Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

Structurally Related Edaravone Analogues: Synthesis, Antiradical, Antioxidant, and Copper-Chelating Properties

Author(s): Alexandre LeBlanc, Miroslava Cuperlovic-Culf, Pier Jr. Morin and Mohamed Touaibia*

Volume 18, Issue 10, 2019

Page: [779 - 790] Pages: 12

DOI: 10.2174/1871527318666191114092007

Price: $65

Abstract

Background: The current therapeutic options available to patients diagnosed with Amyotrophic Lateral Sclerosis (ALS) are limited and edaravone is a compound that has gained significant interest for its therapeutic potential in this condition.

Objectives: The current work was thus undertaken to synthesize and characterize a series of edaravone analogues.

Methods: A total of 17 analogues were synthesized and characterized for their antioxidant properties, radical scavenging potential and copper-chelating capabilities.

Results: Radical scavenging and copper-chelating properties were notably observed for edaravone. Analogues bearing hydrogen in position 1 and a phenyl at position 3 and a phenyl in both positions of pyrazol-5 (4H)-one displayed substantial radical scavenging, antioxidants and copper-chelating properties. High accessibility of electronegative groups combined with higher electronegativity and partial charge of the carbonyl moiety in edaravone might explain the observed difference in the activity of edaravone relative to the closely related analogues 6 and 7 bearing hydrogen at position 1 and a phenyl at position 3 (6) and a phenyl in both positions (7).

Conclusion: Overall, this study reveals a subset of edaravone analogues with interesting properties. Further investigation of these compounds is foreseen in relevant models of oxidative stress-associated diseases in order to assess their therapeutic potential in such conditions.

Keywords: Amyotrophic lateral sclerosis, edaravone, antioxidant properties, radical scavenging abilities, copper-chelating assay.

Graphical Abstract
[1]
Sayre LM, Perry G, Smith MA. Oxidative stress and neurotoxicity. Chem Res Toxicol 2008; 21(1): 172-88.
[http://dx.doi.org/10.1021/tx700210j] [PMID: 18052107]
[2]
Rosini M, Simoni E, Milelli A, Minarini A, Melchiorre C. Oxidative stress in Alzheimer’s disease: Are we connecting the dots? J Med Chem 2014; 57(7): 2821-31.
[http://dx.doi.org/10.1021/jm400970m] [PMID: 24131448]
[3]
Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A. Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Aβ(1-42)-induced rat model of Alzheimer’s disease. Free Radic Res 2014; 48(2): 146-58.
[http://dx.doi.org/10.3109/10715762.2013.857018] [PMID: 24151909]
[4]
Fay DS, Fluet A, Johnson CJ, Link CD. In vivo aggregation of beta-amyloid peptide variants. J Neurochem 1998; 71(4): 1616-25.
[http://dx.doi.org/10.1046/j.1471-4159.1998.71041616.x] [PMID: 9751195]
[5]
Butterfield DA. β-Amyloid-associated free radical oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. Chem Res Toxicol 1997; 10(5): 495-506.
[http://dx.doi.org/10.1021/tx960130e] [PMID: 9168246]
[6]
Hensley K, Carney JM, Mattson MP, et al. A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: Relevance to Alzheimer disease. Proc Natl Acad Sci USA 1994; 91(8): 3270-4.
[http://dx.doi.org/10.1073/pnas.91.8.3270] [PMID: 8159737]
[7]
Yaribeygi H, Panahi Y, Javadi B, Sahebkar A. The underlying role of oxidative stress in neurodegeneration: A mechanistic review. CNS Neurol Disord Drug Targets 2018; 17(3): 207-15.
[http://dx.doi.org/10.2174/1871527317666180425122557] [PMID: 29692267]
[8]
Matsuda M, Shimomura I. Roles of adiponectin and oxidative stress in obesity-associated metabolic and cardiovascular diseases. Rev Endocr Metab Disord 2014; 15(1): 1-10.
[http://dx.doi.org/10.1007/s11154-013-9271-7] [PMID: 24026768]
[9]
Eren E, Ellidag HY, Cekin Y, Ayoglu RU, Sekercioglu AO, Yılmaz N. Heart valve disease: The role of calcidiol deficiency, elevated parathyroid hormone levels and oxidative stress in mitral and aortic valve insufficiency. Redox Rep 2014; 19(1): 34-9.
[http://dx.doi.org/10.1179/1351000213Y.0000000069] [PMID: 24192717]
[10]
Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347(9004): 781-6.
[http://dx.doi.org/10.1016/S0140-6736(96)90866-1] [PMID: 8622332]
[11]
Street DA, Comstock GW, Salkeld RM, Schüep W, Klag MJ. Serum antioxidants and myocardial infarction. Are low levels of carotenoids and alpha-tocopherol risk factors for myocardial infarction? Circulation 1994; 90(3): 1154-61.
[http://dx.doi.org/10.1161/01.CIR.90.3.1154] [PMID: 8087925]
[12]
Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992; 86(3): 803-11.
[http://dx.doi.org/10.1161/01.CIR.86.3.803] [PMID: 1516192]
[13]
Wang J, Li JZ, Lu AX, Zhang KF, Li BJ. Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho-p38 expression. Oncol Lett 2014; 7(4): 1159-64.
[http://dx.doi.org/10.3892/ol.2014.1863] [PMID: 24944685]
[14]
Granados-Principal S, El-Azem N, Pamplona R, et al. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem Pharmacol 2014; 90(1): 25-33.
[http://dx.doi.org/10.1016/j.bcp.2014.04.001] [PMID: 24727461]
[15]
Tekiner-Gulbas B, Westwell AD, Suzen S. Oxidative stress in carcinogenesis: New synthetic compounds with dual effects upon free radicals and cancer. Curr Med Chem 2013; 20(36): 4451-9.
[http://dx.doi.org/10.2174/09298673113203690142] [PMID: 23834180]
[16]
Knekt P, Reunanen A, Takkunen H, Aromaa A, Heliövaara M, Hakulinen T. Body iron stores and risk of cancer. Int J Cancer 1994; 56(3): 379-82.
[http://dx.doi.org/10.1002/ijc.2910560315] [PMID: 8314326]
[17]
Watanabe T, Yuki S, Egawa M, Nishi H. Protective effects of MCI-186 on cerebral ischemia: Possible involvement of free radical scavenging and antioxidant actions. J Pharmacol Exp Ther 1994; 268(3): 1597-604.
[PMID: 8138971]
[18]
Yoneda Y, Uehara T, Yamasaki H, Kita Y, Tabuchi M, Mori E. Hospital-based study of the care and cost of acute ischemic stroke in Japan. Stroke 2003; 34(3): 718-24.
[http://dx.doi.org/10.1161/01.STR.0000056171.55342.FF] [PMID: 12624297]
[19]
Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001; 344(22): 1688-700.
[http://dx.doi.org/10.1056/NEJM200105313442207] [PMID: 11386269]
[20]
Gurney ME, Fleck TJ, Himes CS, Hall ED. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 1998; 50(1): 62-6.
[http://dx.doi.org/10.1212/WNL.50.1.62] [PMID: 9443458]
[21]
Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2002; (2): CD001447
[http://dx.doi.org/10.1002/14651858.CD001447] [PMID: 12076411]
[22]
Chico L, Ienco EC, Bisordi C, et al. Amyotrophic lateral sclerosis and oxidative stress: A double-blind therapeutic trial after curcumin supplementation. CNS Neurol Disord Drug Targets 2018; 17(10): 767-79.
[http://dx.doi.org/10.2174/1871527317666180720162029] [PMID: 30033879]
[23]
Li L, Liu J, She H. Targeting macrophage for the treatment of amyotrophic lateral sclerosis. CNS Neurol Disord Drug Targets 2019; 18(5): 366-71.
[http://dx.doi.org/10.2174/1871527318666190409103831] [PMID: 30963986]
[24]
Caballero-Villarraso J, Galvan A, Escribano BM, Tunez I. Interrelationships among gut microbiota and host: paradigms, role in neurodegenerative diseases and future prospects. CNS Neurol Disord Drug Targets 2017; 16(8): 945-64.
[PMID: 28714393]
[25]
Watanabe T, Yuki S, Egawa M, Nishi H. Protective effects of MCI-186 on cerebral ischemia: Possible involvement of free radical scavenging and antioxidant actions. J Pharmacol Exp Ther 1994; 268(3): 1597-604.
[PMID: 8138971]
[26]
Ito H, Wate R, Zhang J, et al. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol 2008; 213(2): 448-55.
[http://dx.doi.org/10.1016/j.expneurol.2008.07.017] [PMID: 18718468]
[27]
Kamogawa E, Sueishi Y. A multiple free-radical scavenging (MULTIS) study on the antioxidant capacity of a neuroprotective drug, edaravone as compared with uric acid, glutathione, and trolox. Bioorg Med Chem Lett 2014; 24(5): 1376-9.
[http://dx.doi.org/10.1016/j.bmcl.2014.01.045] [PMID: 24507926]
[28]
Nakagawa H, Ohyama R, Kimata A, Suzuki T, Miyata N. Hydroxyl radical scavenging by edaravone derivatives: Efficient scavenging by 3-methyl-1-(pyridin-2-yl)-5-pyrazolone with an intramolecular base. Bioorg Med Chem Lett 2006; 16(23): 5939-42.
[http://dx.doi.org/10.1016/j.bmcl.2006.09.005] [PMID: 16997555]
[29]
Pérez-González A, Galano A. OH radical scavenging activity of Edaravone: mechanism and kinetics. J Phys Chem B 2011; 115(5): 1306-14.
[http://dx.doi.org/10.1021/jp110400t] [PMID: 21190324]
[30]
Yamamoto Y, Kuwahara T, Watanabe K, Watanabe K. Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Rep 1996; 2(5): 333-8.
[http://dx.doi.org/10.1080/13510002.1996.11747069] [PMID: 27406414]
[31]
Chegaev K, Cena C, Giorgis M, et al. Edaravone derivatives containing NO-donor functions. J Med Chem 2009; 52(2): 574-8.
[http://dx.doi.org/10.1021/jm8007008] [PMID: 19113954]
[32]
Zhang T, Li Z, Dong J, Nan F, Li T, Yu Q. Edaravone promotes functional recovery after mechanical peripheral nerve injury. Neural Regen Res 2014; 9(18): 1709-15.
[http://dx.doi.org/10.4103/1673-5374.141808] [PMID: 25374594]
[33]
Zhou S, Yu G, Chi L, et al. Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Neurotoxicology 2013; 38: 136-45.
[http://dx.doi.org/10.1016/j.neuro.2013.07.007] [PMID: 23932983]
[34]
Tokuda E, Ono S, Ishige K, et al. Ammonium tetrathiomolybdate delays onset, prolongs survival, and slows progression of disease in a mouse model for amyotrophic lateral sclerosis. Exp Neurol 2008; 213(1): 122-8.
[http://dx.doi.org/10.1016/j.expneurol.2008.05.011] [PMID: 18617166]
[35]
Doiron JA, Leblanc LM, Hébert MJ, et al. Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors. Chem Biol Drug Des 2017; 89(4): 514-28.
[http://dx.doi.org/10.1111/cbdd.12874] [PMID: 27717142]
[36]
Liégeois C, Lermusieau G, Collin S. Measuring antioxidant efficiency of wort, malt, and hops against the 2,2′-azobis(2-amidinopropane) dihydrochloride-induced oxidation of an aqueous dispersion of linoleic acid. J Agric Food Chem 2000; 48(4): 1129-34.
[http://dx.doi.org/10.1021/jf9911242] [PMID: 10775361]
[37]
Li X, Wang H, Lu Z, et al. Development of multifunctional pyrimidinylthiourea derivatives as potential anti-Alzheimer agents. J Med Chem 2016; 59(18): 8326-44.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00636] [PMID: 27552582]
[38]
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7: 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[39]
Wang LF, Zhang HY. A theoretical investigation on DPPH radical-scavenging mechanism of edaravone. Bioorg Med Chem Lett 2003; 13(21): 3789-92.
[http://dx.doi.org/10.1016/j.bmcl.2003.07.016] [PMID: 14552780]
[40]
Wan X, Luo MX, Jie C, Wu T, Yu GY, et al. Edaravone protects against vascular oxidative damage induced by AAPH in chick embryo. Int J Pharm Sci Dev Res 2016; 2(1): 019-22.
[http://dx.doi.org/10.17352/ijpsdr.000007]
[41]
Banci L, Bertini I, Ciofi-Baffoni S, Kozyreva T, Zovo K, Palumaa P. Affinity gradients drive copper to cellular destinations. Nature 2010; 465(7298): 645-8.
[http://dx.doi.org/10.1038/nature09018] [PMID: 20463663]
[42]
Tokuda E, Ono S, Ishige K, Naganuma A, Ito Y, Suzuki T. Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis. Toxicology 2007; 229(1-2): 33-41.
[http://dx.doi.org/10.1016/j.tox.2006.09.011] [PMID: 17097207]
[43]
Gilson MK, Gilson HSR, Potter MJ. Fast assignment of accurate partial atomic charges: an electronegativity equalization method that accounts for alternate resonance forms. J Chem Inf Comput Sci 2003; 43(6): 1982-97.
[http://dx.doi.org/10.1021/ci034148o] [PMID: 14632449]
[44]
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 2001; 46(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[45]
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45(12): 2615-23.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[46]
Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem 2011; 54(8): 2529-91.
[http://dx.doi.org/10.1021/jm1013693] [PMID: 21413808]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy