Design, Synthesis and In-Vitro Testing of New Sinapic Acid Derivatives as Anti-Alzheimer Disease
DOI:
https://doi.org/10.22401/ANJS.29.2.03Keywords:
Cholinesterase, Sinapic acid derivatives, Docking, Amides, Schiff base, ADME studiesAbstract
In the past few decades, the cholinergic theory of Alzheimer's disease has been promoted as a crucial tool for the creation of new drugs. Cholinesterases (ChEs) play a dynamic part in the regulation of cholinergic transmission. The inhibition of ChEs is believed to be involved in the cumulative brain acetylcholine level and accordingly has been considered in the management of Alzheimer’s disease. In this study, new sinapic acid derivatives were designed by docking, synthesized, and predicted for their ADME properties. They were then tested in vitro for their ChEs inhibitory activity. Based on the docking study, 10 new amide and Schiff base sinapic acid derivatives were synthesized and characterized using 1HNMR and 13CNMR. The in vitro testing yielded good results at 50 and 100 mM concentrations. Six new compounds showed good and potent affinity to inhibit ChEs, proving more potent than the parent compound (sinapic acid) and rivastigmine, and largely similar to that of donepezil for acetylcholinesterase (brain ChE). Compounds S4 and S9 exhibited superior activity, resembling donepezil. In vivo and animal testing studies will be needed to ascertain the resulting activity and safety of these new compounds.
References
[1] Toka, F.; Koçyiğit-Kaymakçıoğlu, B.; Sağlık, B.N.; Levent, S.; Özkay, Y. and Kaplancıklı, Z.A.; "Synthesis and biological evaluation of new pyrazolone Schiff bases as monoamine oxidase and cholinesterase inhibitors". Bioorg. Chem., 84: 41–50, 2019.
[2] Mahmood, A.A.J.; Zainal, A.A. and Khalaf, M.M.; "Cholinesterase activity in non-alcoholic-fatty liver disease in diabetic patients taking oral antidiabetic drugs". Curr. Top. Pharmacol., 25: 43–51, 2021.
[3] Zheng, Q.; Sun, W.; Qu, M. and Bais, S.; "Synergistic Effect of Selected Hydroxy Cinnamic Acid Derivative (HCA) With Rivastigmine in Dementia". Pharm. Lett., 9(11): 54-62, 2017.
[4] Pourtaher, H.; Hasaninejad, A. and Iraji, A.; "Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease". Sci. Rep., 12:15236, 2022.
[5] aheri, M.; Aslani, S.; Ghafouri, H.; Mohammadi, A.; Akbary Moghaddam, V.; Moradi, N. and Naeimi, H.; "Synthesis, in vitro biological evaluation and molecular modelling of new 2-chloro-3-hydrazinopyrazine derivatives as potent acetylcholinesterase inhibitors on PC12 cells". BMC Chem., 16:7, 2022.
[6] Chen, Y.; Zhu, J.; Mo, J.; Yang, H.; Jiang, X.; Lin, H.; Gu, K.; Pei, Y.; Wu, L.; Tan, R.; Hou, J.; Chen, J.; Lv, Y.; Bian, Y. and Sun, H.; "Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer’s disease". J. Enzyme Inhib. Med. Chem., 33(1): 290-302, 2018.
[7] Mahmood, A.A.J.; "Synthesis, antioxidant and antimicrobial activities for new 4,4'- methylenedianiline amide compounds". Egypt. J. Chem., 64(12): 6999–7005, 2021.
[8] Szwajgier, D.; "Anticholinesterase activity of selected phenolic acids and flavonoids - interaction testing in model solutions". Ann. Agric. Environ. Med., 22(4): 690-4, 2015.
[9] Haji Ali, S.; Osmaniye, D.; Sağlık, B.N.; Levent, S.; Özkay, Y. and Kaplancıklı, Z.A.; "Design, Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors". Molecules, 27(7):2121, 2022.
[10] Motebennur, S.L.; Nandeshwarappa, B.P. and Katagi, M.S.; "Drug Candidates for the Treatment of Alzheimer’s Disease: New Findings from 2021 and 2022". Drugs Drug Candidates, 2(3):571-590, 2023.
[11] Hussein, W.; Sağlık, B.N.; Levent, S.; Korkut, B.; Ilgın, S.; Özkay, Y. and Kaplancıklı, Z.A.; "Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer's Disease". Molecules, 23(8):2033, 2018.
[12] Nguyen, V.P.T.; Stewart, J.D.; Ioannou, I. and Allais, F.; "Sinapic Acid and Sinapate Esters in Brassica: Innate Accumulation, Biosynthesis, Accessibility via Chemical Synthesis or Recovery From Biomass, and Biological Activities". Front. Chem., 9:664602, 2021.
[13] Mahmood, A.A.J.; Khalaf, M.M. and Zainal, A.A.; "Cholinesterases activities in diabetic and hyperlipidemic patient". Indian J. Public Health Res. Dev., 10(10): 2812–2816, 2019.
[14] Chen, C.; "Sinapic Acid and Its Derivatives as Medicine in Oxidative Stress-Induced Diseases and Aging". Oxid. Med. Cell Longev., 3571614, 2016.
[15] Guo, Y.; Yang, H.; Huang, Z.; Tian, S.; Li, Q.; Du, C.; Chen, T.; Liu, Y.; Sun, H. and Liu, Z.; "Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer's Diseases". Molecules, 25(3):489, 2020.
[16] Dgachi, Y.; Bautista-Aguilera, O.M.; Benchekroun, M.; Martin, H.; Bonet, A.; Knez, D.; Godyń, J.; Malawska, B.; Gobec, S.; Chioua, M.; Janockova, J.; Soukup, O.; Chabchoub, F.; Marco-Contelles, J. and Ismaili, L.; "Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease". Molecules, 21(5):634, 2016.
[17] Nićiforović, N. and Abramovič, H.; "Sinapic Acid and Its Derivatives: Natural Sources and Bioactivity". Compr. Rev. Food Sci. Food Saf., 13(1):34-51, 2014.
[18] Saleh, A. and Mahmood, A.; "Docking Study for New 7-Aminocephalosporinic Acid Derivatives as Potential Inhibitors for β-Lactamases". Iraqi J. Pharm., 20: 23-32, 2023.
[19] Saleh, A.A. and Mahmood, A.A.J.; "New P-Aminodiphenylamine Amide Compounds: Design, Synthesis And Anti Β-Lactamases Activity Evaluation". Chem. Probl., 1(22), 20-32, 2024.
[20] Srivastava, K.A.; Verma, S. and Shubhra, S.; "Synthesis and Biological activity of some Novel Chalcone derivatives containing [1, 3, 4] oxadiazole-2(3H)-thione". Res. J. Recent Sci., 4: 74-79, 2015.
[21] Galge, R.; Raju, A. and Degani, M.S.; "Synthesis and In Vitro Antimicrobial Activity of 1,3,4-Oxadiazole-2-thiol and its Analogs". J. Heterocycl. Chem., 52(2), 352-357, 014.
[22] Mahmood, A.A.J. and Bahnam, S.P.; "Docking, synthesis and β-lactamase inhibitory activity evaluation for new amide compounds" Kimya Problemlеri, 22(2): 139-149, 2024.
[23] Mahmood, A.A.J.; "Synthesis, antimicrobial and antioxidant activities evaluation for new amide compounds". In: AIP Conference Proceedings, Proceedings of the 5th International Conference on Buildings, Construction and Environmental Engineering, Amman, Jordan, November 21–23, 2023; Fattah, M.Y., Al-Mukhtar, M., Al-Dahawai, A. and Al-Barrak, A., Eds.; AIP Publishing: Melville, NY, 2024.
[24] Mahmood, A.A.J.; Al-Iraqi, M.A. and Abachi, F.T.; "New 4,4'-Methylenedianiline Monobactame Compounds: Synthesis, Antioxidant and Antimicrobial Activities Evaluation". In: AIP Conference Proceedings, Proceedings of the 4th International Conference on Materials Engineering & Science, Duhok, Kurdistan Region, Iraq, October 6–7, 2021; Dahham, O.S., Ed.; AIP Publishing: Melville, NY, 2022.
[25] Mahmood A AJ. and Ahmed O. A.H. “In vitro Inhibition of Human Plasma and Erythrocyte Cholinesterases by a Selected Drugs (Enzymes Inhibitors)”. Tikrit J. of Pharm. Sci., 7(2): 12-19, 2011.
[26] Mahmood, A.A.J.; "In vitro inhibition of human blood cholinesterases and protection against chlorpyriphos (organophosphate) by weak anticholinesterase drugs". Iraqi J. Pharm., 11(1),18-29, 2011.
[27] [27] Mustafa, Y.F.; Mahmood, A.A.J. and Qasim, I.T.; "Synthesis of new metoclopramide derivatives and in vitro evaluation of their human cholinesterases protection against Chlorpyrifos". Iraqi J. Pharm., 11(2), 58-69, 2011.
[28] Ahmed, O.A. and Mohammad, F.K.; "A simplified eleclromelric technique for rapid measurement of human blood cholinesterase activity". Internet J. Toxicol., 2:55-58, 2005.
[29] Bahnam, S.; Jasim, M. and Mahmood, A.A.J.; "In silico study of new schiff base-and amide-boronic acid derivatives as potential inhibitors of β-lactamases". Indian Drugs, 9, 28, 37-48 2023.
[30] Artunç, T.; Cetinkaya, Y. and Menzek, A.; "Investigation of cholinesterase and α-glucosidase enzyme activities, and molecular docking and dft studies for 1,2-disubstituted cyclopentane derivatives with phenyl and benzyl units". Mol. Diversity, 29, 1305–1321, 2025.
[31] Mohammad, F.K.; Alias, A.S. and Ahmed, O.A.; "Electrometric measurement of plasma, erythrocyte and whole blood cholinesterase activities in healthy human volunteers". J. Med. Toxicol., 3:25-30, 2007.
[32] Bashir, M.; Oglah, M. and Mahmood, A.; "In silico study of nsaids conjugated with coumarins as new anti-inflammatory compounds". Indian Drugs, 61: 20-29, 2024.
[33] Ertl, P. and Schuffenhauer, A.; "Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions". J. Cheminform., 1(1):8, 2009.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Ahmed A. J. Mahmood
This work is licensed under a Creative Commons Attribution 4.0 International License.
.jpg)
