Acetylcholinesterase inhibitors with a thiazolium scaffold: structural features and binding modes

Authors

  • O. L. Kobzar V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine
  • A. D. Ocheretniuk V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine
  • I. M. Mischenko V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine
  • O. P. Kozachenko V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine
  • V. S. Brovarets V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine
  • A. I. Vovk V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Ukraine

DOI:

https://doi.org/10.24959/ophcj.19.971

Keywords:

thiazolium salts, acetylcholinesterase, molecular docking

Abstract

Aim. To assess the structural features of substituents and the role of a thiazolium scaffold in mechanisms of acetylcholinesterase inhibition by thiazolium salts.
Results and discussion. On the basis of activities of model compounds at pH 6.5 and pH 8.0 and the results of molecular docking the binding modes of quaternized derivatives of 5-(2-hydroxyethyl)-4-methylthiazole with different substituents in position 3 and 5 were analyzed. The presence of (N)3-benzyl substituent provides the inhibitor fixation in the catalytic anionic site, whereas acyl fragments of substituents in position 5 are situated in the peripheral anionic site. Logarithms of ІС50 values of the thiazolium inhibitors, except for the compounds containing O-acyl carbocyclic groups, linearly depend on the calculated docking energies in case of a thiazolium, ion as well as a neutral tetrahedral intermediate of the thiazolium ring opening.
Experimental part. Thiazolium salts were synthesized by the known methods. The activity of acetylcholinesterase was studied by Ellman’s method. Molecular docking to the active site of acetylcholinesterase was performed using an AutoDock 4.2 program.
Conclusions. Structural fragments of substituents in positions 3 and 5 of the heterocyclic scaffold provide binding of the inhibitor in the catalytic anionic site and the peripheral anionic site of acetylcholinesterase, respectively. The heterocyclic scaffold can be bound to the enzyme as a thiazolium ion or a neutral tetrahedral
intermediate of the ring opening reaction.

Downloads

Download data is not yet available.

