Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

Author(s): Ralph C. Gomes, Renata P. Sakata*, Wanda P. Almeida*, Fernando Coelho*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 4 , 2019

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Abstract:

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease.

Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase.

Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS).

Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

Keywords: Alzheimer disease, morita-baylis-hillman, spirocyclohexadienones, heterocycles, acetylcholinesterase, inhibitors.

[1]
Graham, W.V.; Bonito-Oliva, A.; Sakmar, J.P. Update on Alzheimer’s disease therapy and prevention strategies. Annu. Rev. Med., 2017, 68, 413-430.
[2]
Schettens, P.; Blennov, K.; Breteler, M.M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alhzeimer’s disease. Lancet, 2016, 388, 505-517.
[3]
Masters, C.L.; Bateman, R.; Blennow, K.; Rove, C.C.; Sperling, R.A.; Cummings, J.L. Alzheimer’s disease. Nat. Rev. Dis. Primers., 2015, 1, 1-18. (article number 15056).
[4]
Contestabile, A. The history of the cholinergic hypothesis. Behav. Brain Res., 2011, 221, 334-340.
[5]
Craig, L.A.; Hong, N.S.; McDonald, R.J. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci. Biobehav. Rev., 2011, 35, 1397-1409.
[6]
Terry, Jr, P.T.; Buccafusco, J.J. The cholinergic hypothesis pf age and Alzheimer’s disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther., 2003, 306, 821-827.
[7]
Francis, P.T.; Palmer, A.M.; Snape, M.; Wilcock, G.K. The Colinergic hypothesis of Alhzeimer’s disease: A review progress. J. Neurol. Neurosurg. Psychiatry, 1999, 66, 137-147.
[8]
Čolović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.S.; Vasić, V.M. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr. Neuropharmacol., 2013, 11, 315-335.
[9]
Takeda, A.; Loveman, E.; Clegg, A.; Kirby, J.; Picot, J.; Payne, E.; Green, C. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer’s disease. Int. J. Geriatr. Psychiatry, 2006, 21, 17-28.
[10]
Nhan, H.S.; Chiang, K.; Koo, E.K.H. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol., 2015, 129, 1-19.
[11]
Cacquevel, M.; Aeschbach, L.; Houacine, J.; Fraering, P.C. Alzheimer’s disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified γ-secretase complexes. PLoS One, 2012, 7, e35133.
[12]
Ahmed, M.; Davis, J.; Aucoin, D.; Sato, T.; Ahuja, S.; Aimoto, S.; Elliott, J.I.; Van Nostrand, W.E.; Smith, S.O. Structural conversion of neurotoxic amyloid (1–42) oligomers to fibrils. Nat. Struct. Mol. Biol., 2010, 17, 561-567.
[13]
Dickerson, T.J.; Beuscher, A.E.; Hixon, M.S.; Yamamoto, N.; Xu, Y.; Olson, A.J.; Janda, K.D. Discovery of acetylcholinesterase peripheral anionic site ligands through computational refinement of a directed library. Biochemistry, 2005, 44, 14845-14853.
[14]
Bourne, Y.; Radic, Z.; Kolb, H.C.; Sharpless, K.B.; Taylor, P.; Marchot, P. Structural insights into conformational flexibility at the peripheral site and within the active center gorge of AChE. Chem. Biol. Interact., 2005, 157, 159-165.
[15]
Yang, Y.L.; Chang, F.R.; Wu, Y.C. Annosqualine: A novel alkaloid from the stems of Annona squamosa. Helv. Chim. Acta, 2004, 87, 1392-1399.
[16]
Yeh, L-A.; Chen, J.; Baculi, F.; Gingrich, D.E.; Shen, T.Y. Inhibition of metalloproteinase by futoenone derivatives. Bioorg. Med. Chem. Lett., 1995, 5, 1637-1642.
[17]
Chen, D.F.; Zhang, S-X.; Kozuka, M.; Sun, Q-Z.; Feng, J.; Wang, Q.; Mukainaka, T.; Nobukuni, Y.; Tokuda, H.; Nishino, H.; Wang, H-K.; Morris-Natschke, S.L.; Lee, K-H. Interiotherins C and D, two new lignans from Kadsura interior and Antitumor-promoting effects of related Neolignans on Epstein−Barr virus activation. J. Nat. Prod., 2002, 65, 1242-1245.
[18]
Honda, T.; Shigehisa, H. Novel and efficient synthetic path to Proaporphine alkaloids: Total synthesis of (±)-Stepharine and (±)-Pronuciferine. Org. Lett., 2006, 8, 657-659.
[19]
Traoré, M.; Ahmed, A.S.; Peuchmaur, M.; Wong, Y.S. Hypervalent iodine (III)-mediated tandem oxidative reactions: Application for the synthesis of bioactive polyspirocyclohexa-2,5-dienones. Tetrahedron, 2010, 66, 5863-5872.
[20]
Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success. J. Med. Chem., 2009, 52, 6752-6756.
[21]
Lovering, F. Escape from flatland 2: Complexity and promiscuity. MedChemComm, 2013, 4, 515-519.
[22]
Zheng, Y.; Tice, C.M.; Singh, S.B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett., 2014, 24, 3673-3682.
[23]
Marson, C. New and unusual scaffolds in medicinal chemistry. Chem. Soc. Rev., 2011, 40, 5514-5533.
[24]
Molvi, K.I.; Haque, N.; Awen, B.Z.S.; Zameeruddin, M. Synthesis of Spiro compounds as medicinal agents; new opportunities for drug design and discovery. part I: A review. World J. Pharm. Pharmaceut. Sci., 2014, 3, 536-563.
[25]
Almansour, A.I.; Kumar, R.S.; Arumugam, N.; Basiri, A.; Kia, Y.; Ali, M.A.; Farooq, M.; Murugaiyah, V. A facile ionic liquid promoted synthesis, Cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized Spiropyrrolidines. Molecules, 2015, 20, 2296-2309.
[26]
Ahsraf, A.M.; Ismail, R.; Choon, T.S.; Kumar, R.S.; Osman, H.; Arumugam, N.; Almansour, A.I.; Elumalai, K.; Singh, A. AChE inhibitor: A regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro [5.3′]-oxindole-spiro- [6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c] [1,3] thiazole. Bioorg. Med. Chem. Lett., 2012, 22(1), 508-511.
[27]
Kia, Y.; Osman, H.; Suresh, K.R.; Basiri, A.; Murugaiyah, V. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(7), 1815-1819.
[28]
Ito, Y.; Takuma, K.; Mizoguchi, H.; Nagai, T.; Yamada, K. A novel Azaindolizinone derivative ZSET1446 (Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves Methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2. J. Pharmacol. Exp. Ther., 2007, 320, 819-827.
[29]
Efremov, I.V.; Vajdos, F.F.; Borzilleri, K.A.; Capetta, S.; Chen, H.; Dorff, P.H.; Dutra, J.K.; Goldstein, S.W.; Mansour, M.; McColl, A.; Noell, S.; Oborski, C.E.; O’Connell, J.N.; O’Sullivan, T.J.; Pandit, J.; Wang, H.; Wei, B-Q.; Withka, J.M. Discovery and optimization of a novel Spiropyrrolidine inhibitor of b-Secretase (BACE1) through fragment-based drug design. J. Med. Chem., 2012, 55, 9069-9088.
[30]
Martins, L.J.; Ferreira, B.R.V.; Almeida, W.P.; Coelho, F. An easy access to halogenated and non-halogenated spiro-hexadienones. Tetrahedron Lett., 2014, 55, 5264-5267.
[31]
Ellman, G.L. Tissue sulphydryl groups. Arch. Biochem. Biophys., 1959, 82, 70-77.
[32]
Brand-Williams, W.; Cuvelier, M.E.; Berset, C. Use of a free radical method to evaluate antioxidant activity. LWT-Food Sci.Technol, 1995, 28, 25-30.
[33]
Nimse, S.B.; Pal, D. Free radicals, natural antioxidants and their reaction mechanisms. RSC Advances, 2015, 5, 27986-28006.
[34]
Trott, O.; Olson, A. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[35]
Gaussian 09, Revision D.01, Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A.; Peralta Jr, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, Ö.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian, Inc., Wallingford CT 2009.
[36]
Coelho, F.; Almeida, W.P.; Veronese, D.; Mateus, C.R.; Lopes, E.C.S.; Rossi, R.C.; Silveira, G.P.C.; Pavam, C.H. Ultrasound in Baylis–Hillman reactions with aliphatic and aromatic aldehydes: scope and limitations. Tetrahedron, 2002, 58, 7437-7447.
[37]
Ferreira, B.R.V.; Pirovani, R.V.; Souza-Filho, L.G.; Coelho, F. Nájera oxime-derived palladacycles catalyze intermolecular Heck reaction with Morita–Baylis–Hillman adducts. An improved and highly efficient synthesis of α-benzyl-β-ketoesters. Tetrahedron, 2009, 65, 7712-7717.
[38]
Pirovani, R.V.; Ferreira, B.R.V.; Coelho, F. Highly functionalized Spirocyclohexadienones from Morita-Baylis-Hillman adducts. Synlett, 2009, 2333-2337.
[39]
Heinrich, A.C.J.; Thiedemann, B.; Gates, P.J.; Staubitz, A. Dual selectivity: Electrophile and nucleophile selective cross-coupling reactions on a single aromatic substrate. Org. Lett., 2013, 15, 4666-4669.
[40]
Hey, D.H.; Jones, G.H. Perkins, M.J. Internuclear cyclisation. Part XXVI. Photolysis of 2-iodo-N-methylbenzanilide in benzene. J. Chem. Soc. (C), 1971, 116-122.
[41]
Krapcho, A.P. Synthesis of carbocyclic spiro compounds via Intramolecular alkylation routes. Synthesis, 1974, 383-419.
[42]
Ficini, J.; Revial, G.; Genêt, J.P. Acylation of ynamines by enol-lactones: A new method of stereoselective spiroannelation. Tetrahedron Lett., 1981, 22, 629-632.
[43]
Marx, J.N.; Norman, L. Synthesis of (-)-acorone and related spirocyclic sesquiterpenes. J. Org. Chem., 1975, 40, 1602-1606.
[44]
Nifontov, Y.V. Spirocyclohexadienones. 7. Three-component condensation of 1- or 2-methoxynaphthalene with isobutyraldehyde and nitriles. Russ. Chem. Bull., 2003, 52, 437-440.
[45]
Rios, R. Enantioselective methodologies for the synthesis of spiro compounds. Chem. Soc. Rev., 2012, 41, 1060-1074.
[46]
Carreira, E.M.; Fessard, T.C. Four-membered ring-containing spirocycles: Synthetic strategies and opportunities. Chem. Rev., 2014, 104, 8257-8322.
[47]
da Silva, G.S.; Figueiró, M.; Tormena, C.F.; Coelho, F.; Almeida, W.P. Effects of novel acylhydrazones derived from 4-quinolone on the acetylcholinesterase activity and Aβ42 peptide fibrils formation. J. Enzyme Inhib. Med. Chem., 2016, 31, 1464-1470.
[48]
Salih, E.; Chishti, S.B.; Vicedomine, P.; Cohen, S.G.; Chiara, D.C.; Cohen, J.B. Active-site peptides of acetylcholinesterase of electrophorus electricus: labelling of His-440 by 1-bromo-[2-14C] pinacolone and Ser-200 by tritiated diisopropyl fluorophosphate. Biochim. Biophys. Acta, 1994, 1208, 324-331.
[49]
Kryger, G.; Silman, I.; Sussman, J. Structure of acetylcholinesterase complexed with E2020 (Aricept®): implications for the design of new anti-Alzheimer drugs. Structure, 1999, 7, 297-307.
[50]
Ordentlich, A.; Barak, D.; Kronmat, C.; Ariel, N.; Segall, Y.; Velan, B.; Shafferman, A. Functional characteristics of the Oxyanion hole in human Acetylcholinesterase. J. Biol. Chem., 1998, 273, 19509-19517.
[51]
Sussman, J.L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I.A. Atomic structure of Acetylcholinesterase from Torpedo Californica: A prototypic acetylcholine-binding protein. Science, 1991, 253, 872-879.
[52]
Shen, T.; Tai, K.; Henchman, R.H.; McCammon, J.A. Molecular dynamics of Acetylcholinesterase. Acc. Chem. Res., 2002, 35, 332-340.
[53]
Bajda, M.; Wieckowska, A.; Hebda, M.; Guzior, N.; Sotriffer, C.A.; Barbara, M.B. Structure based search for new inhibitors of cholinesterase. Int. J. Mol. Sci., 2013, 14, 5608-5632.
[54]
Bonda, D.J.; Wang, X.; Perry, G.; Nunomura, A.; Tabaton, M.; Zhu, X.; Smith, M.A. Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacol, 2010, 59, 290-294.
[55]
Lucini, L.; Pellizzoni, M.; Pellegrino, R.; Molinari, G.P.; Colla, G. Phytochemical constituents and in vitro radical scavenging activity of different Aloe species. Food Chem., 2015, 170, 501-507.
[56]
Samochocki, M.; Höffle, A.; Fehrenbacker, A.; Jostock, R.; Ludwig, J.; Christner, C.; Radina, M.; Zerlin, M.; Ullmer, C.; Pereira, E.F.R.; Lübbert, H.; Albuquerque, E.X.; Maelicke, A. Galantamine is an allosterically potentiating ligand of neuronal nicotinic nut not of muscarinic acetylcholine receptors. J. Pharmacol. Exp. Ther., 2003, 305, 1024-1036.


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VOLUME: 15
ISSUE: 4
Year: 2019
Page: [373 - 382]
Pages: 10
DOI: 10.2174/1573406414666181109114214
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