Design, Synthesis, Evaluation and Toxicity Studies of Novel Acridine
Derivatives in Zebra Fish Larvae

Remya      Ramachandran Surajambika; Ramalakshmi      Natarajan; Nalini      Nagarajan

doi:10.2174/0115734072256561231008183612

Abstract

Background: Alzheimer’s disease (AD) is a complex neurodegenerative condition for which a single protein-targeting medication is not enough to provide a cure. All the medications now available for AD are palliative. FDA has approved five medications for the treatment of AD, i.e., tacrine, donepezil, galantamine, rivastigmine, and memantine. Due to hepatotoxicity, tacrine is no longer utilized in clinical practice. Due to the lack of therapeutic efficiency of single-target medications and the multifaceted etiology of AD, multitarget-directed ligands have been developed.

Objectives: The present research focused on incorporating a flavone nucleus into the amino group of 9-amino acridine nucleus to make it an acetylcholinesterase (AChE) and butyryl cholinesterase inhibitor (BuChE) with less toxicity.

Methods: We designed and synthesized ten flavone-substituted acridine derivatives and evaluated them for in vitro AChE and BuChE inhibitory activity. Molecular modeling studies were conducted using AutoDock Vina with hAChE (PDB ID: 4EY7) and hBuChE (PDB ID: 4TPK). The toxicity profile of the most active novel compound tested on zebrafish larvae for determining the liver and cardiac toxicity and LD50 value of the compound were determined.

Results: In vitro AChE and BuChE inhibitory study by Ellman assay showed acceptable results. The compound AF2 showed the highest activity with an IC₅₀ value of 0.99 ± 0.1 μM for AChE and 1.78 ± 0.19 for BuChE. The in vivo acute toxicity studies conducted on zebra fish larvae did not show cardiac and hepatotoxicity, and the LD₅₀ value was found to be 1000 μL.

Conclusion: The results highlighted the AChE and BuChE inhibitory effects of the novel acridine- flavone hybrids, and they can be promising multitarget-directed ligands for AD.

Graphical Abstract

[1]
2023 Alzheimer’s disease facts and figures. Alzheimers Dement.,  2023, 19(4), 1598-1695.
 [http://dx.doi.org/10.1002/alz.13016] [PMID: 36918389]

[2]
Koola, M.M Galantamine-Memantine combination in the treatment of Alzheimer’s disease and beyond. Psychiatry Res.,  2020, 293, 113409.
 [http://dx.doi.org/10.1016/j.psychres.2020.113409] [PMID: 32829072]

[3]
Lockridge, O; Norgren, R.B, Jr; Johnson, R.C; Blake, T.A Naturally occurring genetic variants of human acetylcholinesterase and butyrylcholinesterase and their potential impact on the risk of toxicity from cholinesterase inhibitors. Chem. Res. Toxicol.,  2016, 29(9), 1381-1392.
 [http://dx.doi.org/10.1021/acs.chemrestox.6b00228] [PMID: 27551784]

[4]
Cieslikiewicz-Bouet, M; Naldi, M; Bartolini, M; Pérez, B; Servent, D; Jean, L; Aráoz, R; Renard, P.Y Functional characterization of multifunctional ligands targeting acetylcholinesterase and alpha 7 nicotinic acetylcholine receptor. Biochem. Pharmacol.,  2020, 177, 114010.
 [http://dx.doi.org/10.1016/j.bcp.2020.114010] [PMID: 32360492]

[5]
Li, Q; Yang, H; Chen, Y; Sun, H Recent progress in the identification of selective butyrylcholinesterase inhibitors for Alzheimer’s disease. Eur. J. Med. Chem.,  2017, 132, 294-309.
 [http://dx.doi.org/10.1016/j.ejmech.2017.03.062] [PMID: 28371641]

[6]
Rajeshwari, R; Chand, K; Candeias, E; Cardoso, S; Chaves, S; Santos, M New multitarget hybrids bearing tacrine and phenylbenzothiazole motifs as potential drug candidates for alzheimer’s disease. Molecules,  2019, 24(3), 587.
 [http://dx.doi.org/10.3390/molecules24030587] [PMID: 30736397]

[7]
Tripathi, R.K.P.; M Sasi, V.; Gupta, S.K.; Krishnamurthy, S.; Ayyannan, S.R. Design, synthesis, and pharmacological evaluation of 2-amino-5-nitrothiazole derived semicarbazones as dual inhibitors of monoamine oxidase and cholinesterase: Effect of the size of aryl binding site. J. Enzyme Inhib. Med. Chem.,  2018, 33(1), 37-57.
 [http://dx.doi.org/10.1080/14756366.2017.1389920] [PMID: 29098902]

[8]
Ramalakshmi, N R S, R.; C N, N. Multitarget directed ligand approaches for alzheimer’s disease: A comprehensive review. Mini Rev. Med. Chem.,  2021, 21(16), 2361-2388.
 [http://dx.doi.org/10.2174/1389557521666210405161205] [PMID: 33820504]

[9]
Fancellu, G; Chand, K; Tomás, D; Orlandini, E; Piemontese, L; Silva, D.F; Cardoso, S.M; Chaves, S; Santos, M.A Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease. J. Enzyme Inhib. Med. Chem.,  2020, 35(1), 211-226.
 [http://dx.doi.org/10.1080/14756366.2019.1689237] [PMID: 31760822]

[10]
Butini, S; Guarino, E; Campiani, G; Brindisi, M; Coccone, S.S; Fiorini, I; Novellino, E; Belinskaya, T; Saxena, A; Gemma, S Tacrine based human cholinesterase inhibitors: Synthesis of peptidic-tethered derivatives and their effect on potency and selectivity. Bioorg. Med. Chem. Lett.,  2008, 18(19), 5213-5216.
 [http://dx.doi.org/10.1016/j.bmcl.2008.08.076] [PMID: 18786825]

[11]
Kandiah, N; Pai, M.C; Senanarong, V; Looi, I; Ampil, E; Park, K.W; Karanam, A.K; Christopher, S Rivastigmine: The advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson’s disease dementia. Clin. Interv. Aging,  2017, 12, 697-707.
 [http://dx.doi.org/10.2147/CIA.S129145] [PMID: 28458525]

[12]
Fu, J; Bao, F; Gu, M; Liu, J; Zhang, Z; Ding, J; Xie, S.S; Ding, J Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease. J. Enzyme Inhib. Med. Chem.,  2020, 35(1), 118-128.
 [http://dx.doi.org/10.1080/14756366.2019.1687460] [PMID: 31694418]

[13]
Zanon, V.S; Lima, J.A; Amaral, R.F; Lima, F.R.S; Kitagawa, D.A.S; França, T.C.C; Vargas, M.D Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer’s disease. J. Biomol. Struct. Dyn.,  2021, 39(16), 6112-6125.
 [http://dx.doi.org/10.1080/07391102.2020.1796796] [PMID: 32715924]

[14]
Guo, Y; Yang, H; Huang, Z; Tian, S; Li, Q; Du, C Design, synthesis, and evaluation of acetylcholinesterase and butyrylcholinesterase dual-target inhibitors against alzheimer’s diseases. Molecules,  2020, 25(3), 489.

[15]
Sarıkaya, G; Çoban, G; Parlar, S; Tarikogullari, A.H; Armagan, G; Erdoğan, M.A; Alptüzün, V; Alpan, A.S Multifunctional cholinesterase inhibitors for Alzheimer’s disease: Synthesis, biological evaluations, and docking studies of o/p -propoxyphenylsubstituted-1 H -benzimidazole derivatives. Arch. Pharm.,  2018, 351(8), 1800076.
 [http://dx.doi.org/10.1002/ardp.201800076] [PMID: 29984517]

[16]
Akram, M; Rauf, A; Saeed, A; Ahmed, F; Mubeen, S; Ashraf, M; Hussain, S; Qureshi, A.M Synthesis, biological evaluation and molecular docking studies of Mannich bases derived from 1, 3, 4-oxadiazole- 2-thiones as potential urease inhibitors. Trop. J. Pharm. Res.,  2018, 17(1), 127-134.
 [http://dx.doi.org/10.4314/tjpr.v17i1.18]

[17]
Mariki, A.A; Anaeigoudari, A; Zahedifar, M; Pouramiri, B; Ayati, A; Lotfi, S Design, green synthesis, and biological evaluation of new substituted tetrahydropyrimidine derivatives as acetylcholinesterase inhibitors. Polycycl. Aromat. Compd.,  2021, 2021.
 [http://dx.doi.org/10.1080/10406638.2021.1933102]

[18]
Sharma, K. Cholinesterase inhibitors as Alzheimer’s therapeutic (Review). Mol. Med. Rep. ,  2019, 20(2), 1479-1487.
 [http://dx.doi.org/10.3892/mmr.2019.10374] [PMID: 31257471]

[19]
Pavithra, P; Remya, R.S; Ramalakshmi, N Chalcones and flavones as multifunctional anticancer agents—A comprehensive review. Curr. Bioact. Compd.,  2022, 18, 84-107.

