Citation: ZHANG Chenglu, WANG Jing, LI Yizheng, LI Chuanyin, SUN Xiaona. Synthesis and Design of Multi-Heterocyclic Molecules with Duoble 1, 2, 4-Triazole Motifs as Inhibitors of Cell Division Cycle Protein 25B Phosphatases[J]. Chinese Journal of Applied Chemistry, ;2018, 35(2): 154-164. doi: 10.11944/j.issn.1000-0518.2018.02.170004 shu

Synthesis and Design of Multi-Heterocyclic Molecules with Duoble 1, 2, 4-Triazole Motifs as Inhibitors of Cell Division Cycle Protein 25B Phosphatases

College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, Liaoning 116029, China

Corresponding author: ZHANG Chenglu, zhangchenglu@lnnu.edu.cn
Received Date: 3 January 2017
Revised Date: 7 March 2017
Accepted Date: 14 April 2017

Fund Project: Supported by the Technology Research Program of Liaoning Provincial Department of Education(No.2009A426)the Technology Research Program of Liaoning Provincial Department of Education 2009A426

Figures(1)

Heterocyclic molecules containing 1, 2, 4-triazole motif are important for drug screening due to their better broad spectrum of bioactivities. For structure-activity relationship study, twenty-eight novel multi-heterocyclic molecules[TM1~TM3(a~f)] and[TM4~TM5(a~e)] containing duo 1, 2, 4-triazole motifs were synthesized by the conjugation with piperazine and s-triazine, respectively. The structures of target molecules were confirmed via infrared(IR), proton nuclear magnetic resonance(¹H NMR) and high resolution mass spectrometry(HRMS). In order to investigate the effect of 4-amino substituent on 1, 2, 4-triazole for bioactivities, the comparison between compounds 6-morpholine-2, 4-(5-thioether-4-amino-3-n-pentyl-1, 2, 4-triazole)-1, 3, 5-triazine(C), 6-pyrrole-2, 4-(5-mercapto-4-amino-3-n-pentyl-1, 2, 4-triazole)-1, 3, 5-triazine(D) and target molecules were also performed. The inhibitory activities against cell division cycle protein 25B(Cdc25B) phosphatases of synthesized molecules were evaluated. Twenty one molecules exhibit good activities, and nine among them are more potent than the positive control Na₃VO₄.
- 1, 2, 4-triazole,
- piperazine,
- s-triazine,
- cell division cycle protein 25B inhibitor
1. [1]
  Shelke S H, Mhaske P C, Kasam S K. Synthesis and Pharmacological Evaluation of a Novel Series of 2-((2-Arylthiazol-4-yl)methyl)-5-(alkyl/alkylnitrile thio)-1, 3, 4-Oxadiazole Derivatives as Possible Antifungal Agents[J]. Heterocycl Chem, 2014,51(6):1893-1897.
2. [2]
  Argade N D, Kalrale B K, Gill C H. Microwave Assisted Improved Method for the Synthesis of Pyrazole Containing 2, 4, -Disubstituted Oxazole-5-One and Their Antimicrobial Activity[J]. J Chem, 2008,5(1):120-129.
3. [3]
  Sayed E S, Tamany E S, Fattah M E. Regioselective Synthesis, Characterization and Antimicrobial Evaluation of S-Glycosides and S, N-Diglycosides of 1, 2-Dihydro-5-(1H-indol-2-yl)-1, 2, 4-Triazole-3-Thione[J]. Eur J Med Chem, 2013,66:106-113. doi: 10.1016/j.ejmech.2013.04.047
4. [4]
  Luszczki J J, Plech T, Wujec M. Effect 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[J]. Eur J Pharm, 2012,690(1/3):99-106.
5. [5]
  PENG Jiajian, DENG Youquan. Ionic Liquids Catalyzed One-Pot Synthesis of 3, 4-Dihydropyrimidin-2(1H)-Ones[J]. Chinese J Org Chem, 2002,22(1):71-73.
6. [6]
  Karthikeyan S, Holla B S, Kumari N S. Synthesis and Antimicrobial Studies of Novel Dichloro Fluorophenyl Containing Aminotriazolothiadiazines[J]. Eur J Med Chem, 2008,43(2):309-314. doi: 10.1016/j.ejmech.2007.03.024
7. [7]
  Gilani S J, Khan S A, Siddiqui N. Synthesis, Anticonvulsant and Toxicity Screening of Newer Pyrimidine Semicar-bazone Derivatives[J]. Eur J Med Chem, 2010,45(6):2467-2472. doi: 10.1016/j.ejmech.2010.02.031
8. [8]
  Plech T, Wujec M, Kosikowska U. Studies on the Synthesis and Antibacterial Activity of 3, 6-Disubstituted 1, 2, 4-Triazolo[3, 4-b]1, 3, 4-Thiadiazoles[J]. Eur J Med Chem, 2012,47:580-584. doi: 10.1016/j.ejmech.2011.10.055
9. [9]
  Badr S M, Barwa R M. Synthesis of some New[1, 2, 4] Triazolo[3, 4-b] [1, 3, 4] Thiadiazines and[1, 2, 4] Triazolo[3, 4-b] [1, 3, 4] Thiadiazoles Starting from 5-Nitro-2-Furoic Acid and Evaluation of Their Antimicrobial Activity[J]. Bioorg Med Chem, 2011,19(15):4506-4512. doi: 10.1016/j.bmc.2011.06.024
10. [10]
  Goswami B N, Kattaky J C, Baruah J N. Synthesis and Antibacterial Activity of 1-(2, 4-Dichlorobenzoyl)-4-Substituted Thiosemicarbazides, 1, 2, 4-Triazoles and Their Methyl Derivatives[J]. Hetercycl Chem, 1984,21(4):1225-1229. doi: 10.1002/jhet.v21:4
11. [11]
  Holla B S, Poojary K N, Kalluraya B. Synthesis, Characterisation and Antifungal Activity of Some N-Bridged Heterocycles Derived from 3-(3-Bromo-4-methoxyphenyl)-4-amino-5-mercapto-1, 2, 4-triazole[J]. Farmaco, 1996,51(12):793-799.
12. [12]
  Papakonstantinou-Garoufalias S S, Tani E, Todoulou O. Medicinal Chemistry:Synthesis and Pharmacochemical Investigation of Some Novel 1, 2, 4-4H-Triazoles with Potential Antiviral Activity[J]. Pharm Pharmacol, 1998,50(1):117-124. doi: 10.1111/jphp.1998.50.issue-1
13. [13]
  Turan-Zitouni G, Kaplancikli Z A, Erol K. Synthesis and Analgesic Activity of Some Triazoles and Triazolo-thiadiazines[J]. Farmaco, 1999,54(4):218-223. doi: 10.1016/S0014-827X(99)00016-6
14. [14]
  Goadsby P J. Advances in the Pharmacotherapy of Migraine. How Knowledge of Pathophysiology is Guiding Drug Development[J]. Drugs in R&D, 1999,2(6):361-374.
15. [15]
  Dean F M, Sargent M V, Katrizky A R. In Comprehensive Heterocyclic Chemistry[J]. New York, 1984,4531.
16. [16]
  LIU Yaqing, HU Fulin, HUANG Xiang. Synthesis and Application of Triazine Derivatives[J]. Chem Bioeng, 2013,30(12):18-27.
17. [17]
  WU Qin, WANG Zhenchao, WEI Xue. Synthesis and Antibacterial Activities of 1-Substituted-4-[5-(4-Substitutedphenyl)-1, 3, 4-Thiadiazol-2-Sulfonyl] Piperazine Derivatives[J]. Chinese J Synth Chem, 2014,22(4):429-434.
18. [18]
  JIANG Dahong, HUANG Min. Design and Synthesis of Thieno[3, 2-d]Pyrimidine Derivatives Containing a Piperazine Unit as Aanticancer Agents[J]. Chem Reag, 2012,34(9):797-799.
19. [19]
  LI Gangyue, YAN Shenggang, JIANG Shan. Synthesis of Piperazine Derivatives Containing Pyridinemethyl/Thiazolemethyl and Their Biological Activities[J]. Chinese J Org Chem, 2008,28(11):2001-2006.
20. [20]
  JI Dan, LU Junrui, XIN Cunwei. Synthesis and Biological Activities of Novel 5-Methy-1, 2, 4-triazoles-3-thione[J]. Chinese J Org Chem, 2013,33(8):1062-1068.
21. [21]
  LIU Junhu, LIU Yong, JIAN Junyou. Synthesis and Fungicidal Activities of Novel Quinazoline Derivatives Containing 1, 2, 4-Triazole Schiff-Base Unit[J]. Chinese J Org Chem, 2013,33(2):370-374.
22. [22]
  WANG Xue. Synthesis and Activity of 3-Fatyl-1, 2, 4-triazole Mannich Base[D]. Dalian: Liaoning Normal University, 2015(in Chinese).
23. [23]
  Raval J, Patel N H, Patel H V. In Vitro Antimycobacterial Activity of Novel N'-(4-(Substituted phenyl-amino)-6-(pyridin-2-ylamino)-1, 3, 5-triazin-2-yl)isonicotinohydrazide[J]. Med Chem Res, 2011,20(3):274-279.
24. [24]
  LIU Yaning, SUN Xiaona, GAO Ran. Synthesis and Bioactivities of Multiheteocyclic Molecules Based on s-Triazine[J]. Chinese J Org Chem, 2017,37:2057-2065.
25. [25]
  Lavecchia A, Giovanni C D, Pesapane A. Discovery of New Inhibitors of Cdc25B Dual Specificity Phosphatases by Structure-Based Virtual Screening[J]. J Med Chem, 2012,55(9):4142-4158. doi: 10.1021/jm201624h
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