Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and Preliminary Biological Evaluation of New Phthalazinone Derivatives with PARP-1 and Cholinesterase Inhibitory Activities

Author(s): Yu Lin, Chengzhi Gao, Zhuyong Wang, Ruifeng Zhang, Yajun Chen and Zhenli Min*

Volume 20, Issue 1, 2023

Published on: 10 August, 2022

Page: [56 - 70] Pages: 15

DOI: 10.2174/1570180819666220531144809

Price: $65

Abstract

Background: Alzheimer's disease (AD) is the most common brain disorder and remains a major health concern worldwide. Considering the highly complex mechanisms of AD, the search for agents based on a multitarget-directed ligands (MTDLs) strategy to treat AD may be more promising than the traditional “one drug-one target” strategy. Inhibition of Poly (ADP-ribose) polymerases-1 (PARP-1) has a potentially therapeutical effect on AD. Therefore, it is worthy to investigate compounds that target both PARP-1 and cholinesterase, which perhaps produces new agents against AD.

Objective: To search for new agents with PARP-1 and cholinesterase inhibitory activities for the treatment of AD.

Methods: A series of 21 novel compounds incorporated the respective pharmacophores of two marketed drugs, namely the 4-benzyl phthalazinone moiety of a PARP-1 inhibitor, Olaparib, and the Nbenzylpiperidine moiety of an AChE inhibitor, Donepezil, into one molecule was synthesized. The inhibitory activities of all the synthesized compounds against the enzymes PARP-1, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated. The binding modes of the most potent compound inside the PARP-1 and the human BChE (hBChE) were investigated by molecular docking.

Results: N-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-2-fluoro-5-((1, 2-dihydro-1-oxophthalazin-4- yl)methyl)benzamide (30) exhibited the most potent inhibitory effect on PARP-1 enzyme (IC50=8.18±2.81nM) and moderate BChE inhibitory activity (IC50=1.63±0.52μM), while its AChE inhibitory activity (IC50=13.48±2.15μM) was weaker than Donepezil (IC50=0.04±0.01μM). Further molecular docking studies revealed that four hydrogen bonds were formed between 30 and PARP-1, meanwhile, 30 interacted with the critical residues His438 and Trp82 of hBChE through hydrogen bonds and hydrophobic interactions, which were necessary for hBChE inhibitory potency.

Conclusion: A new compound with potent PARP-1 inhibitory activity and moderate BChE inhibitory activity was obtained, which merited to be further investigated as an anti-AD drug. The studies gave a clue to search for new agents based on PARP-1 and cholinesterase dual-inhibited activities to treat AD.

Keywords: PARP-1 inhibitor, Olaparib, AChE, BChE, Alzheimer's disease, cholinesterase dual-inhibited activities.

