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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors

Author(s): Naseer Maliyakkal*, Ipek Baysal, Anandkumar Tengli, Gulberk Ucar*, Mohammad Ali Abdullah Almoyad, Della Grace Thomas Parambi, Nicola Gambacorta, Orazio Nicolotti, Asmy Appadath Beeran and Bijo Mathew*

Volume 25, Issue 8, 2022

Published on: 03 June, 2021

Page: [1314 - 1326] Pages: 13

DOI: 10.2174/1386207324666210603125452

Price: $65

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Abstract

Background: Chalcones with methoxy substituent are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes.

Methods: A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials.

Results: In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop- 2-en-1-one (TMf) was provided with a MAO-A inhibition constant value equal to 3.47±0.09 μM with a selectivity of 0.008, thus comparable to that of moclobemide, a well known potent hMAOA inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2- en-1-one (TMh) show good MAO-B inhibition with inhibition constant of 0.46±0.009 μM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 μM. Compound TMf appeared as the most promising antioxidant molecule with IC50 values, relative to DPPH and H2O2 radical activities equal to 6.02±0.17 and 7.25±0.07 μM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out.

Conclusion: The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.

Keywords: Chalcones, monoamine oxidase, reversibility, cytotoxicity, blood-brain barrier, antioxidant.

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[1]
Pisani, L.; Catto, M.; Leonetti, F.; Nicolotti, O.; Stefanachi, A.; Campagna, F.; Carotti, A. Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases. Curr. Med. Chem., 2011, 18(30), 4568-4587.
[http://dx.doi.org/10.2174/092986711797379302] [PMID: 21864289]
[2]
Naoi, M.; Maruyama, W. Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease. Expert Rev. Neurother., 2009, 9(8), 1233-1250.
[http://dx.doi.org/10.1586/ern.09.68] [PMID: 19673610]
[3]
Dezsi, L.; Vecsei, L. Monoamine oxidase B inhibitors in Parkinson’s Disease. CNS Neurol. Disord. Drug Targets, 2017, 16(4), 425-439.
[http://dx.doi.org/10.2174/1871527316666170124165222] [PMID: 28124620]
[4]
Carradori, S.; Secci, D.; Petzer, J.P. MAO inhibitors and their wider applications: a patent review. Expert Opin. Ther. Pat., 2018, 28(3), 211-226.
[http://dx.doi.org/10.1080/13543776.2018.1427735] [PMID: 29324067]
[5]
Youdim, M.B.; Edmondson, D.; Tipton, K.F. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci., 2006, 7(4), 295-309.
[http://dx.doi.org/10.1038/nrn1883] [PMID: 16552415]
[6]
Ramsay, R.R. Inhibitor design for monoamine oxidases. Curr. Pharm. Des., 2013, 19(14), 2529-2539.
[http://dx.doi.org/10.2174/1381612811319140004] [PMID: 23116392]
[7]
Mathew, B.; Parambi, D.G.T.; Sivasankarapillai, V.S.; Uddin, M.S.; Suresh, J.; Mathew, G.E.; Joy, M.; Marathakam, A.; Gupta, S.V. Perspective design of chalcones for the management of cns disorders: A Mini-Review. CNS Neurol. Disord. Drug Targets, 2019, 18(6), 432-445.
[http://dx.doi.org/10.2174/1871527318666190610111246] [PMID: 31187716]
[8]
Zhang, X.; Rakesh, K.P.; Bukhari, S.N.A.; Balakrishna, M.; Manukumar, H.M.; Qin, H.L. Multi-targetable chalcone analogs to treat deadly Alzheimer’s disease: Current view and upcoming advice. Bioorg. Chem., 2018, 80, 86-93.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.009] [PMID: 29890362]
[9]
Guglielmi, P.; Mathew, B.; Secci, D.; Carradori, S. Chalcones: Unearthing their therapeutic possibility as monoamine oxidase B inhibitors. Eur. J. Med. Chem., 2020, 205, 112650.
[http://dx.doi.org/10.1016/j.ejmech.2020.112650] [PMID: 32920430]
[10]
Cao, Z.; Yang, J.; Xu, R.; Song, Q.; Zhang, X.; Liu, H.; Qiang, X.; Li, Y.; Tan, Z.; Deng, Y. Design, synthesis and evaluation of 4-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer’s disease treatment. Bioorg. Med. Chem., 2018, 26(5), 1102-1115.
[http://dx.doi.org/10.1016/j.bmc.2018.01.030] [PMID: 29409707]
[11]
Tian, C.; Qiang, X.; Song, Q.; Cao, Z.; Ye, C.; He, Y.; Deng, Y.; Zhang, L. Flurbiprofen-chalcone hybrid Mannich base derivatives as balanced multifunctional agents against Alzheimer’s disease: Design, synthesis and biological evaluation. Bioorg. Chem., 2020, 94, 103477.
[http://dx.doi.org/10.1016/j.bioorg.2019.103477] [PMID: 31818478]
[12]
Robinson, S.J.; Petzer, J.P.; Petzer, A.; Bergh, J.J.; Lourens, A.C. Selected furanochalcones as inhibitors of monoamine oxidase. Bioorg. Med. Chem. Lett., 2013, 23(17), 4985-4989.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.050] [PMID: 23860591]
[13]
Shalaby, R.; Petzer, J.P.; Petzer, A.; Ashraf, U.M.; Atari, E.; Alasmari, F.; Kumarasamy, S.; Sari, Y.; Khalil, A. SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 863-876.
[http://dx.doi.org/10.1080/14756366.2019.1593158] [PMID: 30915862]
[14]
Parambi, D.G.T.; Oh, J.M.; Baek, S.C.; Lee, J.P.; Tondo, A.R.; Nicolotti, O.; Kim, H.; Mathew, B. Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors. Bioorg. Chem., 2019, 93, 103335.
[http://dx.doi.org/10.1016/j.bioorg.2019.103335] [PMID: 31606547]
[15]
Lakshminarayanan, B.; Baek, S.; Lee, J.; Kannappan, N.; Mangiatordi, G.; Nicolotti, O.; Subburaju, T.; Kim, H.; Mathew, B. Ethoxylated head of chalcones as a new class of multitargeted MAO inhibitors. ChemistrySelect, 2019, 4, 6614-6619.
[http://dx.doi.org/10.1002/slct.201901093]
[16]
Hitge, R.; Smit, S.; Petzer, A.; Petzer, J.P. Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase. Bioorg. Med. Chem. Lett., 2020, 30(12), 127188.
[http://dx.doi.org/10.1016/j.bmcl.2020.127188] [PMID: 32299731]
[17]
Mathew, B.; Uçar, G.; Mathew, G.E.; Mathew, S.; Kalatharakkal Purapurath, P.; Moolayil, F.; Mohan, S.; Varghese Gupta, S. Monoamine oxidase inhibitory activity: methyl- versus chlorochalcone derivatives. ChemMedChem, 2016, 11(24), 2649-2655.
[http://dx.doi.org/10.1002/cmdc.201600497] [PMID: 27902880]
[18]
Mathew, B.; Mathew, G.E.; Uçar, G.; Baysal, I.; Suresh, J.; Vilapurathu, J.K.; Prakasan, A.; Suresh, J.K.; Thomas, A. Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies. Bioorg. Chem., 2015, 62, 22-29.
[http://dx.doi.org/10.1016/j.bioorg.2015.07.001] [PMID: 26189013]
[19]
Morales-Camilo, N.; Salas, C.O.; Sanhueza, C.; Espinosa-Bustos, C.; Sepúlveda-Boza, S.; Reyes-Parada, M.; Gonzalez-Nilo, F.; Caroli-Rezende, M.; Fierro, A. Synthesis, biological evaluation, and molecular simulation of chalcones and aurones as selective MAO-B inhibitors. Chem. Biol. Drug Des., 2015, 85(6), 685-695.
[http://dx.doi.org/10.1111/cbdd.12458] [PMID: 25346162]
[20]
Hammuda, A.; Shalaby, R.; Rovida, S.; Edmondson, D.E.; Binda, C.; Khalil, A. Design and synthesis of novel chalcones as potent selective monoamine oxidase-B inhibitors. Eur. J. Med. Chem., 2016, 114, 162-169.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.038] [PMID: 26974383]
[21]
Mathew, B.; Mathew, G.E.; Ucar, G.; Joy, M.; Nafna, E.K.; Lohidakshan, K.K.; Suresh, J. Monoamine oxidase inhibitory activity of methoxy-substituted chalcones. Int. J. Biol. Macromol.,, 2017, 104(Pt A), 1321-1329.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.05.162] [PMID: 28577983]
[22]
Sahu, N.K.; Balbhadra, S.S.; Choudhary, J.; Kohli, D.V. Exploring pharmacological significance of chalcone scaffold: a review. Curr. Med. Chem., 2012, 19(2), 209-225.
[http://dx.doi.org/10.2174/092986712803414132] [PMID: 22320299]
[23]
Singh, P.; Anand, A.; Kumar, V. Recent developments in biological activities of chalcones: a mini review. Eur. J. Med. Chem., 2014, 85, 758-777.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.033] [PMID: 25137491]
[24]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev., 2017, 117(12), 7762-7810.
[http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]
[25]
Chiaradia, L.D.; Mascarello, A.; Purificação, M.; Vernal, J.; Cordeiro, M.N.; Zenteno, M.E.; Villarino, A.; Nunes, R.J.; Yunes, R.A.; Terenzi, H. Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg. Med. Chem. Lett., 2008, 18(23), 6227-6230.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.105] [PMID: 18930396]
[26]
Carradori, S.; Silvestri, R. New frontiers in selective human MAO-B inhibitors. J. Med. Chem., 2015, 58(17), 6717-6732.
[http://dx.doi.org/10.1021/jm501690r] [PMID: 25915162]
[27]
Jeong, G.S.; Kaipakasseri, S.; Lee, S.R.; Marraiki, N.; Batiha, G.E.; Dev, S.; Palakkathondi, A.; Kavully, F.S.; Gambacorta, N.; Nicolotti, O.; Mathew, B.; Kim, H. Selected 1,3-benzodioxine-containing chalcones as multipotent oxidase and acetylcholinesterase inhibitors. Chem. Med. Chem., 2020, 15(23), 2257-2263.
[http://dx.doi.org/10.1002/cmdc.202000491] [PMID: 32924264]
[28]
Harilal, S.; Jose, J.; Parambi, D.G.T.; Kumar, R.; Unnikrishnan, M.K.; Uddin, M.S.; Mathew, G.E.; Pratap, R.; Marathakam, A.; Mathew, B. Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules. Brain Res. Bull., 2020, 160, 121-140.
[http://dx.doi.org/10.1016/j.brainresbull.2020.03.018] [PMID: 32315731]
[29]
Di, L.; Kerns, E.H.; Fan, K.; McConnell, O.J.; Carter, G.T. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem., 2003, 38(3), 223-232.
[http://dx.doi.org/10.1016/S0223-5234(03)00012-6] [PMID: 12667689]
[30]
Alberga, D.; Trisciuzzi, D.; Montaruli, M.; Leonetti, F.; Mangiatordi, G.F.; Nicolotti, O. A new approach for drug target and bioactivity prediction: The multifingerprint similarity search algorithm (MuSSeL). J. Chem. Inf. Model., 2019, 59(1), 586-596.
[http://dx.doi.org/10.1021/acs.jcim.8b00698] [PMID: 30485097]
[31]
Montaruli, M.; Alberga, D.; Ciriaco, F.; Trisciuzzi, D.; Tondo, A.R.; Mangiatordi, G.F.; Nicolotti, O. Accelerating drug discovery by early protein drug target prediction based on a multi-fingerprint similarity search. Molecules, 2019, 24(12), 2233.
[http://dx.doi.org/10.3390/molecules24122233] [PMID: 31207991]
[32]
Reis, J.; Cagide, F.; Chavarria, D.; Silva, T.; Fernandes, C.; Gaspar, A.; Uriarte, E.; Remião, F.; Alcaro, S.; Ortuso, F.; Borges, F. Discovery of new chemical entities for old targets: insights on the lead optimization of chromone-based monoamine oxidase B (MAO-B) inhibitors. J. Med. Chem., 2016, 59(12), 5879-5893.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00527] [PMID: 27244485]
[33]
Fotakis, G.; Timbrell, J.A. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicol. Lett., 2006, 160(2), 171-177.
[http://dx.doi.org/10.1016/j.toxlet.2005.07.001] [PMID: 16111842]
[34]
Sharma, O.P.; Bhat, T.K. Analytical methods DPPH antioxidant assay revisited. Food Chem., 2009, 113, 1202-1205.
[http://dx.doi.org/10.1016/j.foodchem.2008.08.008]
[35]
Re, R.; Pellegrini, N.; Proteggente, A.; Pannala, A.; Yang, M.; Rice-Evans, C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic. Biol. Med., 1999, 26(9-10), 1231-1237.
[http://dx.doi.org/10.1016/S0891-5849(98)00315-3] [PMID: 10381194]
[36]
Son, S.Y.; Ma, J.; Kondou, Y.; Yoshimura, M.; Yamashita, E.; Tsukihara, T. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc. Natl. Acad. Sci. USA, 2008, 105(15), 5739-5744.
[http://dx.doi.org/10.1073/pnas.0710626105] [PMID: 18391214]
[37]
Binda, C.; Wang, J.; Pisani, L.; Caccia, C.; Carotti, A.; Salvati, P.; Edmondson, D.E.; Mattevi, A. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs. J. Med. Chem., 2007, 50(23), 5848-5852.
[http://dx.doi.org/10.1021/jm070677y] [PMID: 17915852]
[38]
Schrödinger Release 2018-4: Schrödinger Suite 2018-2 Protein Preparation Wizard; 2018.
[39]
Mangiatordi, G.F.; Alberga, D.; Pisani, L.; Gadaleta, D.; Trisciuzzi, D.; Farina, R.; Carotti, A.; Lattanzi, G.; Catto, M.; Nicolotti, O. A rational approach to elucidate human monoamine oxidase molecular selectivity. Eur. J. Pharm. Sci., 2017, 101, 90-99.
[http://dx.doi.org/10.1016/j.ejps.2017.02.008] [PMID: 28188911]
[40]
LigPrep; Schrödinger “LLC.”: New York, NY, , 2018.
[41]
Schrödinger, Release 2018-4: Prime; Schrödinger, LLC: New York, NY, 2018.
[42]
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936]

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