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CNS & Neurological Disorders - Drug Targets

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ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

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Research Article

Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer’s Disease

Author(s): Reeta, Seung Cheol Baek, Jae Pil Lee, T.M. Rangarajan*, Ayushee, Rishi Pal Singh, Manjula Singh, Giuseppe Felice Mangiatordi, Orazio Nicolotti, Hoon Kim* and Bijo Mathew*

Volume 18, Issue 8, 2019

Page: [643 - 654] Pages: 12

DOI: 10.2174/1871527318666190906101326

Price: $65

Abstract

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B.

Objectives: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer’s Disease (AD).

Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed.

Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively.

Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

Keywords: Alzheimer's disease, ethyl acetohydroxamate-chalcones, hMAOs, AChE, selective competitive and reversible inhibitor, molecular docking.

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[1]
Jiang XW, Lu HY, Xu Z, et al. In Silico analyses for key genes and molecular genetic mechanism in epilepsy and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 608-17.
[2]
Singh A, Hasan A, Tiwari S, Pandey LM. Therapeutic advancement in Alzheimer disease, new hopes on the horizon? CNS Neurol Disord Drug Targets 2018; 17(8): 571-89.
[http://dx.doi.org/10.2174/1871527317666180627122448] [PMID: 29952273]
[3]
Neelakandan AR, Rajanikant GK. Commentary endophenotypes as disease modifiers: Decoding the biology of Alzheimer’s by genome-wide association studies. CNS Neurol Disord Drug Targets 2018; 17(1): 6-8.
[http://dx.doi.org/10.2174/1871527317666180213143832] [PMID: 29437016]
[4]
Ayton S, Lei P, Bush AI. Metallostasis in Alzheimer’s disease. Free Radic Biol Med 2013; 62: 76-89.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.10.558] [PMID: 23142767]
[5]
Beg T, Jyoti S, Naz F, et al. Protective effect of kaempferol on the transgenic drosophila model of Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17(6): 421-9.
[http://dx.doi.org/10.2174/1871527317666180508123050] [PMID: 29745345]
[6]
Medina-Franco JL, Giulianotti MA, Welmaker GS, Houghten RA. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov Today 2013; 18(9-10): 495-501.
[http://dx.doi.org/10.1016/j.drudis.2013.01.008] [PMID: 23340113]
[7]
Catto M, Trisciuzzi D, Alberga D, Mangiatordi GF, Nicolotti O. Multitarget drug design for neurodegenerative diseases. Methods in Pharmacology and Toxicology 2019; pp. 93-105.
[8]
Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008; 51(3): 347-72.
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[9]
Knez D, Sova M, Košak U, Gobec S. Dual inhibitors of cholinesterases and monoamine oxidases for Alzheimer’s disease. Future Med Chem 2017; 9(8): 811-32.
[http://dx.doi.org/10.4155/fmc-2017-0036] [PMID: 28504893]
[10]
Pisani L, De Palma A, Giangregorio N, et al. Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazine, a water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity. Eur J Pharm Sci 2017; 109: 381-8.
[http://dx.doi.org/10.1016/j.ejps.2017.08.004] [PMID: 28801274]
[11]
Pisani L, Farina R, Catto M, et al. Exploring basic tail modifications of coumarin-based dual acetylcholinesterase-monoamine oxidase b inhibitors. Identification of water-soluble, brain-permeant neuroprotective multitarget agents. J Med Chem 2016; 59(14): 6791-806.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00562] [PMID: 27347731]
[12]
Pisani L, Farina R, Soto-Otero R, et al. Searching for multi-targeting neurotherapeutics against Alzheimer’s discovery of potent ache-MAO B inhibitors through the decoration of the 2H-Chromen-2-one structural motif. Molecules 2016; 21(3): 362.
[http://dx.doi.org/10.3390/molecules21030362] [PMID: 26999091]
[13]
Farina R, Pisani L, Catto M, et al. Structure-based design and optimization of multitarget-directed 2 H-chromen-2-one derivatives as potent inhibitors of monoamine oxidase b and cholinesterases. J Med Chem 2015; 58(14): 5561-78.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00599] [PMID: 26107513]
[14]
Mathew B, Mathew GE, Suresh J, et al. Monoamine oxidase inhibitors, perspective design for the treatment of depression and neurological disorders. Curr Enzym Inhib 2016; 12: 115-22.
[http://dx.doi.org/10.2174/1573408012666160402001715]
[15]
Dezsi L, Vecsei L. Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord Drug Targets 2017; 16(4): 425-39.
[http://dx.doi.org/10.2174/1871527316666170124165222] [PMID: 28124620]
[16]
Zhang X, Rakesh KP, Bukhari SNA, Balakrishna M, Manukumar HM, Qin HL. 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]
[17]
Pisani L, Catto M, Leonetti F, et al. Targeting monoamine oxidases with multipotent ligands, an emerging strategy in the search of new drugs against neurodegenerative diseases. Curr Med Chem 2011; 18(30): 4568-87.
[http://dx.doi.org/10.2174/092986711797379302] [PMID: 21864289]
[18]
Mathew B, Suresh J, Anbazhagan S, Paulraj J, Krishnan GK. Heteroaryl chalcones mini-review about their therapeutic voyage. Biomed Prev Nut 2014; 4: 451-8.
[http://dx.doi.org/10.1016/j.bionut.2014.04.003]
[19]
Mahapatra DK, Asati V, Bharti SK. Chalcones and their therapeutic targets for the management of diabetes, structural and pharmacological perspectives. Eur J Med Chem 2015; 92: 839-65.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.051] [PMID: 25638569]
[20]
Bhukari SNA, Jasamai M, Jantan I, Ahmad W. Review of methods and various catalysts used for chalcone synthesis. Mini Rev Org Chem 2013; 10: 73-83.
[http://dx.doi.org/10.2174/1570193X11310010006]
[21]
Liu HR, Liu XJ, Fan HQ, Tang JJ, Gao XH, Liu WK. Design, synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem 2014; 22(21): 6124-33.
[http://dx.doi.org/10.1016/j.bmc.2014.08.033] [PMID: 25260958]
[22]
Robinson SJ, Petzer JP, Petzer A, Bergh JJ, Lourens ACU. Selected furanochalcones as inhibitors of monoamine oxidase. Bioorg Med Chem Lett 2013; 23(17): 4985-9.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.050] [PMID: 23860591]
[23]
Minders C, Petzer JP, Petzer A, Lourens ACU. Monoamine oxidase inhibitory activities of heterocyclic chalcones. Bioorg Med Chem Lett 2015; 25(22): 5270-6.
[http://dx.doi.org/10.1016/j.bmcl.2015.09.049] [PMID: 26432037]
[24]
Mathew B, Ucar G, Raphael C, Mathew GE, Joy M, Machaba KE. Characterization of thienylchalcones as hMAO-B inhibitors: Synthesis, biochemistry and molecular dynamics studies. ChemistrySelect 2017; 2: 11113-9.
[http://dx.doi.org/10.1002/slct.201702141]
[25]
Hammuda A, Shalaby R, Rovida S, Edmondson DE, Binda C, Khalil A. Design and synthesis of novel chalcones as potent selective monoamine oxidase-B inhibitors. Eur J Med Chem 2016; 114: 162-9.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.038] [PMID: 26974383]
[26]
Zaib S, Farooq Rizvi SU, Aslam S, Ahmad M, Al-Rashida M, Iqbal J. Monoamine oxidase inhibition and molecular modeling studies of piperidyl-thienyl and 2-pyrazoline derivatives of chalcones. Med Chem 2015; 11(5): 497-505.
[http://dx.doi.org/10.2174/1573406410666141229101130] [PMID: 25544115]
[27]