« Previous Next »
Graphical Abstract

[1]
McDade, E.; Bateman, R.J. Stop Alzheimer’s before it starts. Nature, 2017, 547(7662), 153-155.
[http://dx.doi.org/10.1038/547153a] [PMID: 28703214]
[2]
Talesa, V.N. Acetylcholinesterase in Alzheimer’s disease. Mech. Ageing Dev., 2001, 122(16), 1961-1969.
[http://dx.doi.org/10.1016/S0047-6374(01)00309-8] [PMID: 11589914]
[3]
Hardy, J. The amyloid hypothesis for Alzheimer’s disease: A critical reappraisal. J. Neurochem., 2009, 110(4), 1129-1134.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06181.x] [PMID: 19457065]
[4]
Carreiras, M.; Mendes, E.; Perry, M.; Francisco, A.; Marco-Contelles, J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr. Top. Med. Chem., 2013, 13(15), 1745-1770.
[http://dx.doi.org/10.2174/15680266113139990135] [PMID: 23931435]
[5]
Praticò, D. Oxidative stress hypothesis in Alzheimer’s disease: A reappraisal. Trends Pharmacol. Sci., 2008, 29(12), 609-615.
[http://dx.doi.org/10.1016/j.tips.2008.09.001] [PMID: 18838179]
[6]
Srivastava, S.; Ahmad, R.; Khare, S.K. Alzheimer’s disease and its treatment by different approaches: A review. Eur. J. Med. Chem., 2021, 216, 113320.
[http://dx.doi.org/10.1016/j.ejmech.2021.113320] [PMID: 33652356]
[7]
Rabinovici, G.D. Controversy and progress in Alzheimer’s disease-FDA approval of aducanumab. N. Engl. J. Med., 2021, 385(9), 771-774.
[http://dx.doi.org/10.1056/NEJMp2111320] [PMID: 34320284]
[8]
Curtin, N.J.; Szabo, C. Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat. Rev. Drug Discov., 2020, 19(10), 711-736.
[http://dx.doi.org/10.1038/s41573-020-0076-6] [PMID: 32884152]
[9]
Shen, Y.T.; Evans, J.C.; Zafarana, G.; Allen, C.; Piquette-Miller, M. Zafarana. G.; Allen, C.; Piquette-Miller, M. BRCA status does not predict synergism of a carboplatin and Olaparib combination in high-grade serous ovarian cancer cell lines. Mol. Pharm., 2018, 15(7), 2742-2753.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00246] [PMID: 29750868]
[10]
Papeo, G.; Orsini, P.; Avanzi, N.R.; Borghi, D.; Casale, E.; Ciomei, M.; Cirla, A.; Desperati, V.; Donati, D.; Felder, E.R.; Galvani, A.; Guanci, M.; Isacchi, A.; Posteri, H.; Rainoldi, S.; Riccardi-Sirtori, F.; Scolaro, A.; Montagnoli, A. Discovery of stereospecific PARP-1 inhibitor isoindolinone NMS-P515. ACS Med. Chem. Lett., 2019, 10(4), 534-538.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00569] [PMID: 30996792]
[11]
de Gooijer, M.C.; Buil, L.C.M.; Çitirikkaya, C.H.; Hermans, J.; Beijnen, J.H.; van Tellingen, O. ABCB1 attenuates the brain penetration of the PARP inhibitor AZD2461. Mol. Pharm., 2018, 15(11), 5236-5243.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00742] [PMID: 30252484]
[12]
Thapa, K.; Khan, H.; Sharma, U.; Grewal, A.K.; Singh, T.G. Poly (ADP-ribose) polymerase-1 as a promising drug target for neurodegenerative diseases. Life Sci., 2021, 267, 118975.
[http://dx.doi.org/10.1016/j.lfs.2020.118975] [PMID: 33387580]
[13]
McGurk, L.; Rifai, O.M.; Bonini, N.M. Poly (ADP-Ribosylation) in age-related neurological disease. Trends Genet., 2019, 35(8), 601-613.
[http://dx.doi.org/10.1016/j.tig.2019.05.004] [PMID: 31182245]
[14]
Correani, V.; Martire, S.; Mignogna, G.; Caruso, L.B.; Tempera, I.; Giorgi, A.; Grieco, M.; Mosca, L.; Schininà, M.E.; Maras, B.; d’Erme, M. Poly(ADP-ribosylated) proteins in β-amyloid peptide-stimulated microglial cells. Biochem. Pharmacol., 2019, 167, 50-57.
[http://dx.doi.org/10.1016/j.bcp.2018.10.026] [PMID: 30414941]
[15]
David, K.K.; Andrabi, S.A.; Dawson, T.M.; Dawson, V.L. Parthanatos, a messenger of death. Front. Biosci., 2009, 14, 1116-1128.
[http://dx.doi.org/10.2741/3297] [PMID: 19273119]
[16]
Kadam, A.; Jubin, T.; Roychowdhury, R.; Garg, A.; Parmar, N.; Palit, S.P.; Begum, R. Insights into the functional aspects of poly(ADP‐ribose) polymerase‐1 (PARP‐1) in mitochondrial homeostasis in Dictyostelium discoideum. Biol. Cell, 2020, 112(8), 222-237.
[http://dx.doi.org/10.1111/boc.201900104] [PMID: 32324907]
[17]
Raina, R.; Sen, D. Can crosstalk between DOR and PARP reduce oxidative stress mediated neurodegeneration? Neurochem. Int., 2018, 112, 206-218.
[http://dx.doi.org/10.1016/j.neuint.2017.07.011] [PMID: 28739183]
[18]
Jang, S.; Kim, E.W.; Zhang, Y.; Lee, J.; Cho, S.Y.; Ha, J.; Kim, H.; Kim, E. Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer’s mouse: Involvement of PARP-1. Biochem. Biophys. Res. Commun., 2018, 500(2), 333-338.
[http://dx.doi.org/10.1016/j.bbrc.2018.04.068] [PMID: 29654761]
[19]
Ruan, Q.; Ruan, J.; Zhang, W.; Qian, F.; Yu, Z. Targeting NAD + degradation: The therapeutic potential of flavonoids for Alzheimer’s disease and cognitive frailty. Pharmacol. Res., 2018, 128, 345-358.
[http://dx.doi.org/10.1016/j.phrs.2017.08.010] [PMID: 28847709]
[20]
Salech, F.; Ponce, D.P.; Paula-Lima, A.C.; SanMartin, C.D.; Behrens, M.I. Nicotinamide, a poly [ADP-ribose]polymerase 1 (PARP-1) Inhibitor, as an adjunctive therapy for the treatment of Alzheimer’s disease. Front. Aging Neurosci., 2020, 12, 255.
[http://dx.doi.org/10.3389/fnagi.2020.00255] [PMID: 32903806]
[21]
Czapski, G.A.; Cieślik, M.; Wencel, P.L.; Wójtowicz, S.; Strosznajder, R.P.; Strosznajder, J.B. Inhibition of poly(ADP-ribose) polymerase-1 alters expression of mitochondria-related genes in PC12 cells: Relevance to mitochondrial homeostasis in neurodegenerative disorders. Biochim. Biophys. Acta Mol. Cell Res., 2018, 1865(2), 281-288.
[http://dx.doi.org/10.1016/j.bbamcr.2017.11.003] [PMID: 29128369]
[22]
Maramai, S.; Benchekroun, M.; Gabr, M.T.; Yahiaoui, S. Multitarget therapeutic strategies for Alzheimer’s disease: Review on emerging target combinations. BioMed Res. Int., 2020, 2020, 1-27.
[http://dx.doi.org/10.1155/2020/5120230] [PMID: 32714977]
[23]
Zondagh, L.S.; Malan, S.F.; Joubert, J. Design, synthesis and biological evaluation of edaravone derivatives bearing the N -benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 1596-1605.
[http://dx.doi.org/10.1080/14756366.2020.1801673] [PMID: 32779503]
[24]
Ye, C.; Xu, R.; Cao, Z.; Song, Q.; Yu, G.; Shi, Y.; Liu, Z.; Liu, X.; Deng, Y. Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer’s disease agents. Bioorg. Chem., 2021, 111, 104895.
[http://dx.doi.org/10.1016/j.bioorg.2021.104895] [PMID: 33887586]
[25]
Wang, Y.Q.; Wang, P.Y.; Wang, Y.T.; Yang, G.F.; Zhang, A.; Miao, Z.H. An update on poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors: Opportunities and challenges in cancer therapy. J. Med. Chem., 2016, 59(21), 9575-9598.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00055] [PMID: 27416328]
[26]
Jain, P.G.; Patel, B.D. Medicinal chemistry approaches of poly ADP-Ribose polymerase 1 (PARP1) inhibitors as anticancer agents - A recent update. Eur. J. Med. Chem., 2019, 165, 198-215.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.024] [PMID: 30684797]
[27]
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]
[28]
Gao, C.Z.; Dong, W.; Cui, Z.W.; Yuan, Q.; Hu, X.M.; Wu, Q.M.; Han, X.; Xu, Y.; Min, Z.L. Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 150-162.
[http://dx.doi.org/10.1080/14756366.2018.1530224] [PMID: 30427217]
[29]
Sang, Z.; Qiang, X.; Li, Y.; Yuan, W.; Liu, Q.; Shi, Y.; Ang, W.; Luo, Y.; Tan, Z.; Deng, Y.; Yong, D. Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2015, 94, 348-366.
[http://dx.doi.org/10.1016/j.ejmech.2015.02.063] [PMID: 25778991]
[30]
http://vina.scripps.edu/, version platform independent, Apache license
[31]
Dawicki-McKenna, J.M.; Langelier, M.F.; DeNizio, J.E.; Riccio, A.A.; Cao, C.D.; Karch, K.R.; McCauley, M.; Steffen, J.D.; Black, B.E.; Pascal, J.M. PARP-1 activation requires local unfolding of an autoinhibitory domain. Mol. Cell, 2015, 60(5), 755-768.
[http://dx.doi.org/10.1016/j.molcel.2015.10.013] [PMID: 26626480]
[32]
Košak, U.; Brus, B.; Knez, D.; Žakelj, S.; Trontelj, J.; Pišlar, A.; Šink, R.; Jukič, M.; Živin, M.; Podkowa, A.; Nachon, F.; Brazzolotto, X.; Stojan, J.; Kos, J.; Coquelle, N.; Sałat, K.; Colletier, J.P.; Gobec, S. The magic of crystal structure-based inhibitor optimization: development of a butyrylcholinesterase inhibitor with picomolar affinity and in vivo activity. J. Med. Chem., 2018, 61(1), 119-139.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01086] [PMID: 29227101]
[33]
http://adfr.scripps.edu/AutoDockFR/agfr.html version 1.0, platform independent, LGPL OpenSource software license.
[34]
Laskowski, R.A.; Swindells, M.B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 2011, 51(10), 2778-2786.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[35]
Dolles, D.; Hoffmann, M.; Gunesch, S.; Marinelli, O.; Möller, J.; Santoni, G.; Chatonnet, A.; Lohse, M.J.; Wittmann, H.J.; Strasser, A.; Nabissi, M.; Maurice, T.; Decker, M. Möller, j.; Santoni, G.; Chatonnet, A.; Lohse, M.J.; Wittmann, H.J.; Strasser, A.; Nabissi, M.; Maurice, T.; Decker, M. Structure-activity relationships and computational investigations into the development of potent and balanced dual-acting butyrylcholinesterase inhibitors and human cannabinoid receptor 2 ligands with pro-cognitive in vivo profiles. J. Med. Chem., 2018, 61(4), 1646-1663.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01760] [PMID: 29400965]
[36]
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]
[37]
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]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy