Synthesis of new piperazine compounds and investigation of their anticholinesterase effects

Yıl 2017, Cilt: 42 Sayı: 3, 526 - 532, 30.09.2017

Yusuf Özkay

https://doi.org/10.17826/cutf.323967

Cited By: 1

Öz

Purpose: The aim of present study is to evaluate anticholinesterase activities of some new piperazine compounds.

Materials and Methods: Ten new piperazine derivatives were synthesized. Structure elucidation of the synthesized compounds was performed by spectroscopic medhods.  Inhibitory activities of these compounds on acetylcholine esterase (AChE) and butrylcholine esterase (BChE) enzymes have been determined by Ellman’s colorimetric assay. Enzyme kinetic studies were performed for the most active compound 2b by using Lineweaver–Burk plots.

Results: The compound 2b including chloro substituent was found as the most active derivative with 82.95 %, 66.93 % and 42.63 % inhibition rates at 1 mM, 0.1 mM and 0.01 mM concentrations, respectively. Non-competitive type of inhibition was determined for compound 2b as a result of enzyme kinetic studies. 

Conclusion: None of the compounds showed activity as much as standard drug donepezil. However, compound 2b and 2c displayed a promising and selective inhibitory activity against AChE.

Anahtar Kelimeler

AChE, BChE, Piperazine, inhibition

Yeni piperazin bileşiklerinin sentezi ve antikolinesteraz etkilerinin araştırılması

Öz

Amaç: Bu çalışmada bazı yeni piperazin bileşiklerinin antikolinesteraz etkinliklerinin değerlendirilmesi amaçlanmıştır.

Gereç ve Yöntem: On yeni piperazin türevi sentezlenmiştir. Sentezlenen bileşiklerin yapı aydınlatmaları spektroskopik yöntemler ile gerçekleştirilmiştir. Bu bileşiklerin asetilkolin esteraz (AChE) ve butirilkolin esteraz enzimleri üzerindeki etkileri, Elmann kolorimetrik metodu ile belirlenmiştir. En etkili 2b bileşiği için Lineweaver–Burk grafiği kullanılarak enzim kinetik çalışmaları gerçekleştirilmiştir.

Bulgular: Klor değişken grubu içeren 2b kodlu bileşiğin 1mM, 0.1 mM and 0.01 mM konsantrasyonlarda sırasıyla % 82.95, % 66.93 ve %42.63 inhibisyon oranları ile en etkili türev olduğu belirlenmiştir. Enzim kinetik çalışmaları sonucunda 2b kodlu bileşiğin non-kompetitif tip inhibisyon gösterdiği tespit edilmiştir.

Sonuç: Hiçbir bileşik standart ilaçlar donepezil ve takrin kadar etki göstermemiştir. Ancak 2b ve 2c kodlu bileşikler AChE enzimine karşı seçici ve umut verici düzeyde inhibisyon sergilemiştir.

Anahtar Kelimeler

AChE, BChE, Piperazin, inhibisyon.

Kaynakça

• 1. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Adv Drug Del Rev. 2008;60:1463-70.
• 2. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer’s disease: current status and new perspectives. Lancet Neurol. 2003;2:539-47.
• 3. Ucar G, Gokhan N, Yesilada A, Bilgin AA. N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: a novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson’s and Alzheimer’s diseases. Neurosci Lett. 2005;382:327-31.
• 4. Vitorovic-Todorovic MD, Juranic IO, Mandic LM, Drakulic BJ. 4-Aryl-4-oxo-N-phenyl-2-aminylbuty-ramides as acetyl- and butyrylcholinesterase inhibitors. preparation, anticholinesterase activity, docking study, and 3D structure–activity relationship based on molecular interaction fields. Bioorg Med Chem. 2010;18:1181-93.
• 5. Yu L, Cao R, Yi W, Yan Q, Chen C, Ma L. Synthesis of 4-[(diethylamino)methyl]-phenol derivatives as novel cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorg Med Chem. Lett. 2010;20:3254-58.
• 6. Hassan KM. Molecular interactions of cholinesterases inhibitors using in silico methods: current status and future prospects. New Biotechnol. 2009;5:331-46.
• 7. Darvesh S, Grantham DL, Hopkins DA. Distribution of butyrylcholinesterase in the human amygdala and hippocampal formation. J Comp Neurol. 1998;393:374-90.
• 8. Weinstock M, Groner E. Rational design of a drug for Alzheimer’s disease with cholinesterase inhibitory and neuroprotective activity. Chem Biol Interact. 2008;175:216-21.
• 9. Zhang J, Zhu D, Sheng R, Wu H, Hu Y, Wang F. BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide. Eur J Pharmacol. 2009;613:1-9.
• 10. Mustazza C, Borioni A, Rosaria DGM, Gatta F, Ferretti R. Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer’s disease. Eur J Med. Chem. 2002;37:91-109.
• 11. Kryger G, Israel S, Sussman JL. Structure of acetylcholinesterase complexed with E2020 (AriceptÒ): implications for the design of new anti-Alzheimer drugs. Structure. 1999;3:297-307.
• 12. Araujo JQ, Araujo dBM, Boas HLV, de Alencastro RB, Castro HC, Rodrigues CR. Receptor-dependent (RD) 3D-QSAR approach of a series of benzylpiperidine inhibitors of human acetylcholinesterase (HuAChE). Eur J Med Chem. 2011;46:39-51.
• 13. Dvir H, Silman I, Harel M, Rosenberry TL, Sussman JL. Acetylcholinesterase: from 3D structure to function. Chem Biol Interact. 2010;187:10-22.
• 14. Meena P, Nemaysh V, Khatri M, Manral A, Luthra PM, Tiwari M. Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer’s disease. Bioorg Med Chem. 2015;23:1135-48.
• 15. Varadaraju KR, Kumar JR, Mallesha L, Muruli A, Mohana KNS, Mukunda CK et al. Virtual screening and biological evaluation of piperazine derivatives as human acetylcholinesterase inhibitors. Int J Alzheimers Dis. 2013;2013:653962.
• 16. Marc J, Ezoulin M, Shao B, Xia Z, Xie Q, Li J et al. Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice. Int J Neuropsychopharmacol. 2009;12:1409-19.
• 17. Kaya B, Özkay Y, Temel HE, Kaplancikli ZA. Synthesis and biological evaluation of novel piperazine containing hydrazone derivatives. J Chem. 2016; 2016:5878410.
• 18. Demir Özkay Ü, Can ÖD, Sağlık BN, Acar Çevik U, Levent S, Özkay Y et al. Design, synthesis, and AChE inhibitory activity of new benzothiazole–piperazines. Bioorg Med Chem Lett. 2016;26:5387-94.
• 19. Sağlık BN, Ilgın S, Özkay Y. Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes. Eur J Med Chem. 2016;124:1026-40.
• 20. Mohsen UA, Kaplancikli ZA, Özkay Y, Yurttaş, L. Synthesis and evaluation of anti-acetylcholinesterase activity of some benzothiazole based new piperazine-dithiocarbamate derivatives. Drug Res. 2015;65:176-83.
• 21. Yurttaş L, Kaplancikli, ZA, Özkay, Y. Design, synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors. J Enz Inhib Med Chem. 2013;28:1040-47.
• 22. Özturan-Özer E, Unsal-Tan O, Ozadali K, Küçükkılınç T, Balkan A, Uçar G. Synthesis, molecular modeling and evaluation of novel N-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Aβ aggregation. Bioorg Med Chem Lett. 2013;23:440-3.
• 23. Altıntop MD, Gurkan-Alp AS, Özkay Y, Kaplancıklı ZA, Synthesis and biological evaluation of a series of dithiocarbamates as new cholinesterase inhibitors. Arch Pharm Chem Life Sci. 2013;346:571-6.
• 24. Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7:88-95.
• 25. Cacabelos R. Donepezil in Alzheimer’s disease: from conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat. 2007;3:303-33.
• 26. Huang W, Yu H, Sheng R, Li J, Hu Y. Identification of pharmacophore model, synthesis and biological evaluation of N-phenyl-1- arylamide and N-phenylbenzenesulfonamide derivatives as BACE 1 inhibitors. Bioorg Med Chem. 2008;16:10190-7.
• 27. Sheng R, Lin X, Li J, Jiang Y, Shang Z, Hu Y. Design, synthesis, and evaluation of 2-phenoxy-indan-1-one derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett. 2005;15:3834-7.
• 28. Leurs R, Bakker RA, Timmerman H, de Esch IJ. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005;4:107-20.