et al Discovery of [1,2,4]-triazolo [1,5-a]pyrimidine-7(4H)-one derivatives as positive modulators of GABA_A1 receptor with potent anticonvulsant activity and low toxicity. European journal of medicinal chemistry 2019; 185: 111824
• 47 Wagle S, Adhikari AV, Kumari NS. Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants. European journal of medicinal chemistry 2009; 44: 1135-1143
• 48 Bayoumi A, Ghiaty A, El-Morsy A. et al Synthesis and evaluation of some new 1,2,4-triazolo(4,3-a)quinoxalin-4(5H)- one derivatives as AMPA receptor antagonists. Bull Fac Pharm 2012; 50: 141-146
• 49 Deng XQ, Quan ZS, Xiao CR. et al Synthesis and anticonvulsant activity of substituted[1,2,4]triazolo[4,3-a]quinazolines. Chin J Org Chem 2011; 31: 2082-2087
• 50 Zhang HJ, Jin P, Wang SB. et al Synthesis and Anticonvulsant Activity Evaluation of 4-Phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one and Its Derivatives. Archiv der Pharmazie 2015; 348: 564-574
• 51 Wang SB, Jin P, Li FN. et al Synthesis and anticonvulsant activity of novel purine derivatives. European journal of medicinal chemistry 2014; 84: 574-583
• 52 Wang SB, Piao GC, Zhang HJ. et al Synthesis of 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives and evaluation of their anticonvulsant activities. Molecules (Basel, Switzerland) 2015; 20: 6827-6843
• 53 Dong ZQ, Liu XM, Wei CX. et al Design, synthesis of 6-substituted-pyrido[3,2-d]pyridazine derivatives with anticonvulsant activity. Medicinal chemistry (Shariqah (United Arab Emirates)) 2015; 11: 595-601
• 54 Zhang Guo-Rui, Ren Yang, Yin Xiu-Mei, Quan Zhe-Shan. Synthesis and Evaluation of the Anticonvulsant Activities of New 5-substitued-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one Derivatives. Lett Drug Des Dis 2018; 15: 406-413
• 55 Deng XQ, Song MX, Wang SB. et al Synthesis and evaluation of the anticonvulsant activity of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives. Journal of enzyme inhibition and medicinal chemistry 2014; 29: 272-280
• 56 Wu HF, Han RB, Jin CZ. et al Synthesis of Novel 8-alkylamino-5, 6-dihydro-4H-benzo[f] [1,2,4]triazolo [4,3-a]azepines as Anticonvulsant Agents. CNS & neurological disorders drug targets 2016; 15: 1333-1343