References

  1. Martorana, A., Esposito, Z., Koch, G. (2010). Beyond the cholinergic hypothesis: do current drugs work in Alzheimer`s disease? CNS Neuroscience & Therapeutics. 16 (4), 235–245. https://doi.org/10.1111/j.1755-5949.2010.00175.x
  2. Colovic, M. B., Krstic, D. Z., Lazarevic–Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11 (3), 315–335. https://doi.org/10.2174/1570159x11311030006
  3. Soreq, H., & Seidman, S. (2001). Acetylcholinesterase – new roles for an old actor. Nature Reviews Neuroscience, 2 (4), 294–302. https://doi.org/10.1038/35067589
  4. Bartolini, M., Bertucci, C., Cavrini, V., & Andrisano, V. (2003). β–Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochemical Pharmacology, 65 (3), 407–416. https://doi.org/10.1016/S0006-2952(02)01514-9
  5. Yurttaş, L., Kaplancıklı, Z. A., & Özkay, Y. (2012). Design, synthesis and evaluation of new thiazole–piperazines as acetylcholinesterase inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 28 (5), 1040–1047. https://doi.org/10.3109/14756366.2012.709242
  6. Sun, Z.–Q., Tu, L.–X., Zhuo, F.–J., & Liu, S.–X. (2016). Design and discovery of Novel Thiazole acetamide derivatives as anticholinesterase agent for possible role in the management of Alzheimer’s. Bioorganic & Medicinal Chemistry Letters, 26 (3), 747–750. https://doi.org/10.1016/j.bmcl.2016.01.001
  7. Pejchal, V., Štěpánková, Š., Pejchalová, M., Královec, K., Havelek, R., Růžičková, Z., … Lepšík, M. (2016). Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1–[(1R)–1–(6–fluoro–1,3–benzothiazol–2–yl)ethyl]–3–alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo–irreversible inhibitors. Bioorganic & Medicinal Chemistry, 24 (7), 1560–1572. https://doi.org/10.1016/j.bmc.2016.02.033
  8. Zhi, H., Chen, L., Zhang, L., Liu, S., Wan, D. C. C., Lin, H., Hu, C. (2008). Design, synthesis, and biological evaluation of 5H–thiazolo[3,2–a]pyrimidine derivatives as a new type of acetylcholinesterase inhibitors. Arkivoc, 2008 (13), 266–277. https://doi.org/10.3998/ark.5550190.0009.d29
  9. Liu, S., Shang, R., Shi, L., Wan, D. C.–C., & Lin, H. (2014). Synthesis and biological evaluation of 7H–thiazolo[3,2–b]–1,2,4–triazin–7–one derivatives as dual binding site acetylcholinesterase inhibitors. European Journal of Medicinal Chemistry, 81, 237–244. https://doi.org/10.1016/j.ejmech.2014.05.020
  10. Manzetti, S., Zhang, J., & van der Spoel, D. (2014). Thiamin Function, Metabolism, Uptake, and Transport. Biochemistry, 53 (5), 821–835. https://doi.org/10.1021/bi401618y
  11. Bunik, V. I. (2014). Benefits of Thiamin (Vitamin B1) Administration in Neurodegenerative Diseases may be Due to Both the Coenzyme and Non–coenzyme Roles of Thiamin. Journal of Alzheimer’s Disease & Parkinsonism, 4 (6). https://doi.org/10.4172/2161-0460.1000173
  12. Alspach, J. D., Ingraham, L. L. (1977). Inhibition of acetylcholinesterase by thiamine. A structure–function study. Journal of Medicinal Chemistry, 20 (1), 161–164.
  13. Ocheretniuk, A., Kobzar, O., Mischenko, I., … Vovk, A. (2017). N–Phenacylthiazolium Salts as Inhibitors of Cholinesterases. French–Ukrainian Journal of Chemistry, 5(2), 1–14. https://doi.org/10.17721/fujcv5i2p1-14
  14. Ocheretniuk, A. D., Kobzar, O. L., Kozachenko, O. P., Brovarets, V. S., & Vovk, A. I. (2017). Synthesis and the activity assessment of adamantylcontaining thiazolium inhibitors of butyrylcholinesterase. Žurnal organìčnoï ta farmacevtičnoï hìmìï, 15 (4(60)), 48–55. https://doi.org/10.24959/ophcj.17.926
  15. Buchman, E. R., Williams, R. R., & Keresztesy, J. C. (1935). Studies of Crystalline Vitamin B1.1X. Sulfite Cleavage. III. Chemistry of the Basic Product. Journal of the American Chemical Society, 57 (10), 1849–1851. https://doi.org/10.1021/ja01313a026
  16. Sano, T. (1944). Vergleich der Wirksamkeit der verschiedenen Aneurinester von organischen Sauren. Bulletin of the Chemical Society of Japan, 19 (11), 185–205. https://doi.org/10.1246/bcsj.19.185
  17. Matsukawa, T., Yurugi, S. (1951). Studies on vitamin–B1 and its related compounds 13. Syntheses vitamin–B1–esters. Yakugaku Zasshi (Journal of the Pharmaceutical Society of Japan), 71 (2), 69–72.
  18. Sugimoto, H., Yamanish, Y., Iimura, Y., & Kawakami, Y. (2000). Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors. Current Medicinal Chemistry, 7 (3), 303–339. https://doi.org/10.2174/0929867003375191
  19. Washabaugh, M. W., Yang, C. C., Stivers, J. T., & Lee, K.–S. (1992). Mechanism of hydrolysis of a thiazolium ion: General acid–base catalysis of the breakdown of the tetrahedral addition intermediate. Bioorganic Chemistry, 20 (4), 296–312. https://doi.org/10.1016/0045-2068(92)90040-A
  20. Song, H., Dong, C., Qin, M., Chen, Y., Sun, Y., Liu, J., … Guo, Z. (2016). A Thiamine–Dependent Enzyme Utilizes an Active Tetrahedral Intermediate in Vitamin K Biosynthesis. Journal of the American Chemical Society, 138 (23), 7244–7247. https://doi.org/10.1021/jacs.6b03437
  21. Ellman, G. L., Courtney, K. D., jr. Andres, V., Featherstone, R.M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7 (2), 88–95. https://doi.org/10.1016/0006-2952(61)90145-9
  22. Cheung, J., Rudolph, M. J., Burshteyn, F., Cassidy, M. S., Gary, E. N., Love, J., … Height, J. J. (2012). Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands. Journal of Medicinal Chemistry, 55 (22), 10282–10286. https://doi.org/10.1021/jm300871x
  23. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N., Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Research, 28 (1), 235–242. https://doi.org/10.1093/nar/28.1.235
  24. Stewart, J. J. P. (2016). MOPAC2016. Stewart Computational Chemistry, Colorado Springs, CO, USA. Available at: http://OpenMOPAC.net
  25. Morris, G. M., Goodsell, D. S., Halliday, R.S., Huey, R., Hart, W. E., Belew, R. K., Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of Computational Chemistry, 19 (14), 1639–1662. https://doi.org/10.1002/(sici)1096-987x(19981115)19:14<1639::aid-jcc10>3.0.co;2-b

Downloads

Published

2019-06-14

How to Cite

(1)
Kobzar, O. L.; Ocheretniuk, A. D.; Mischenko, I. M.; Kozachenko, O. P.; Brovarets, V. S.; Vovk, A. I. Acetylcholinesterase Inhibitors With a Thiazolium Scaffold: Structural Features and Binding Modes. J. Org. Pharm. Chem. 2019, 17, 26-32.

Issue

Vol. 17 No. 2(66) (2019)

Section

Original Researches

License

Copyright (c) 2019 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).