[20]
Wu, G; Gao, Y; Kang, D; Huang, B; Huo, Z; Liu, H; Poongavanam, V; Zhan, P; Liu, X Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors. MedChemComm,  2018, 9(1), 149-159.
 [http://dx.doi.org/10.1039/C7MD00457E] [PMID: 30108908]

[21]
Sanner, M.F Python: A programming language for software integration and development. J. Mol. Graph. Model.,  1999, 17(1), 57-61.
 [PMID: 10660911]

[22]
Pettersen, E.F; Goddard, T.D; Huang, C.C; Couch, G.S; Greenblatt, D.M; Meng, E.C; Ferrin, T.E UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem.,  2004, 25(13), 1605-1612.
 [http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]

[23]
Hamulakova, S.; Janovec, L.; Soukup, O.; Jun, D.; Kuca, K. Synthesis, in vitro acetylcholinesterase inhibitory activity and molecular docking of new acridine-coumarin hybrids. Int. J. Biol. Macromol.,  2017, 104(Pt A,), 333-338.
 [http://dx.doi.org/10.1016/j.ijbiomac.2017.06.006] [PMID: 28601645]

[24]
Xie, S.S; Lan, J.S; Wang, X; Wang, Z.M; Jiang, N; Li, F; Wu, J.J; Wang, J; Kong, L.Y Design, synthesis and biological evaluation of novel donepezil–coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease. Bioorg. Med. Chem.,  2016, 24(7), 1528-1539.
 [http://dx.doi.org/10.1016/j.bmc.2016.02.023] [PMID: 26917219]

[25]
Patel, S; Shah, U.H Synthesis of Flavones from 2-Hydroxy Acetophenone and aromatic aldehyde derivatives by conventional methods and Green Chemistry Approach. Asian J. Pharm. Clin. Res.,  2017, 10(2), 403-406.
 [http://dx.doi.org/10.22159/ajpcr.2017.v10i2.15928]

[26]
Menezes, M.J; Manjrekar, S; Pai, V A facile microwave assisted synthesis of flavones. Indian J. Chem.,  2009, 48, 1311-1314.

[27]
Roman, G Mannich bases in medicinal chemistry and drug design. Eur. J. Med. Chem.,  2015, 89, 743-816.
 [http://dx.doi.org/10.1016/j.ejmech.2014.10.076] [PMID: 25462280]

[28]
Remya, R.S; Ramalakshmi, N; Nalini, C.N; Niraimathi, V; Amuthalakshmi, S Design synthesis and in vitro evaluation of tacrine- flavone hybrids as multifunctional cholinesterase inhibitors for alzheimer’s disease. Curr. Computeraided Drug Des.,  2022, 18(4), 271-292.
 [http://dx.doi.org/10.2174/1573409918666220804153754] [PMID: 35927818]

[29]
Design, synthesis, and in vitro evaluation of novel acridine derivatives as monoamine oxidase inhibitors. Rasayan J. Chem.,  2022, 15(4), 2318-2325.
 [http://dx.doi.org/10.31788/RJC.2022.1547080]

[30]
Susanti, V.H.E; Setyowati, W A E Synthesis and characterization of some bromochalcones derivatives. IOP Conf. Ser.: Mater. Sci.Eng.,  2019, 578(012002)
 [http://dx.doi.org/10.1088/1757-899X/578/1/012002]

[31]
Mulugeta, D A review of synthesis methods of chalcones, flavonoids, and coumarins. J. Chem. Sci.,  2022, 10(2), 41-52.
 [http://dx.doi.org/10.11648/j.sjc.20221002.12]

[32]
Lahyani, A; Trabelsi, M Ultrasonic-assisted synthesis of flavones by oxidative cyclization of 2′-hydroxychalcones using iodine monochloride. Ultrason. Sonochem.,  2016, 31, 626-630.
 [http://dx.doi.org/10.1016/j.ultsonch.2016.02.018]

[33]
Palmieri, G A practical o-hydroxybenzylamines promoted enantioselective addition of dialkylzincs to aldehydes with asymmetric amplification. Tetrahedron Asymmetry,  2000, 11(16), 3361-3373.
 [http://dx.doi.org/10.1016/S0957-4166(00)00290-1]

[34]
Olyaei, A; Sadeghpour, M Recent advances in the synthesis and synthetic applications of Betti base (aminoalkylnaphthol) and bis-Betti base derivatives. RSC Advances,  2019, 9(32), 18467-18497.
 [http://dx.doi.org/10.1039/C9RA02813G] [PMID: 35515249]

[35]
Olyaei, A; Sadeghpour, M Mannich reaction mechanisms. J. Org. Chem.,  2019, 25(3), 419-423.

[36]
Ellman, G.L; Courtney, K.D; Andres, V, Jr; Featherstone, R.M A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol.,  1961, 7(2), 88-95.
 [http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]

[37]
Camps, P; Formosa, X; Galdeano, C; Gómez, T; Muñoz-Torrero, D; Scarpellini, M; Viayna, E; Badia, A; Clos, M.V; Camins, A; Pallàs, M; Bartolini, M; Mancini, F; Andrisano, V; Estelrich, J; Lizondo, M; Bidon-Chanal, A; Luque, F.J Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. J. Med. Chem.,  2008, 51(12), 3588-3598.
 [http://dx.doi.org/10.1021/jm8001313] [PMID: 18517184]

[38]
Santos Pisoni, D; Sobieski da Costa, J; Gamba, D; Petzhold, C.L; César de Amorim Borges, A; Ceschi, M.A; Lunardi, P; Saraiva Gonçalves, C.A Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones. Eur. J. Med. Chem.,  2010, 45(2), 526-535.
 [http://dx.doi.org/10.1016/j.ejmech.2009.10.039] [PMID: 19954865]

[39]
Keri, R.S; Quintanova, C; Marques, S.M; Esteves, A.R; Cardoso, S.M; Santos, M.A Design, synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg. Med. Chem.,  2013, 21(15), 4559-4569.
 [http://dx.doi.org/10.1016/j.bmc.2013.05.028] [PMID: 23768661]

[40]
Borioni, J.L; Cavallaro, V; Murray, A.P; Peñéñory, A.B; Puiatti, M; García, M.E Design, synthesis and evaluation of cholinesterase hybrid inhibitors using a natural steroidal alkaloid as precursor. Bioorg. Chem.,  2021, 111, 104893.
 [http://dx.doi.org/10.1016/j.bioorg.2021.104893] [PMID: 33882364]

[41]
Li, F.; Wang, Z.M.; Wu, J.J.; Wang, J.; Xie, S.S.; Lan, J.S.; Xu, W.; Kong, L.Y.; Wang, X.B. Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer’s disease. J. Enzyme Inhib. Med. Chem.,  2016, 31(sup3), 41-53.
 [http://dx.doi.org/10.1080/14756366.2016.1201814] [PMID: 27384289]

[42]
Xie, S.S; Wang, X; Jiang, N; Yu, W; Wang, K.D.G; Lan, J.S; Li, Z.R; Kong, L.Y Multi-target tacrine-coumarin hybrids: Cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur. J. Med. Chem.,  2015, 95, 153-165.
 [http://dx.doi.org/10.1016/j.ejmech.2015.03.040] [PMID: 25812965]

[43]
Botura, M.B; de Almeida, R.B.M; de Almeida Luz, R.L.S; Leite, F.H.A A review on the in vitro evaluation of the anticholinesterase activity based on ellman’s method. Mini Rev. Med. Chem.,  2022, 22(13), 1803-1813.
 [http://dx.doi.org/10.2174/1389557521666211027104638] [PMID: 34711159]

[44]
von Hellfeld, R; Brotzmann, K; Baumann, L; Strecker, R; Braunbeck, T Adverse effects in the fish embryo acute toxicity (FET) test: A catalogue of unspecific morphological changes versus more specific effects in zebrafish (Danio rerio) embryos. Environ. Sci. Eur.,  2020, 32(1), 122.
 [http://dx.doi.org/10.1186/s12302-020-00398-3]

[45]
Xiong, Y; Chen, X; Li, F; Chen, Z; Qin, Z Zebrafish larvae acute toxicity test: A promising alternative to the fish acute toxicity test. Aquat. Toxicol.,  2022, 246, 106143.
 [http://dx.doi.org/10.1016/j.aquatox.2022.106143]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/0115734072256561231008183612	Print ISSN 1573-4072
Publisher Name Bentham Science Publisher	Online ISSN 1875-6646

Current Bioactive Compounds

Design, Synthesis, Evaluation and Toxicity Studies of Novel Acridine Derivatives in Zebra Fish Larvae

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract