A Series of New Hydrazone Derivatives: Synthesis, Molecular Docking and Anticholinesterase Activity Studies

Author(s): İrem Bozbey*, Zeynep Özdemir, Harun Uslu, Azime Berna Özçelik, Fatma Sezer Şenol, İlkay Erdoğan Orhan, Mehtap Uysal

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 11 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder.

Objective: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach.

Methods: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman’s method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software.

Results: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 μM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 μM).

Conclusion: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.

Keywords: Alzheimer's disease, AChE inhibitor, BChE inhibitor, 3(2H)-Pyridazinone, hydrazone, molecular docking.

[1]
Brookmeyer, R.; Abdalla, N.; Kawas, C.H.; Corrada, M.M. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement., 2018, 14(2), 121-129.
[http://dx.doi.org/10.1016/j.jalz.2017.10.009] [PMID: 29233480]
[2]
Ballard, C.; Gauthier, S.; Corbett, A.; Brayne, C.; Aarsland, D.; Jones, E. Alzheimer’s disease. Lancet, 2011, 377(9770), 1019-1031.
[http://dx.doi.org/10.1016/S0140-6736(10)61349-9] [PMID: 21371747]
[3]
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[4]
Mehta, M.; Adem, A.; Sabbagh, M. New acetylcholinesterase inhibitors for Alzheimer’s disease. Int. J. Alzheimers Dis., 2012, 2012728983
[http://dx.doi.org/10.1155/2012/728983] [PMID: 22216416]
[5]
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36(4), 375-399.
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[6]
Li, B.; Duysen, E.G.; Carlson, M.; Lockridge, O. The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency. J. Pharmacol. Exp. Ther., 2008, 324(3), 1146-1154.
[http://dx.doi.org/10.1124/jpet.107.133330] [PMID: 18056867]
[7]
Begum, S.; Nizami, S.S.; Mahmood, U.; Masood, S.; Iftikhar, S.; Saied, S. In-vitro evaluation and in-silico studies applied on newly synthesized amide derivatives of N-phthaloylglycine as Butyrylcholinesterase (BChE) inhibitors. Comput. Biol. Chem., 2018, 74, 212-217.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.04.003] [PMID: 29653432]
[8]
Lu, X.; He, S.Y.; Li, Q.; Yang, H.; Jiang, X.; Lin, H.; Chen, Y.; Qu, W.; Feng, F.; Bian, Y.; Zhou, Y.; Sun, H. Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer’s disease. Bioorg. Med. Chem., 2018, 26(8), 1665-1674.
[http://dx.doi.org/10.1016/j.bmc.2018.02.014] [PMID: 29475581]
[9]
Xing, W.; Fu, Y.; Shi, Z.; Lu, D.; Zhang, H.; Hu, Y. Discovery of novel 2,6-disubstituted pyridazinone derivatives as acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2013, 63, 95-103.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.056] [PMID: 23466605]
[10]
Jia, P.; Sheng, R.; Zhang, J.; Fang, L.; He, Q.; Yang, B.; Hu, Y. Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitors. Eur. J. Med. Chem., 2009, 44(2), 772-784.
[http://dx.doi.org/10.1016/j.ejmech.2008.04.018] [PMID: 18550228]
[11]
Alonso, D.; Dorronsoro, I.; Rubio, L.; Muñoz, P.; García-Palomero, E.; Del Monte, M.; Bidon-Chanal, A.; Orozco, M.; Luque, F.J.; Castro, A.; Medina, M.; Martínez, A. Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg. Med. Chem., 2005, 13(24), 6588-6597.
[http://dx.doi.org/10.1016/j.bmc.2005.09.029] [PMID: 16230018]
[12]
Sameem, B.; Saeedi, M.; Mahdavi, M.; Shafiee, A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem., 2017, 128(10), 332-345.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.060] [PMID: 27876467]
[13]
Ohta, Y.; Darwish, M.; Hishikawa, N.; Yamashita, T.; Sato, K.; Takemoto, M.; Abe, K. Therapeutic effects of drug switching between acetylcholinesterase inhibitors in patients with Alzheimer’s disease. Geriatr. Gerontol. Int., 2017, 17(11), 1843-1848.
[http://dx.doi.org/10.1111/ggi.12971] [PMID: 28060449]
[14]
Chiu, P.Y.; Wei, C.Y. Donepezil in the one-year treatment of dementia with Lewy bodies and Alzheimer’s disease. J. Neurol. Sci., 2017, 381(Supp. 322)
[http://dx.doi.org/10.1016/j.jns.2017.08.913]
[15]
Chiou, S.Y.; Huang, C.F.; Hwang, M.T.; Lin, G. Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene-di-N-substituted carbamates. J. Biochem. Mol. Toxicol., 2009, 23(5), 303-308.
[http://dx.doi.org/10.1002/jbt.20286] [PMID: 19827033]
[16]
Cui, Z.; Yang, X.; Shi, Y.; Uzawa, H.; Cui, J.; Dohi, H.; Nishida, Y.; Nishida, Y. Molecular design, synthesis and bioactivity of glycosyl hydrazine and hydrazone derivatives: notable effects of the sugar moiety. Bioorg. Med. Chem. Lett., 2011, 21(23), 7193-7196.
[http://dx.doi.org/10.1016/j.bmcl.2011.09.068] [PMID: 22004723]
[17]
Küçükgüzel, Ş.G.; Mazi, A.; Sahin, F.; Oztürk, S.; Stables, J. Synthesis and biological activities of diflunisal hydrazide-hydrazones. Eur. J. Med. Chem., 2003, 38(11-12), 1005-1013.
[http://dx.doi.org/10.1016/j.ejmech.2003.08.004] [PMID: 14642333]
[18]
Masunari, A.; Tavares, L.C. A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus. Bioorg. Med. Chem., 2007, 15(12), 4229-4236.
[http://dx.doi.org/10.1016/j.bmc.2007.03.068] [PMID: 17419064]
[19]
Bernhardt, P.V.; Wilson, G.J.; Sharpe, P.C.; Kalinowski, D.S.; Richardson, D.R. Tuning the antiproliferative activity of biologically active iron chelators: characterization of the coordination chemistry and biological efficacy of 2-acetylpyridine and 2-benzoylpyridine hydrazone ligands. J. Biol. Inorg. Chem., 2008, 13(1), 107-119.
[http://dx.doi.org/10.1007/s00775-007-0300-4] [PMID: 17899222]
[20]
Salgin-Gökşen, U.; Gökhan-Kelekçi, N.; Göktaş, O.; Köysal, Y.; Kiliç, E.; Işik, S.; Aktay, G.; Özalp, M. 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities. Bioorg. Med. Chem., 2007, 15(17), 5738-5751.
[http://dx.doi.org/10.1016/j.bmc.2007.06.006] [PMID: 17587585]
[21]
Cunha, A.C.; Figueiredo, J.M.; Tributino, J.L.M.; Miranda, A.L.P.; Castro, H.C.; Zingali, R.B.; Fraga, C.A.M.; de Souza, M.C.; Ferreira, V.F.; Barreiro, E.J. Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives. Bioorg. Med. Chem., 2003, 11(9), 2051-2059.
[http://dx.doi.org/10.1016/S0968-0896(03)00055-5] [PMID: 12670656]
[22]
Gürsoy, A.; Karali, N. Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mercaptoacetyl]-hydrazono]-1H-2-indolinones. Eur. J. Med. Chem., 2003, 38(6), 633-643.
[http://dx.doi.org/10.1016/S0223-5234(03)00085-0] [PMID: 12832136]
[23]
Özdemir, Z.; Yılmaz, H.; Sarı, S.; Karakurt, A.; Şenol, F.S.; Uysal, M. Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholi-nesterase inhibitors. Med. Chem. Res., 2017, 26, 2293-2308.
[http://dx.doi.org/10.1007/s00044-017-1930-x]
[24]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[25]
Rama, K.; Sumakanth, M.; Anupama, S.P. Synthesis and docking studies of novel series of 7-(o-triazolo pyridazin-3yl)-4-methyl coumarins. J. Chem. Pharm. Res., 2016, 8(4), 1125-1135.
[26]
Curran, W.V.; Ross, A. 6-Phenyl-4,5-dihydro-3(2H)-pyridazinones. A series of hypotensive agents. J. Med. Chem., 1974, 17(3), 273-281.
[http://dx.doi.org/10.1021/jm00249a004] [PMID: 4204335]
[27]
Dorsch, D.; Stieber, F.; Stiryakichadt, O.; Blaukat, A. Pyridazinone derivatives as Met kinase inhibitors and their preparation and use in the treatment of cancer; Merck Patent G.m.b.H: Germany, 2008.
[28]
Tiryaki, D.; Şüküroğlu, M.; Doğruer, D.S.; Akkol, E.; Özgen, S.; Şahin, M.F. Synthesis of some new 2,6-disubstituted-3(2H)-pyridazinone derivatives and investigation of their analgesic, anti-inflammatory and antimicrobial activities. Med. Chem. Res., 2013, 22, 2553-2560.
[http://dx.doi.org/10.1007/s00044-012-0253-1]
[29]
Utku, S.; Gökçe, M.; Aslan, G.; Bayram, G.; Ülger, M.; Emekdaş, G.; Şahin, M.F. Synthesis and in vitro antimycobacterial activities ofnovel 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/ nonsubstituted acetophenone)hydrazine. Turk. J. Chem., 2011, 35, 331-339.
[30]
Şahin, M.F.; Badıçoglu, B.; Gökçe, M.; Küpeli, E.; Yesilada, E. Synthesis and analgesic and antiinflammatory activity of methyl [6-substitue-3(2H)-pyridazinone-2-yl]acetate derivatives. Arch. Pharm. (Weinheim), 2004, 33, 445-452.
[http://dx.doi.org/10.1002/ardp.200400896]
[31]
Orhan, I.; Aslan, S.; Kartal, M.; Şener, B.; Hüsnü Can Başer, K. Inhibitory effect of Turkish Rosmarinus officinalis L. on acetylcholinesterase and butyrylcholinesterase enzymes. Food Chem., 2008, 108(2), 663-668.
[http://dx.doi.org/10.1016/j.foodchem.2007.11.023] [PMID: 26059146]
[32]
Schmidt, M.W.; Baldridge, K.K.; Boatz, J.A.; Elbert, S.T.; Gordon, M.S.; Jensen, J.H.; Koseki, S.; Matsunaga, N.; Nguyen, K.A.; Su, S.J.; Windus, T.L.; Dupuis, M.; Montgomery, J.A. Using specific methods included in GAMESS may require citing additional articles, as described in the manual. J. Comput. Chem., 1993, 14, 1347-1363.
[http://dx.doi.org/10.1002/jcc.540141112]
[33]
Sanner, M.F. Python: a programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[PMID: 10660911]
[34]
Budhlakoti, P.; Kumar, Y.; Verma, A.; Alok, S. Synthesis, antibacterial activity and molecular properties prediction of some pyridazin-3-one derivatives. Int. J. Pharm. Sci. Res., 2013, 4(4), 1524-1528.
[35]
Zare, L.; Mahmoodi, N.O.; Yahyazadeh, A.; Nikpassand, M. Ultrasound-promoted regio and chemoselective synthesis of pyridazinones and phthalazinones catalyzed by ionic liquid [bmim]Br/AlCl3. Ultrason. Sonochem., 2012, 19(4), 740-744.
[http://dx.doi.org/10.1016/j.ultsonch.2011.11.008] [PMID: 22306425]
[36]
Schmidt, P.; Druey, J. Heilmittelchemische Studien in der heterocyclischen Reihe. 10. Mitteilung. Pyridazine VII. Zur neuen Pyridazin-Synthese. Methylpyridazine. Helv. Chim. Acta, 1954, 37(5), 1467-1471.
[http://dx.doi.org/10.1002/hlca.19540370514]
[37]
Katritzky, A.R.; Boulton, A.J. Advances in Heterocyclic Chemistry, 9th ed; Academic Press: New York, London, Academic Press, 1968.
[38]
Baytaş, S.; İnceler, N.; Mavaneh, K.F.; Uludağ, M.O.; Abacıoğlu, N.; Gökçe, M. Synthesis of antipyrine/pyridazinone hybrids and investigation of their in vivo analgesic and anti-inflammatory activities. Turk. J. Chem., 2012, 36, 734-748.
[39]
Lapinski, L.; Nowak, M.J.; Fulara, J.; Les´, A.; Adamowicz, L. Relation between structure and tautomerism in diazinones and diazinethlones. An experimental matrix isolation and theoretical ab initio study. J. Phys. Chem., 1992, 96, 6250-6254.
[http://dx.doi.org/10.1021/j100194a030]
[40]
Katritzky, A.R.; Lagowski, J.M. Adv, 1st ed; Heterocycl.Chem, 1963.
[41]
Cheung, J.; Rudolph, M.J.; Burshteyn, F.; Cassidy, M.S.; Gary, E.N.; Love, J.; Franklin, M.C.; Height, J.J. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem., 2012, 55(22), 10282-10286.
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[42]
Nachon, F.; Carletti, E.; Ronco, C.; Trovaslet, M.; Nicolet, Y.; Jean, L.; 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. Biochem. J., 2013, 453(3), 393-399.
[http://dx.doi.org/10.1042/BJ20130013] [PMID: 23679855]
[43]
Release, S. 2017-4, Maestro; Schrödinger, LLC: New York, NY, 2017.
[44]
Ozçelik, A.B.; Gökçe, M.; Orhan, I.; Kaynak, F.; Şahin, M.F. Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory activities of novel ester and hydrazide derivatives of 3(2H)-pyridazinone. Arzneimittelforschung, 2010, 60(7), 452-458.
[PMID: 20712136]
[45]
Goodman-Gilman, A.; Hardman, J.G.; Limbird, L.E. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed; , 1996. pages: 105 - 106, 161-163, 171.
[46]
Heo, H.J.; Kim, M.J.; Lee, J.M.; Choi, S.J.; Cho, H.Y.; Hong, B.; Kim, H.K.; Kim, E.; Shin, D.H. Naringenin from Citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia. Dement. Geriatr. Cogn. Disord., 2004, 17(3), 151-157.
[http://dx.doi.org/10.1159/000076349] [PMID: 14739537]
[47]
Orhan, I.E.; Jedrejek, D.; Şenol, F.S.; Salmas, R.E.; Durdaği, S.; Kowalska, I.; Pecio, L.; Oleszek, W. Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives. Phytomedicine, 2018, 42(42), 25-33.
[http://dx.doi.org/10.1016/j.phymed.2018.03.009] [PMID: 29655693]
[48]
Zhou, Y.; Wang, S.; Zhang, Y. Catalytic reaction mechanism of acetylcholinesterase determined by Born-Oppenheimer ab initio QM/MM molecular dynamics simulations. J. Phys. Chem. B, 2010, 114(26), 8817-8825.
[http://dx.doi.org/10.1021/jp104258d] [PMID: 20550161]
[49]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutodockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 16, 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 11
Year: 2020
Published on: 17 July, 2020
Page: [1042 - 1060]
Pages: 19
DOI: 10.2174/1389557519666191010154444
Price: $65

Article Metrics

PDF: 25
HTML: 2