Synthesis, characterization, molecular docking and cholinesterase inhibition studies of new thiazole-hydrazinyl derivatives

Abstract

Alzheimer's disease (AD) results from the destruction or loss of cholinergic cells in the brain that produce or use acetylcholine. Therefore, the main treatment strategy for AD is to increase the level of acetylcholine in the brain. In this study, the synthesis of new thiazole-hydrazinyl derivatives as cholinesterase inhibitors was carried out. The structures of the synthesized compounds were elucidated by 1H-NMR and 13C-NMR data. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects of synthesized target compounds were evaluated using the Ellman method. Molecular docking was performed with Autodock Vina. All synthesized compounds were found to exhibit low activity against AChE. Among the synthesized compounds, only compound 3j was found to selectively inhibit BuChE. According to data from molecular docking, compound 3j formed 10.0 kcal/mol interaction energy at the BuChE active site and key pi-pi staked interactions with Trp82. In conclusion, this study guides the development of selective BuChE inhibitory agents for the treatment of Alzheimer's disease.

Keywords

• Thiazole
• Hydrazine
• Acetylcholinesterase
• Butyrylcholinesterase
• Docking.

Yeni tiyazol-hidrazinil türevlerinin sentezi, karakterizasyonu, moleküler doking ve kolinesteraz inhibisyon çalışmaları

Abstract

Alzheimer hastalığı (AD), beyinde asetilkolin üreten veya kullanan kolinerjik hücrelerin yıkımı veya kaybından kaynaklanmaktadır. Bundan dolayı, AD için ana tedavi stratejisi beyindeki asetilkolin seviyesini arttırmaktır. Bu çalışmada, kolinesteraz inhibitörleri olarak yeni tiyazol-hidrazinil türevlerinin sentezi gerçekleştirilmiştir. Sentezlenen bileşiklerin yapısı 1H-NMR ve 13C-NMR verileri ile aydınlatılmıştır. Sentezlenen hedef bileşiklerin asetilkolinesteraz (AChE) ve butirilkolinesteraz (BChE) inhibitör etkileri Ellman yöntemi kullanılarak değerlendirilmiştir. Moleküler doking çalışması Autodock Vina ile yapılmıştır. Sentezlenen bütün bileşiklerin AChE karşı düşük etkinlik sergilediği bulunmuştur. Sentezlenen bileşikler arasından sadece bileşik 3j seçici olarak BuChE inhibe ettiği bulunmuştur. Dokingden elde edilen verilere göre bileşik 3j, BuChE aktif sitesinde 10.0 kcal/mol etkileşim enerjisi ve Trp82 ile anahtar pi-pi staked etkileşimleri oluşturmuştur. Sonuç olarak, bu çalışma Alzheimer hastalığının tedavisinde seçici BuChE inhibitörü ajan geliştirmede yol göstericidir.

Keywords

• Tiyazol
• Hidrazin
• Asetilkolinesteraz
• Bütirilkolinesteraz
• Doking.

References

1. Ozten, O., Kurt, B.Z., Sonmez, F., Dogan, B. ve Durdagi, S., Synthesis, molecular docking and molecular dynamics studies of novel tacrine-carbamate derivatives as potent cholinesterase inhibitors, Bioorganic Chemistry, 115, 105225i (2021).
2. Wu, J., Kou, X., Ju, H., Zhang, H., Yang, A. ve Shen, R., Design, synthesis and biological evaluation of naringenin carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease, Bioorganic Chemistry Letters, 49, 128316, (2021).
3. Shaikh, S., Dhavan, P., Uparkar, J., Singh, P., Vaidya, S.P., Jadhav, B.L. ve Ramana, M.M.V., Synthesis, characterization, in vitro cholinesterase and hRBCs hemolysis assay and computational evaluation of novel 2,3,4,5-tetrahydrobenzothiazepine appended α-aminophosphonates, Bioorganic Chemistry, 116, 105397, (2021).
4. Xu, Y., Jian, M.M., Han, C., Yang, K., Bai, L.G., Cao, F. ve Ma, Z.Y., Design, synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors, Bioorganic Medicinal Chemistry Letters, 30(6), 126985, (2020).
5. Haroon, M., Khalid, M., Shahzadi, K., Akhtar, T., Saba, S., Rafique, J., Ali, S., Irfan, M., Alam, M.M. ve Imran, M., Alkyl 2-(2-(arylidene) alkylhydrazinyl) thiazole-4-carboxylates: Synthesis, acetyl cholinesterase inhibition and docking studies, Journal of Molecular Structure, 1245, 131063, (2021).
6. Ghotbi, G., Mahdavi, M., Najafi, Z., Moghadam, F.H., Hamzeh-Mivehroud, M., Davaran, S. ve Dastmalchi, S., Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and β-amyloid aggregation for Alzheimer’s disease, Bioorganic Chemistry, 103, 104186, (2020).
7. Makhaeva, G.F., Boltneva, N.P., Lushchekina, S.V., Serebryakova, O.G., Stupina, T.S., Terentiev, A.A., Serkov, I.V., Proshin, A.N., Bachurin, S.O. ve Richardson, R.J., Synthesis, molecular docking and biological evaluation of N,N-disubstituted 2-aminothiazolines as a new class of butyrylcholinesterase and carboxylesterase inhibitors, Bioorganic Medicinal Chemistry, 24(5), 1050-1062, (2016).
8. Matsueda, K., Hongo, M., Tack, J., Aoki, H., Saito, Y. ve Kato, H., Clinical trial: dose‐dependent therapeutic efficacy of acotiamide hydrochloride (Z‐338) in patients with functional dyspepsia–100 mg tid is an optimal dosage, Neurogastroenterology & Motility, 22(6), 618-e173, (2010).

9. Matsunaga, Y., Tanaka, T., Yoshinaga, K., Ueki, S., Hori, Y., Eta, R., Kawabata, Y., Yoshii, K., Matsumura, T., Furuta, S., Takei, M., Tack, J. ve Itoh, Z., Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride, Journal of Pharmacology and Experimental Therapeutics, 336, 791, (2011).
10. Sang, Z., Qiang, X., Li, Y., Xu, R., Cao, Z., Song, Q., Wang, T., Zhang, X., Liu, H., Tan, Z. ve Deng, Y., Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease, European Journal of Medicinal Chemistry, 135, 307-323, (2017).
11. Sang, Z., Qiang, X, Li, Y., Yuan, W., Liu, Q., Shi, Y., Ang, W., Luo, Y., Tan, Z. ve Deng, Y., Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease, European Journal of Medicinal Chemistry, 94, 348, (2015).
12. Ellman, G.L., Courtney, K.D., Andres, V. ve Feather-Stone, R.M., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochemical Pharmacology, 7, 88-95, (1961).
13. Liu, Y., Grimm, M., Dai, W., Hou, M., Xiou, Z.X. ve Cao, Y., CB-Dock: a web server for cavity detection-guided protein–ligand blind docking, Acta Pharmacologica Sinica, 41(1), 138-144, (2019).
14. Trott, O. ve Olson, A.J., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of Computational Chemistry, 31(2), 455-461, (2010).
15. Nachon, F., Carletti, E., Ronco, C., Trovaslet, M., Nicolet, Y., Jean, L. ve Renard, P.Y. Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl-and butyryl-cholinesterase, Biochemical Journal, 453(3), 393-399, (2013).