Screening of new morpholine dithiocarbamate derivatives bearing benzimidazole moiety for anticholinesterase potential

Abstract

Alzheimer’s disease (AD) is basically associated with disturbances of cholinesterase metabolism which result in acetylcholine deficiency. Target of acetylcholinesterase (AChE) inhibitors used in symptomatic therapy of disease is to increase of ACh levels. Consequently, cholinesterase inhibitors were developed to increase acetylcholine is to inhibit AChE and butrylcholinesterase (BuChE). Studies demonstrate the clinical importance of dual inhibitors that inhibit not only the acetylcholinesterase enzyme but also the butyrylcholinesterase enzyme. In recent years, benzimidazoles have attracted particular interest owing to their anticolinesterase activity. In this manner, we have synthesized benzimidazole and morpholine including compounds (2a-i). Final compounds were achieved with the reaction of (benzimidazol-2-yl) methyl morpholine-4-carbodithioate and α-bromoacetophenone derivatives in acetone at room temperature with stirring. Inhibition effects of novel morpholine dithiocarbamates (2a-i) were tested on AChE and BuChE. Compound 2d demonstrated dual inhibitory activity on AChE and BuChE (78±1,56, 70,71±1,53, respectively), with the lowest cytotoxicity to normal cell line.

Keywords

• Acetylcholinesterase
• butrylcholinesterase
• Alzheimer
• benzimidazole

References

1. Parihar, MS., Hemnani T. Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci. (2004); 11(5):456-467. https://doi.org/10.1016/j.jocn.2003.12.007
2. Thacker P.D. Surpising discovery with alzheimer’s medication. Drug Discovery Today. (2003) 1, 8- 9. https://doi.org/10.1016/S1359-6446(03)02685-0
3. Yamada K., Takayagani M., Kamei H., Nagai T., Dohniwa M., Kobayashi K., Ohhara T., Takauma K., Nabeshima T. Effects of memantine and donepezil on amyloid β-induced memory impairment in a delayed-matching to position task in rats. Behav Brain Resb. (2005);162(2):191-9. https://doi.org/10.1016/j.bbr.2005.02.036
4. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stähelin H B, Hartman R, Gharabawi M. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. British Medical Journal. (1999);318(7184):633-8. https://doi.org/10.1136/bmj.318.7184.633
5. Racci, M., Mazzucchelli, M., Porello, E., Lanni, C., Govoni, S. Acetylcholinesterase inhibitors: novel activities of old molecules, Pharm Res. (2004); 50;441-451. https://doi.org/10.1016/j.phrs.2003.12.027
6. Jann, M.W., Shirley, K.L., Small, G.W. Cinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet. (2002);41, 10, 719-739. https://doi.org/10.2165/00003088-200241100-00003
7. Clarissa M Comim 1, Josimar G Pereira, Amanda Steckert, Fabrícia Petronilho, Tatiana Barichello, João Quevedo, Felipe Dal-Pizzol. Rivastigmine reverses habituation memory impairment observed in sepsis survivor rats. Shock. (2009);32(3):270-1. https://doi.org/10.1097/SHK.0b013e31819963c4
8. Şahin H.A. Asetilkolin, kolinesterazlar ve alzheimer hastalığı, Demans Dergisi. (2002); 2:69-73.

9. David G., Wilkinson P.T., Schwam E., Parrish J.P. Cholinesterase inhibitors used in the treatment of alzheimer’s disease. the relationship between pharmacological effects and clinical efficacy, Drugs Aging. (2004):21(7): 453-478. https://doi.org/10.2165/00002512-200421070-00004
10. Neşe Ç. Butrylcholinesterase: Structure And Physiological Importance. Turk J Biochem. (2003); 28(2):54-61. https://doi.org/10.1046/j.1365-3032.2003.00314.x
11. Ha ZY, Ong HC, Oo CW, Yeong KY. Synthesis, Molecular Docking, and Biological Evaluation of Benzimidazole Derivatives as Selective Butyrylcholinesterase Inhibitors. Curr Alzheimer Res. (2020);17(13):1177-1185. https://doi.org/10.2174/1567205018666210218151228
12. Demirayak S, Kayagil I, Yurttas L. Microwave supported synthesis of some novel 1,3-Diarylpyrazino[1,2-a]benzimidazole derivatives and investigation of their anticancer activities. Eur J Med Chem. (2011);46:411-416. https://doi.org/10.1016/j.ejmech.2010.11.007
13. Yurttaş L, Demirayak S, Akalın Çiftci G, Yıldırım ŞU, Kaplancıklı ZA. Synthesis and biological evaluation of some 1,2-disubstituted benzimidazole derivatives as new potential anticancer agents. Arch Pharm Chem Life Sci. (2013);346:403-414. https://doi.org/10.1002/ardp.201200452
14. Chawla A, Ramandeep K, Goyal A. Importance of microwave reactions in the synthesis of novel benzimidazole derivatives: A review. J Chem Pharm Res. 2011;3:925-944.
15. Husain A, Rashid M, Mishra R, Parveen S, Shin DS, Kum D. Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: Design and synthesis as anticancer agents. Bioorg Med Chem Lett. 2012;22:5438-5444. https://doi.org/10.1016/j.bmcl.2012.07.038
16. Alpan AS, Parlar S, Carlino I, Tarikgullari AH, Alptüzün V, Günes HS. Synthesis, biological activity and molecular modeling studies on 1H-benzimidazole derivatives as acetylcholinesterase inhibitors. Bioorg. Med. Chem. (2013);21(17):4928-37. https://doi.org/10.1016/j.bmc.2013.06.065
17. Surve P, Ravindran S, Acharjee A, Rastogi H, Basu S, Honrao P. Metabolite characterization of anti-cancer agent Gefitinib in human hepatocytes. Drug Metab Lett. (2013);7:126-136. https://doi.org/10.2174/1872312808666140317154110
18. Akalın Çiftçi G, Temel HE, Yurttaş L. Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety. Anti-Cancer Agents Med. Chem., (2022);22:1780-1792. https://doi.org/10.2174/1871520621666210708095110
19. Ellman G.L., Courtney K.D., Anders V., Featherstone R.M. A New And Rapid Colorimetric Determination Of Acetylcholinesterase Activity. Biochem. Pharmacol. (1961);7:88-95. https://doi.org/10.1016/0006-2952(61)90145-9
20. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. (1983);65,(1-2):55-63. https://doi.org/10.1016/0022-1759(83)90303-4
21. Keiser K., Johnson C.C., Tipton D.A. Cytotoxicity of mineral trioxide aggregate using human periodontal ligament fibroblasts. Journal of Endodontics. (2000); 26: 288-291. https://doi.org/10.1097/00004770-200005000-00010
22. Yurttaş L, Ozkay Y, Demirci F, Göger G, Ulusoylar-Yıldırım Ş, Abu Mohsen U, Öztürk Ö, Kaplancıklı ZA. Synthesis, anticandidal activity, and cytotoxicity of some thiazole derivatives with dithiocarbamate side chains, Turk J Chem. (2014);38:815-824. https://doi.org/10.3906/kim-1312-62
23. Ji F, Fengqi B, MinGu, Jing L, Zhipeng Z, Jiaoli D, Sai-Sai X and Jinsong D. Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatmentof Alzheimer’s disease, J Enzyme Inhib Med Chem. (2020);35:118-128. https://doi.org/10.1080/14756366.2019.1687460
24. Honghua Z, Yuying W, Yuqing W, Xuelin L, Şuji W, Zhen W. Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer’s disease, Eur J Med Chem. (2022); 240:114606. https://doi.org/10.1016/j.ejmech.2022.114606