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

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

O. L. Kobzar, A. D. Ocheretniuk, I. M. Mischenko, O. P. Kozachenko, V. S. Brovarets, A. I. Vovk

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.


Keywords


thiazolium salts; acetylcholinesterase; molecular docking

References


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

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

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

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

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

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

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

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

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

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

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

Alspach, J. D., Ingraham, L. L. (1977). Inhibition of acetylcholinesterase by thiamine. A structure–function study. Journal of Medicinal Chemistry, 20 (1), 161–164.

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

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

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

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

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.

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

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

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

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

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

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

Stewart, J. J. P. (2016). MOPAC2016. Stewart Computational Chemistry, Colorado Springs, CO, USA. Available at: http://OpenMOPAC.net

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


GOST Style Citations


1. Martorana, A. Beyond the cholinergic hypothesis: do current drugs work in Alzheimer`s disease? / A. Martorana, Z. Esposito, G. Koch // CNS Neurosci. Ther. – 2010. – Vol. 16, Issue 4. – P. 235–245. https://doi.org/10.1111/j.1755-5949.2010.00175.x

2. Acetylcholiesterase inhibitors : pharmacology and toxicology / M. B. Colovic, D. Z. Krstic, T. D. Lazarevic-Pasti et al. // Curr. Neuropharmacol. – 2013. – Vol. 11, Issue 3. – P. 315–335. https://doi.org/10.2174/1570159x11311030006

3. Sereq, H. Acetylcholinesterase – new roles for an old actor / H. Sereq, S. Seidman // Nat. Rev. Neurosci. – 2001. – Vol. 2, Issue 4. – P. 294–302. https://doi.org/10.1038/35067589

4. β–Amyloid aggregation induced by human acetylcholinesterase : inhibition studies / M. Bartolini, C. Bertucci, V. Cavrini, V. Andrisano // Biochem. Pharmacol. – 2003. – Vol. 65, Issue 3. – P. 407–416. https://doi.org/10.1016/S0006-2952(02)01514-9

5. Yurttas, L. Design, synthesis and evaluation of new thiazole–piperazines as acetylcholinesterase inhibitors / L. Yurttas, Z. A. Kaplancıkli, Y. Ozkay // J. Enzyme Inhib. Med. Chem. – 2013. – Vol. 28, Issue 5. – P. 1040–1047. https://doi.org/10.3109/14756366.2012.709242

6. Design and discovery of novel thiazoleacetamide derivatives as anticholinesterase agent for possible role in the management of Alzheimer’s / Z.–Q. Sun, L.–X. Tu, F.–J. Zhuo, S.–X. Liu // Bioorg. Med. Chem. Lett. – 2016. – Vol. 26, Issue 3. – P. 747–750. https://doi.org/10.1016/j.bmcl.2016.01.001

7. 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 / V. Pejchal, S. Stepankova, M. Pejchalova et al. // Bioorg. Med. Chem. – 2016. – Vol. 24, Issue 7. – P. 1560–1572. https://doi.org/10.1016/j.bmc.2016.02.033

8. Design, synthesis, and biological evaluation of 5H–thiazolo[3,2–a]pyrimidine derivatives as a new type of acetylcholinesterase inhibitors / H. Zhi, L. Chen, L. Zhang et al. // Arkivoc. – 2008. – Vol. 2008, Issue 13. – P. 266–277. https://doi.org/10.3998/ark.5550190.0009.d29

9. Synthesis and biological evaluation of 7H–thiazolo[3,2–b]–1,2,4–triazin–7–one derivatives as dual binding site acetylcholinesterase inhibitors / S. Liu, R. Shang, L. Shi et al. // Eur. J. Med. Chem. – 2014. – Vol. 81. – P. 237–244. https://doi.org/10.1016/j.ejmech.2014.05.020

10. Manzetti, S. Thiamin function, metabolism, uptake, and transport / S. Manzetti, J. Zhang, D. van der Spoel // Biochemistry. – 2014. – Vol. 53, Issue 5. – P. 821–835. https://doi.org/10.1021/bi401618y

11. Bunik, V. I. Benefits of thiamin (vitamin B1) administration in neurodegenerative diseases may be due to both the coenzyme and non–coenzyme roles of thiamin / V. I. Bunik // J. Alzheimer’s Dis. Parkinson. – 2014. – Vol. 4, Issue 6. – P. 173–177. https://doi.org/10.4172/2161-0460.1000173

12. Alspach, J. D. Inhibition of acetylcholinesterase by thiamine. A structure–function study / J. D. Alspach, L. L. Ingraham // J. Med. Chem. – 1977. – Vol. 20, Issue 1. – P. 161–164.

13. N–Phenacylthiazolium salts as inhibitors of cholinesterases / A. Ocheretniuk, O. Kobzar, I. Mischenko, A. Vovk // French–Ukrainian J. Chem. – 2017. – Vol. 5, Issue 2. – P. 1–14. https://doi.org/10.17721/fujcV5I2P1-14

14. Synthesis and the activity assessment of adamantyl–containing thiazolium inhibitors of butyrylcholinesterase / A. D. Ocheretniuk, O. L. Kobzar, O. P. Kozachenko et al. // Журн. орг. та фармац. хімії. – 2017. – Т. 15, вип. 4 (60). – P. 48–55. https://doi.org/10.24959/ophcj.17.926

15. Buchman, E. R. Studies of crystalline Vitamin B1.1 X. Sulfite cleavage. III. Chemistry of the basic product / E. R. Buchman, R. R. Williams, J. C. Keresztesy // J. Am. Chem. Soc. – 1935. – Vol. 57, Issue 10. – P. 1849–1851. https://doi.org/10.1021/ja01313a026

16. Sano, T. Vergleich der wirksamkeit der verschiedenen aneurinester von organischen sauren / T. Sano // Bull. Chem. Soc. Jpn. – 1944. – Vol. 19, Issue 11. – P. 185–205. https://doi.org/10.1246/bcsj.19.185

17. Matsukawa, T. Studies on vitamin–B1 and its related compounds 13. Syntheses vitamin–B1–esters / T. Matsukawa, S. Yurugi // Yakugaku Zasshi (J. Pharm. Soc. Jpn). – 1951. – Vol. 71, Issue 2. – P. 69–72.

18. Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors / H. Sugimoto, Y. Yamanishi, Y. Iimura, Y. Kawakami // Curr. Med. Chem. – 2000. – Vol. 7, Issue 3. – P. 303–339. https://doi.org/10.2174/0929867003375191

19. Mechanism of hydrolysis of a thiazolium ion: general acid–base catalysis of the breakdown of the tetrahedral addition intermediate / M. W. Washabaugh, Ch. C. Yang, J. T. Stivers, K.–S. Lee // Bioorg. Chem. – 1992. – Vol. 20, Issue 4. – P. 296–312. https://doi.org/10.1016/0045-2068(92)90040-A

20. A thiamine–dependent enzyme utilizes an active tetrahedral intermediate in vitamin K biosynthesis / H. Song, C. Dong, M. Qin et al. // J. Am. Chem. Soc. – 2016. – Vol. 138, Issue 23. – P. 7244–7247. https://doi.org/10.1021/jacs.6b03437

21. A new and rapid colorimetric determination of acetylcholinesterase activity / G. L. Ellman, K. D. Courtney, V. jr. Andres, R.M. Featherstone // Biochem. Pharmacol. – 1961. – Vol. 7, Issue 2. – P. 88–95. https://doi.org/10.1016/0006-2952(61)90145-9

22. Structures of human acetylcholinesterase in complex with pharmacologically important ligands / J. Cheung, M. J. Rudolph, F. Burshteyn et al. // J. Med. Chem. – 2012. – Vol. 55, Issue 22. – P. 10282–10286. https://doi.org/10.1021/jm300871x

23. The Protein Data Bank / H. M. Berman, J. Westbrook, Z. Feng et al. // Nucleic Acids Res. – 2000. – Vol. 28, Issue 1. – P. 235–242. https://doi.org/10.1093/nar/28.1.235

24. Stewart, J. J. P. MOPAC2016. Stewart Computational Chemistry, Colorado Springs, CO, USA. [Електронний ресурс]. – Available at : http://Open-MOPAC.net

25. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function / G. M. Morris, D. S. Goodsell, R. S. Halliday et al. // J. Comput. Chem. – 1998. – Vol. 19, Issue 14. – P. 1639–1662. https://doi.org/10.1002/(sici)1096-987x(19981115)19:14<1639::aid-jcc10>3.0.co;2-b





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