Mathew B, Haridas A, Suresh J, Mathew GE, Uçar G, Jayaprakash V. Monoamine oxidase inhibitory actions of chalcones. A mini review. Cent Nerv Syst Agents Med Chem 2016; 16(2): 120-36.
[http://dx.doi.org/10.2174/1871524915666151002124443] [PMID: 26429556]
[28]
Mathew B. Unraveling the structural requirements of chalcone chemistry towards monoamine oxidase inhibition. Cent Nerv Syst Agents Med Chem 2019; 19(1): 6-7.
[http://dx.doi.org/10.2174/1871524919666190131160122] [PMID: 30706795]
[29]
Suresh J, Baek SC, Ramakrishnan SP, Kim H, Mathew B. Discovery of potent and reversible MAO-B inhibitors as furanochalcones. Int J Biol Macromol 2018; 108: 660-4.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.11.159] [PMID: 29195801]
[30]
Mathew B, Mathew GE, Ucar G, et al. Monoamine oxidase inhibitory activity of methoxy-substituted chalcones. Int J Biol Macromol 2017; 104: (Pt A): 1321-9.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.05.162] [PMID: 28577983]
[31]
Sasidharan R, Baek SC, Sreedharannair LM, Kim H, Mathew B. Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors. Biomed Pharmacother 2018; 106: 8-13.
[http://dx.doi.org/10.1016/j.biopha.2018.06.064] [PMID: 29940538]
[32]
Chimenti F, Fioravanti R, Bolasco A, et al. Chalcones: A valid scaffold for monoamine oxidases inhibitors. J Med Chem 2009; 52(9): 2818-24.
[http://dx.doi.org/10.1021/jm801590u] [PMID: 19378991]
[33]
Mathew B, Mathew GE, Uçar G, et al. Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies. Bioorg Chem 2015; 62: 22-9.
[http://dx.doi.org/10.1016/j.bioorg.2015.07.001] [PMID: 26189013]
[34]
Mathew B, Uçar G, Yabanoğlu-Çiftçi S, et al. Development of fluorinated thienylchalcones as monoamine oxidase-b inhibitors: Design, synthesis, biological evaluation and molecular docking studies. Lett Org Chem 2015; 12: 605-13.
[http://dx.doi.org/10.2174/1570178612666150903213416]
[35]
Mathew B, Mathew GE, Uçar G, et al. Potent and selective monoamine oxidase-b inhibitory activity: Fluoro- vs. trifluoromethyl-4-hydroxylated chalcone derivatives. Chem Biodivers 2016; 13(8): 1046-52.
[http://dx.doi.org/10.1002/cbdv.201500367] [PMID: 27402375]
[36]
Mathew B, Uçar G, Mathew GE, et al. Monoamine oxidase inhibitory activity: Methyl- versus chloro-chalcone derivatives. ChemMedChem 2016; 11(24): 2649-55.
[http://dx.doi.org/10.1002/cmdc.201600497] [PMID: 27902880]
[37]
Mathew B, Haridas A, Uçar G, et al. Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors. Int J Biol Macromol 2016; 91: 680-95.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.05.110] [PMID: 27262516]
[38]
Mathew B, Haridas A, Uçar G, et al. Synthesis, biochemistry, and computational studies of brominated thienyl chalcones: A new class of reversible MAO-B inhibitors. ChemMedChem 2016; 11(11): 1161-71.
[http://dx.doi.org/10.1002/cmdc.201600122] [PMID: 27159243]
[39]
Sasidharan R, Manju SL, Uçar G, Baysal I, Mathew B. Identification of indole based chalcones: Discovery of potent, selective and reversible class of MAO-B inhibitors. Arch Pharm (Weinheim) 2016; 349(8): 627-37.
[http://dx.doi.org/10.1002/ardp.201600088] [PMID: 27373997]
[40]
Mathew B, Adeniyi AA, Dev S, et al. Pharmacophore based 3D-QSAR analysis of thienyl chalcone as new class of human MAO-B inhibitors. Investigation of combined quantum chemical and molecular dynamics approach. J Phys Chem B 2017; 121(6): 1186-203.
[http://dx.doi.org/10.1021/acs.jpcb.6b09451] [PMID: 28084742]
[41]
Mathew B, Baek SC, Thomas Parambi DG, et al. Potent and highly selective dual-targeting monoamine oxidase-B inhibitors: Fluorinated chalcones of morpholine versus imidazole. Arch Pharm (Weinheim) 2019; 352(4)e1800309
[http://dx.doi.org/10.1002/ardp.201800309] [PMID: 30663112]
[42]
Lakshminarayan B, Baek SC, Kannappan N, et al. Ethoxylated head of chalcones as a new class of multi-targeted MAO inhibitors. ChemistrySelect 2019; 4(21): 6614-9.
[http://dx.doi.org/10.1002/slct.201901093]
[43]
Reeta VR, Rangarajan TM. Ayushee, Singh RP, Singh M. Synthesis of novel chalcones through palladium-catalyzed C-O cross coupling reaction of bromochalcones with ethyl acetohydroxamate and their anti-plasmodial evaluation against plasmodium falcipuram in vitro. Bioorg Chem 2019; 86: 631-40.
[http://dx.doi.org/10.1016/j.bioorg.2019.02.016] [PMID: 30818235]
[44]
Mathew B, Baek SC, Grace TPD, et al. Selected aryl thiosemicarbazones as a new class of multi-targeted monoamine oxidase inhibitors. MedChemComm 2018; 9(11): 1871-81.
[http://dx.doi.org/10.1039/C8MD00399H] [PMID: 30568755]
[45]
Lee HW, Ryu HW, Kang MG, Park D, Oh SR, Kim H. Potent selective monoamine oxidase B inhibition by maackiain, a pterocarpan from the roots of Sophora flavescens. Bioorg Med Chem Lett 2016; 26(19): 4714-9.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.044] [PMID: 27575476]
[46]
Baek SC, Lee HW, Ryu HW, et al. Selective inhibition of monoamine oxidase A by hispidol. Bioorg Med Chem Lett 2018; 28(4): 584-8.
[http://dx.doi.org/10.1016/j.bmcl.2018.01.049] [PMID: 29395970]
[47]
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. 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]
[48]
Baek SC, Park MH, Ryu HW, et al. Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A. Bioorg Chem 2019; 83: 317-25.
[http://dx.doi.org/10.1016/j.bioorg.2018.10.051] [PMID: 30396116]
[49]
Son SY, 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): 5739-44.
[http://dx.doi.org/10.1073/pnas.0710626105] [PMID: 18391214]
[50]
Binda C, Wang J, Pisani L, et al. Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: Safinamide and coumarin analogs. J Med Chem 2007; 50(23): 5848-52.
[http://dx.doi.org/10.1021/jm070677y] [PMID: 17915852]
[51]
Cheung J, Rudolph MJ, Burshteyn F, et al. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 2012; 55(22): 10282-6.
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[52]
Parambi DGT, Oh JM, Baek SC, et al. Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors. Bioorg Chem 2019; 93103335
[53]
Genheden S, Ryde U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov 2015; 10(5): 449-61.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[54]
Announcing Schrödinger Software Release 2019-1. Available form: https://www.schrodinger.com/news/announcing-schr%C3B6dinger-software-release-2019-1.
[55]
Montaruli M, Alberga D, Ciriaco F, et al. Accelerating drug discovery by early protein drug target prediction based on multi-fingerprint similarity search. Molecules 2019; 24(12): 2233.
[http://dx.doi.org/10.3390/molecules24122233] [PMID: 31207991]
[56]
Nicolotti O, Miscioscia TF, Leonetti F, Muncipinto G, Carotti A. Screening of matrix metalloproteinases available from the protein data bank: Insights into biological functions, domain organization, and zinc binding groups. J Chem Inf Model 2007; 47(6): 2439-48.
[http://dx.doi.org/10.1021/ci700119r] [PMID: 17958346]
[57]
Alberga D, Trisciuzzi D, Montaruli M, Leonetti F, Mangiatordi GF, Nicolotti O. A new approach for drug target and bioactivity prediction: The Multi-fingerprint Similarity Search aLgorithm (MuSSeL). J Chem Inf Model 2019; 59(1): 586-96.
[http://dx.doi.org/10.1021/acs.jcim.8b00698] [PMID: 30485097]
[58]
Gaulton A, Hersey A, Nowotka M, et al. The ChEMBL database in 2017. Nucleic Acids Res 2017; 45(D1): D945-54.
[http://dx.doi.org/10.1093/nar/gkw1074] [PMID: 27899562]

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