Synthesis of new 1,3,4-thiadiazole derivatives, investigation of their AChE effects

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and one of the most prevalent neurodegenerative diseases. It begins with mild cognitive impairment and progressively affects all aspects of the patient’s life functions. Alzheimer’s disease is more commonly seen in the elderly and has a progressive incidence. With the global increase in the elderly population, Alzheimer’s disease poses a significant threat. Additionally, current medications do not prevent AD, highlighting the need for new drug molecules to be used in AD treatment. Although 1,3,4-thiadiazoles have many biological activities such as anticancer and antiviral, their activities on acetylcholinesterase (AChE) are also being investigated. For this purpose, three new 1,3,4-thiadiazole compounds were synthesized in this study. The structure determinations of these compounds were carried out using 1H-NMR and HRMS spectrophotometric methods. Activity studies were conducted in vitro using the modified Ellman method. As a result of the activity tests, compound 3b showed the closest effect to donepezil with an IC50= 0.096±0.004 µM.

Keywords

• Acetylcholinesterase
• Alzheimer’s Disease
• Acetylcholinesterase
• Alzheimer’s Disease
• Molecular docking
• 1,3,4-Thiadiazole

References

1. Tarı Ö and Yağmurtaşan R. Investigation of the structures of compounds with Alzheimer’s Disease and anti-Alzheimer effects. Hacettepe University Journal of the Faculty of Pharmacy. (2023);43(2):150-173. https://doi.org/10.52794/hujpharm.1175099
2. Mesut I. Determination of acetylcholinesterase gene expression and some biomarker levels in alzheimer type dementia and coronary artery disease patients and investigation of in vitro effects of some phenolic compounds on this enzyme activity by determination of acetylcholinesterase enzyme activity [Ph.D.] Ataturk University Institute of Science. (2015).
3. Osmaniye D and Kaplancıklı ZA. Synthesis of new piperazine derivatives against Alzheimer’s Disease and evaluation of their biological activities. Journal of Health Sci. (2022);31(3):330-335. https://doi.org/10.34108/eujhs.979093
4. Zhou B, Zhang B, Li X, Liu X, Li H, Li D, Cui Z, Geng H, Zhou L. New 2-aryl-9-methyl-β-carbolinium salts as potential acetylcholinesterase inhibitor agents: Synthesis, bioactivity and structure-activity relationship. Sci Rep. (2018);24;8(1):1559. https://doi.org/10.1038/s41598-018-19999-3.
5. Osmaniye D and Kaya Çavuşoğlu B. Synthesis and characterization of new imidazole derivatives as potential anticholinesterase agents. Süleyman Demirel Uni F Art Sci J Sci. (2021);16(1):301-307.
6. Zhang P, Xu S, Zhu Z, Xu J. Multi-target design strategies for the improved treatment of Alzheimer’s disease. Eur J Med Chem. (2019);15;176:228-247. https://doi.org/10.1016/j.ejmech.2019.05.020
7. Hussein W, Sağlık BN, Levent S, Korkut B, Ilgın S, Özkay Y, Kaplancıklı ZA. Synthesis and biological evaluation of new cholinesterase inhibitors for Alzheimer’s Disease. Molecules. (2018);14;23(8):2033. https://doi.org/10.3390/molecules23082033
8. Demir Özkay Ü, Can ÖD, Sağlık BN, Acar Çevik U, Levent S, Özkay Y, Ilgın S, Atlı Ö. Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines. Bioorg Med Chem Lett. (2016);26(22):5387-5394. https://doi.org/10.1016/j.bmcl.2016.10.041

9. Long J, Qin F, Luo J, Zhong G, Huang S, Jing L, Yi T, Liu J, Jiang N. Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg Chem. (2024);143:107026. https://doi.org/10.1016/j.bioorg.2023.107026
10. Mutlu NB, Değim Z, Yilmaz Ş, Eşsiz D, Nacar A. New perspective for the treatment of Alzheimer diseases: liposomal rivastigmine formulations. Drug Dev Ind Pharm. (2011);37(7):775-789. https://doi.org/10.3109/03639045.2010.541262
11. Tahtacı H. Synthesis and characterization of schiff base derivatives containing 2-amino-1,3,4-thiadiazole ring. AKU J Sci Eng. (2017);17(2):460-468. https://doi.org/10.5578/fmbd.59713
12. Çevik UA, Osmaniye D, Levent S, Sağlik BN, Çavuşoğlu BK, Karaduman AB, Özkay Y, Kaplancikli ZA. Synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives as possible anticancer agents. Acta Pharm. (2020);70(4):499-513. https://doi.org/10.2478/acph-2020-0034
13. Gour VK, Yahya S, Shahar Yar M. Unveiling the chemistry of 1,3,4-oxadiazoles and thiadiazols: A comprehensive review. Arch Pharm (Weinheim). (2024); 357(1):e2300328. https://doi.org/10.1002/ardp.202300328
14. Saikia R, Bharali J, Borthakur S, Kalita PK, Sarma P, Saikia PJ, Dutta MM, Borthakur SK. One pot synthetic approach to 2-methyl-5-phenyl-7-amino-[1,3,4]-thiadiazolo[3,2-a]pyrimidine-6-carbonitrile derivatives with antifungal evaluation. J Heterocycl Chem.(2024);61(5):771-777. https://doi.org/10.1002/jhet.4801
15. Kandemir L. Research on the synthesis and biological activities of various 2,5-disubstituted-1,3,4-thiadiazole and 1,2,4-triazole-3-thion derivatives [Ph.D.] Marmara University Institute of Health Sciences. (2013).
16. Fascio ML, Sepúlveda CS, Damonte EB, D’Accorso NB. Synthesis and antiviral activity of some imidazo[1,2-b][1,3,4]thiadiazole carbohydrate derivatives. Carbohydr Res. (2019);480:61-66. https://doi.org/10.1016/j.carres.2019.05.003
17. Serban G. Future prospects in the treatment of parasitic diseases: 2-Amino-1,3,4-thiadiazoles in leishmaniasis. Molecules.(2019);24(8):1557. https://doi.org/10.3390/molecules24081557.
18. Ellman GL, Courtney KD, Andress V Jr, Feather-Stone RM. 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
19. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem. (2012);55(22):10282-10286.
20. Schrödinger, L. 2020: New York, NY, USA.
21. Release, S. 2020: LLC, New York, NY.
22. Glide, Version 7.1, Schrödinger, LLC: New York, NY, USA, 2021.