Synthesis and Cholinesterase Inhibitory Potentials of (5-formylfuran-2-yl) methyl 3,4-dimethoxy/nitro benzoates

Öz

Cholinesterase (ChE) inhibitors are an important group of drugs used in Alzheimer's, glaucoma, and myasthenia gravis. In recent years, cholinesterase inhibition potentials of compounds have been investigated in new drug discovery studies. In this study (5-formylfuran-2-yl) methyl 4-nitro benzoate (compound 1) and newly designed (5-formylfuran-2-yl) methyl 3,4-dimethoxybenzoate (compound 2) were synthesized. The chemical structures of the synthesized compounds were characterized by spectral data (HRMS, 1H NMR, and 13C NMR). The ChE inhibitory activity of the compounds was evaluated using in vitro colorimetric Ellman method. Compound 1 and compound 2 exhibited inhibitory activity against AChE at IC50 values of 3.25 μM and 8.45 μM, respectively. Compound 1 and Compound 2 showed inhibitory activity against BuChE at IC50 values of 8.45 μM and 14.44 μM, respectively. In Docking simulations with 1EVE and 1P0I, the binding free energy scores of compound 1 were higher than the binding free energy scores of compound 2. In this respect, in silico molecular docking studies overlapped with in vitro enzyme inhibition studies. These derivatives can be used to develop new drugs such as cholinesterase inhibitors.

Anahtar Kelimeler

• Benzoate
• cholinesterase
• inhibition
• molecular docking
• synthesis

Kaynakça

1. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R, 2015, Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada. PloS one, 10(12): e0144337–e0144337.
2. Bajda M, Wieckowska A, Hebda M, Szałaj N, Sotriffer C, Malawska B, 2013, Structure-Based Search for New Inhibitors of Cholinesterases. International journal of molecular sciences, 14: 5608–5632.
3. Bourne Y, Taylor P, Radić Z, Marchot P, 2003, Structural Insights into Ligand Interactions at The Acetylcholinesterase Peripheral Anionic Site. The EMBO journal, 22(1): 1–12.
4. Carotti A, de Candia M, Catto M, Borisova TN, Varlamov A V, Méndez-Álvarez E, Soto-Otero R, Voskressensky LG, Altomare C, 2006, Ester Derivatives of Annulated Tetrahydroazocines: A New Class of Selective Acetylcholinesterase Inhibitors. Bioorganic & Medicinal Chemistry, 14(21): 7205–7212.
5. Chen Z-R, Huang J-B, Yang S-L, Hong F-F, 2022, Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules, 27(6): 1816–1836.
6. Colletier J-P, Fournier D, Greenblatt HM, Stojan J, Sussman JL, Zaccai G, Silman I, Weik M, 2006, Structural Insights into Substrate Traffic and Inhibition in Acetylcholinesterase. The EMBO Journal, 25(12): 2746–2756.
7. Contestabile A, 2011, The History of The Cholinergic Hypothesis. Behavioural Brain Research, 221(2): 334–340.
8. Dhorajiwala TM, Halder ST, Samant L, 2019, Comparative In Silico Molecular Docking Analysis of L-Threonine-3-Dehydrogenase, a Protein Target Against African Trypanosomiasis Using Selected Phytochemicals. Journal of Applied Biotechnology Reports, 6(3): 101–108.

9. Ding Z, Luo X, Ma Y, Chen H, Qiu S, Sun G, Zhang W, Yu C, Wu Z, Zhang J, 2018, Eco-Friendly Synthesis of 5-Hydroxymethylfurfural (HMF) and Its Application to The Ferrier-Rearrangement Reaction. Journal of Carbohydrate Chemistry, 37: 1–13.
10. Ellman GL, Courtney KD, Andres V, Featherstone RM, 1961, A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity. Biochemical Pharmacology, 7(2): 88–95.
11. Giacobini E, 2003, Cholinergic Function and Alzheimer’s Disease. International Journal of Geriatric Psychiatry, 18(S1): S1–S5.
12. Ha YZ, Mathew S, Yeong YK, 2020, Butyrylcholinesterase: A Multifaceted Pharmacological Target and Tool. Current Protein & Peptide Science, 21(1): 99–109.
13. Johnson G, Moore WS, 2006, The Peripheral Anionic Site of Acetylcholinesterase: Structure, Functions and Potential Role in Rational Drug Design. Current Pharmaceutical Design, 12(2): 217–225.
14. Karran E, De Strooper B, 2022, The Amyloid Hypothesis in Alzheimer Disease: New Insights from New Therapeutics. Nature Reviews Drug Discovery, 21: 306–318.
15. Klinkenberg I, Sambeth A, Blokland A, 2011, Acetylcholine and Attention. Behavioural Brain Research, 221(2): 430–442.
16. Koca M, Bilginer S, 2022, New Benzamide Derivatives and their Nicotinamide/Cinnamamide Analogs as Cholinesterase Inhibitors. Molecular Diversity, 26(2): 1201–1212.
17. Koca M, Yerdelen K, ANIL B, Kasap Z, 2015, Microwave-Assisted Synthesis, Molecular Docking, and Cholinesterase Inhibitory Activities of New Ethanediamide and 2-Butenediamide Analogues. Chemical & pharmaceutical bulletin, 63: 210–217.
18. Krátký M, Štěpánková Š, Vorčáková K, Vinšová J, 2016, Synthesis And In Vitro Evaluation of Novel Rhodanine Derivatives as Potential Cholinesterase Inhibitors. Bioorganic Chemistry, 68: 23–29.
19. Krygowski TM, Stȩpień BT, 2005, Sigma- and Pi-Electron Delocalization: Focus on Substituent Effects. Chemical Reviews, 105(10): 3482–3512.
20. Lineweaver H, Burk D, 1934, The Determination of Enzyme Dissociation Constants. Journal of the American Chemical Society, 56(3): 658–666.
21. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ, 2009, AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry, 30(16): 2785–2791.
22. Muir JL, 1997, Acetylcholine, Aging, and Alzheimer’s Disease. Pharmacology Biochemistry and Behavior, 56(4): 687–696.
23. Osmaniye D, Evren AE, Sağlık BN, Levent S, Özkay Y, Kaplancıklı ZA, 2022, Design, Synthesis, Biological Activity, Molecular Docking, and Molecular Dynamics of Novel Benzimidazole Derivatives as Potential Ache/MAO-B Dual Inhibitors. Archiv der Pharmazie, 355(3): 2100450.
24. Özbey F, Taslimi P, Gülçin İ, Maraş A, Göksu S, Supuran CT, 2016, Synthesis Of Diaryl Ethers with Acetylcholinesterase, Butyrylcholinesterase and Carbonic Anhydrase Inhibitory Actions. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(sup2): 79–85.
25. Sharma K, 2019, Cholinesterase Inhibitors as Alzheimer’s Therapeutics. Mol Med Rep, 20(2): 1479–1487.
26. Silman I, Sussman JL, 2008, Acetylcholinesterase: How is Structure Related to Function? Chemico-Biological Interactions, 175(1): 3–10.
27. Sugimoto H, Yamanish Y, Iimura Y, Kawakami Y, 2012, Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors. Current Medicinal Chemistry, 7(3): 303–339.
28. Szwajgier D, 2013, Anticholinesterase Activity of Phenolic Acids and their Derivatives. Zeitschrift für Naturforschung C, 68(3–4): 125–132.
29. Tecalco–Cruz AC, Pedraza-Chaverri J, Briones-Herrera A, Cruz-Ramos E, López–Canovas L, Zepeda–Cervantes J, 2022, Protein Degradation-Associated Mechanisms that are Affected in Alzheimer´s Disease. Molecular and Cellular Biochemistry, 477(3): 915–925. Uğur Güller, Pınar Güller MÇ, 2021, Radical Scavenging and Antiacetylcholinesterase Activities of Ethanolic Extracts of Carob, Clove, and Linden. Altern Ther Health Med, 27(5): 33–37.
30. Xing S, Li Q, Xiong B, Chen Y, Feng F, Liu W, Sun H, 2021, Structure and Therapeutic Uses of Butyrylcholinesterase: Application in Detoxification, Alzheimer’s Disease, and Fat Metabolism. Medicinal Research Reviews, 41(2): 858–901.
31. Yılmaz S, Akbaba Y, Özgeriş B, Köse LP, Göksu S, Gülçin İ, Alwasel SH, Supuran CT, 2016, Synthesis And Inhibitory Properties of Some Carbamates on Carbonic Anhydrase and Acetylcholine Esterase. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(6): 1484–1491.
32. Zhou S, Huang G, 2022, The Biological Activities of Butyrylcholinesterase Inhibitors. Biomedicine & Pharmacotherapy, 146: 112556–112566.
33. Zhou Y, Wang S, Zhang Y, 2010, Catalytic Reaction Mechanism of Acetylcholinesterase Determined by Born−Oppenheimer Ab Initio QM/MM Molecular Dynamics Simulations. The Journal of Physical Chemistry B, 114(26): 8817–8825.