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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

新型苯并二甲吡唑杂合物用于阿尔茨海默氏病的合成及生物学评价

卷 16, 期 9, 2019

页: [815 - 820] 页: 6

弟呕挨: 10.2174/1567205016666191011112624

价格: $65

摘要

背景：阿尔茨海默氏病（AD）涉及许多因素，例如淀粉样蛋白斑块，神经原纤维缠结，胆碱能缺乏和氧化应激。为了应对这种疾病的复杂性，药物开发的新方法是创建一个能够同时作用于不同靶标的分子。 目的：我们构思了八种可能抑制胆碱酯酶和清除自由基的药物。 方法：我们通过Passerini多组分反应合成了新分子，并通过氧自由基吸收能力（ORAC）测定了它们对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制活性以及其抗氧化活性。还执行了利平斯基关于药物相似性和计算机模拟ADME预测的规则。 结果：化合物4f [IC 50（EeAChE）＝0.30μM； m / z（MH +）。 IC50（eqBuChE）= 0.09μM； ORAC = 0.64 TE]和4h [IC50（EeAChE）= 1μM； IC50（eqBuChE）= 0.03μM; ORAC = 0.50 TE]被确定为进一步开发的热门产品。 结论：Passerini反应使我们能够轻松合成感兴趣的双靶分子来治疗AD。

关键词: 阿尔茨海默氏病，抗氧化剂，胆碱酯酶，色酮，多奈哌齐，ORAC，Passerini反应。

« Previous Next »
[1]
Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science 314(5800): 777-81. (2006).
[http://dx.doi.org/10.1126/science.1132814] [PMID: 17082447]
[2]
Finder VH. Alzheimer’s disease: a general introduction and pathomechanism. J Alzheimers Dis 22(Suppl. 3): 5-19. (2010).
[http://dx.doi.org/10.3233/JAD-2010-100975] [PMID: 20858960]
[3]
Bush AI. Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15(2): 223-40. (2008).
[http://dx.doi.org/10.3233/JAD-2008-15208] [PMID: 18953111]
[4]
Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, et al. Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem 277(43): 40302-8. (2002).
[http://dx.doi.org/10.1074/jbc.M206428200] [PMID: 12192006]
[5]
Wilkinson D, Wirth Y, Goebel C. Memantine in patients with moderate to severe Alzheimer’s disease: meta-analyses using realistic definitions of response. Dement Geriatr Cogn Disord 37(1-2): 71-85. (2014).
[http://dx.doi.org/10.1159/000353801] [PMID: 24107324]
[6]
Perez DI, Martinez A, Gil C, Campillo NE. From biotopic inhibitors to multitarget drugs for the future treatment of Alzheimer’s disease. Curr Med Chem 22(33): 3789-806. (2015).
[PMID: 26264921]
[7]
Agis-Torres A, Sölhuber M, Fernández M, Sánchez-Montero JM. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for Alzheimer’s disease. Curr Neuropharmacol 12(1): 2-36. (2014).
[http://dx.doi.org/10.2174/1570159X113116660047] [PMID: 24533013]
[8]
Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 51(3): 347-72. (2008).
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[9]
León R, García AG, Marco-Contelles J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med Res Rev 33(1): 139-89. (2013).
[http://dx.doi.org/10.1002/med.20248] [PMID: 21793014]
[10]
Rosini M, Simoni E, Caporaso R, Minarini A. Multitarget strategies in Alzheimer’s disease: benefits and challenges on the road to therapeutics. Future Med Chem 8(6): 697-711. (2016).
[http://dx.doi.org/10.4155/fmc-2016-0003] [PMID: 27079260]
[11]
Ismaili L, Refouvelet B, Benchekroun M, Brogi S, Brindisi M, Gemma S, et al. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer’s disease. Prog Neurobiol 151: 4-34. (2017).
[http://dx.doi.org/10.1016/j.pneurobio.2015.12.003] [PMID: 26797191]
[12]
Sadowski M, Wisniewski T. Disease modifying approaches for Alzheimer’s pathology. Curr Pharm Des 13(19): 1943-54. (2007).
[http://dx.doi.org/10.2174/138161207781039788] [PMID: 17627527]
[13]
Bartolini M, Bertucci C, Cavrini V, Andrisano V. β-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol 65(3): 407-16. (2003).
[http://dx.doi.org/10.1016/S0006-2952(02)01514-9] [PMID: 12527333]
[14]
Greig NH, Utsuki T, Ingram DK, Wang Y, Pepeu G, Scali C, et al. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent. Proc Natl Acad Sci USA 102(47): 17213-8. (2005).
[http://dx.doi.org/10.1073/pnas.0508575102] [PMID: 16275899]
[15]
Benchekroun M, Romero A, Egea J, León R, Michalska P, Buendía I, et al. The Antioxidant additive approach for Alzheimer’s disease therapy: New ferulic (lipoic) acid plus melatonin modified tacrines as cholinesterases inhibitors, direct antioxidants, and nuclear factor (erythroid-derived 2)-like 2 activators. J Med Chem 59(21): 9967-73. (2016).
[http://dx.doi.org/10.1021/acs.jmedchem.6b01178] [PMID: 27736061]
[16]
Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, et al. Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 210: 340-52. (2012).
[http://dx.doi.org/10.1016/j.neuroscience.2012.02.046] [PMID: 22441036]
[17]
Kumar A, Singh A. Ekavali. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67(2): 195-203. (2015).
[http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID: 25712639]
[18]
Ismaili L, do Carmo Carreiras M. Multicomponent reactions for multitargeted compounds for Alzheimer’s disease. Curr Top Med Chem 17(31): 3319-27. (2017).
[http://dx.doi.org/10.2174/1568026618666180112155424] [PMID: 29332584]
[19]
Biggs-Houck JE, Younai A, Shaw JT. Recent advances in multicomponent reactions for diversity-oriented synthesis. Curr Opin Chem Biol 14(3): 371-82. (2010).
[http://dx.doi.org/10.1016/j.cbpa.2010.03.003] [PMID: 20392661]
[20]
Keri RS, Budagumpi S, Pai RK, Balakrishna RG. Chromones as a privileged scaffold in drug discovery: a review. Eur J Med Chem 78: 340-74. (2014).
[http://dx.doi.org/10.1016/j.ejmech.2014.03.047] [PMID: 24691058]
[21]
Dávalos A, Gómez-Cordovés C, Bartolomé B. Extending applicability of the oxygen radical absorbance capacity (ORAC-fluorescein) assay. J Agric Food Chem 52(1): 48-54. (2004).
[http://dx.doi.org/10.1021/jf0305231] [PMID: 14709012]
[22]
Dgachi Y, Bautista-Aguilera OM, Benchekroun M, et al. Synthesis and biological evaluation of benzochromenopyrimidinones as cholinesterase inhibitors and potent antioxidant, non-hepatotoxic agents for Alzheimer’s disease. Molecules 21(5): 634. (2016).
[http://dx.doi.org/10.3390/molecules21050634] [PMID: 27187348]
[23]
Decker M. Homobivalent quinazolinimines as novel nanomolar inhibitors of cholinesterases with dirigible selectivity toward butyrylcholinesterase. J Med Chem 49(18): 5411-3. (2006).
[http://dx.doi.org/10.1021/jm060682m] [PMID: 16942014]
[24]
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2): 88-95. (1961).
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[25]
Banfi L, Riva R. The Passerini reaction in organic reactions John Wiley & Sons, Inc. (2004).
[26]
Benchekroun M, Ismaili L, Pudlo M, Luzet V, Gharbi T, Refouvelet B, et al. Donepezil-ferulic acid hybrids as anti-Alzheimer drugs. Future Med Chem 7(1): 15-21. (2015).
[http://dx.doi.org/10.4155/fmc.14.148] [PMID: 25582330]
[27]
Contreras JM, Rival YM, Chayer S, Bourguignon JJ, Wermuth CG. Aminopyridazines as acetylcholinesterase inhibitors. J Med Chem 42(4): 730-41. (1999).
[http://dx.doi.org/10.1021/jm981101z] [PMID: 10052979]
[28]
Benchekroun M, Bartolini M, Egea J, Romero A, Soriano E, Pudlo M, et al. Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids. ChemMedChem 10(3): 523-39. (2015).
[http://dx.doi.org/10.1002/cmdc.201402409] [PMID: 25537267]
[29]
Fang L, Kraus B, Lehmann J, Heilmann J, Zhang Y, Decker M. Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates. Bioorg Med Chem Lett 18(9): 2905-9. (2008).
[http://dx.doi.org/10.1016/j.bmcl.2008.03.073] [PMID: 18406135]
[30]
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1-3): 3-26. (2001).
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]

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