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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase Inhibitors

Author(s): Martin Krátký*, Karolína Jaklová, Šárka Štěpánková, Katarína Svrčková, Václav Pflégr and Jarmila Vinšová

Volume 20, Issue 23, 2020

Page: [2094 - 2105] Pages: 12

DOI: 10.2174/1568026620666200819154722

Price: $65

Abstract

Background: Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. Objective: That is why we designed twenty-two analogues of a dual AChEBuChE salicylanilide inhibitor, N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide 1, to improve its potency.

Methods: We prepared N,N-disubstituted (thio)carbamates via direct acylation with (thio)carbamoyl chloride, N-n-alkyl monosubstituted carbamates using isocyanates as well as its salicylanilide core analogues. The derivatives were evaluated in vitro against AChE from electric eel and BuChE from equine serum using spectrophotometric Ellman’s method.

Results: The compounds showed moderate inhibition of both AChE and BuChE with IC50 from 18.2 to 196.6 μmol.L-1 and 9.2 to 196.2 μmol.L-1, respectively. Importantly, based on the substitution pattern, it is possible to modulate selectivity against AChE or BuChE and some derivatives also produced a balanced inhibition. In general, the most promising analogues were N-alkyl (C2-C6) carbamates and isomers with a changed position of phenolic hydroxyl. N-[3,5-Bis(trifluoromethyl)phenyl]-3-bromo-5- hydroxybenzamide 4a was the best inhibitor of both cholinesterases.

Conclusion: A wide range of the derivatives improved the activity of the hit 1, they were superior to carbamate drug rivastigmine against AChE and some of them also against BuChE. The most promising derivatives also fit physicochemical space and structural features for CNS drugs together with an escalated lipophilicity.

Keywords: Acetylcholinesterase, Benzamides, Butyrylcholinesterase, Carbamates, Enzyme inhibition, Salicylanilides, Thiocarbamates.

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[1]
Colović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.M.; Vasić, V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr. Neuropharmacol., 2013, 11(3), 315-335.
[http://dx.doi.org/10.2174/1570159X11311030006] [PMID: 24179466]
[2]
Greig, N.H.; Utsuki, T.; Yu, Q.; Zhu, X.; Holloway, H.W.; Perry, T.; Lee, B.; Ingram, D.K.; Lahiri, D.K. A new therapeutic target in Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr. Med. Res. Opin., 2001, 17(3), 159-165.
[http://dx.doi.org/10.1185/03007990152673800] [PMID: 11900310]
[3]
World Alzheimer Report. The state of the art of dementia research: New frontiers, 2018. Available from: https://www.alz.co.uk/research/WorldAlzheimerReport2018.pdf
[4]
Crous-Bou, M.; Minguillón, C.; Gramunt, N.; Molinuevo, J.L. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res. Ther., 2017, 9(1), 71.
[http://dx.doi.org/10.1186/s13195-017-0297-z] [PMID: 28899416]
[5]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: targeting the cholinergic system. Curr. Neuropharmacol., 2016, 14(1), 101-115.
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[6]
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[7]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[8]
Medeiros, R.; Baglietto-Vargas, D.; LaFerla, F.M. The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci. Ther., 2011, 17(5), 514-524.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00177.x] [PMID: 20553310]
[9]
Pohanka, M. Alzheimer’s disease and oxidative stress: a review. Curr. Med. Chem., 2014, 21(3), 356-364.
[http://dx.doi.org/10.2174/09298673113206660258] [PMID: 24059239]
[10]
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36(4), 375-399.
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[11]
Giacobini, E. Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer’s disease? Drugs Aging, 2001, 18(12), 891-898.
[http://dx.doi.org/10.2165/00002512-200118120-00001] [PMID: 11888344]
[12]
Furukawa-Hibi, Y.; Alkam, T.; Nitta, A.; Matsuyama, A.; Mizoguchi, H.; Suzuki, K.; Moussaoui, S.; Yu, Q.S.; Greig, N.H.; Nagai, T.; Yamada, K. Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice. Behav. Brain Res., 2011, 225(1), 222-229.
[http://dx.doi.org/10.1016/j.bbr.2011.07.035] [PMID: 21820013]
[13]
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]
[14]
Jing, L.; Wu, G.; Kang, D.; Zhou, Z.; Song, Y.; Liu, X.; Zhan, P. Contemporary medicinal-chemistry strategies for the discovery of selective butyrylcholinesterase inhibitors. Drug Discov. Today, 2019, 24(2), 629-635.
[http://dx.doi.org/10.1016/j.drudis.2018.11.012] [PMID: 30503804]
[15]
Shaikh, S.; Verma, A.; Siddiqui, S.; Ahmad, S.S.; Rizvi, S.M.D.; Shakil, S.; Biswas, D.; Singh, D.; Siddiqui, M.H.; Shakil, S.; Tabrez, S.; Kamal, M.A. Current acetylcholinesterase-inhibitors: a neuroinformatics perspective. CNS Neurol. Disord. Drug Targets, 2014, 13(3), 391-401.
[http://dx.doi.org/10.2174/18715273113126660166] [PMID: 24059296]
[16]
Ghosh, A.K.; Brindisi, M. Organic carbamates in drug design and medicinal chemistry. J. Med. Chem., 2015, 58(7), 2895-2940.
[http://dx.doi.org/10.1021/jm501371s] [PMID: 25565044]
[17]
Imramovsky, A.; Stepankova, S.; Vanco, J.; Pauk, K.; Monreal-Ferriz, J.; Vinsova, J.; Jampilek, J. Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking. Molecules, 2012, 17(9), 10142-10158.
[http://dx.doi.org/10.3390/molecules170910142] [PMID: 22922284]
[18]
Krátký, M.; Štěpánková, Š.; Vorčáková, K.; Švarcová, M.; Vinšová, J. Novel cholinesterase inhibitors based on O-aromatic N,Ndisubstituted carbamates and thiocarbamates. Molecules, 2016, 21(2), 191.
[http://dx.doi.org/10.3390/molecules21020191] [PMID: 26875979]
[19]
Krátký, M.; Štěpánková, Š.; Vorčáková, K.; Vinšová, J. Investigation of salicylanilide and 4-chlorophenol-based Nmonosubstituted carbamates as potential inhibitors of acetyl- and butyrylcholinesterase. Bioorg. Chem., 2018, 80, 668-673.
[http://dx.doi.org/10.1016/j.bioorg.2018.07.017] [PMID: 30059892]
[20]
Krátký, M.; Štěpánková, Š.; Houngbedji, N.-H.; Vosátka, R.; Vorčáková, K.; Vinšová, J. 2-Hydroxy-N-phenylbenzamides and their esters inhibit acetylcholinesterase and butyrylcholinesterase. Biomolecules, 2019, 9(11), 698.
[http://dx.doi.org/10.3390/biom9110698] [PMID: 31694272]
[21]
Paraskevopoulos, G.; Monteiro, S.; Vosátka, R.; Krátký, M.; Navrátilová, L.; Trejtnar, F.; Stolaříková, J.; Vinšová, J. Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis, antimicrobial activity and cytotoxicity. Bioorg. Med. Chem., 2017, 25(4), 1524-1532.
[http://dx.doi.org/10.1016/j.bmc.2017.01.016] [PMID: 28126437]
[22]
Cheng, Y.; Hu, X.-Q.; Gao, S.; Lu, L.-Q.; Chen, J.R.; Xiao, W.J. Formal [4+1] cycloaddition of camphor-derived sulfonium salts with aldimines: enantioselective synthesis of 2,3-dihydrobenzofurans. Tetrahedron, 2013, 69, 3810-3816.
[http://dx.doi.org/10.1016/j.tet.2013.03.059]
[23]
Zdrazilova, P.; Stepankova, S.; Komers, K.; Ventura, K.; Cegan, A. Half-inhibition concentrations of new cholinesterase inhibitors. Z. Natforsch. C J. Biosci., 2004, 59(3-4), 293-296.
[http://dx.doi.org/10.1515/znc-2004-3-430] [PMID: 15241943]
[24]
Sinko, G.; Calić, M.; Bosak, A.; Kovarik, Z. Limitation of the Ellman method: cholinesterase activity measurement in the presence of oximes. Anal. Biochem., 2007, 370(2), 223-227.
[http://dx.doi.org/10.1016/j.ab.2007.07.023] [PMID: 17716616]
[25]
Krátký, M.; Volková, M.; Novotná, E.; Trejtnar, F.; Stolaříková, J.; Vinšová, J. Synthesis and biological activity of new salicylanilide N,N-disubstituted carbamates and thiocarbamates. Bioorg. Med. Chem., 2014, 22(15), 4073-4082.
[http://dx.doi.org/10.1016/j.bmc.2014.05.064] [PMID: 24953953]
[26]
Krátký, M.; Vinšová, J. Salicylanilide N-monosubstituted carbamates: Synthesis and in vitro antimicrobial activity. Bioorg. Med. Chem., 2016, 24(6), 1322-1330.
[http://dx.doi.org/10.1016/j.bmc.2016.02.004] [PMID: 26879856]
[27]
Smith, B.D.; Goodenough-Lashua, D.M.; D’Souza, C.J.E.; Norton, K.J.; Schmidt, L.M.; Tung, J.C. Substituent effects on the barrier to carbamate C–N rotation. Tetrahedron Lett., 2004, 45, 2747-2749.
[http://dx.doi.org/10.1016/j.tetlet.2004.02.037]
[28]
Vaneststammer, R.; Engberts, J.B. Hindered internal rotation in carbamates: An NMR study of the conformations of alkyl and aryl N-(alkylsulfonylmethyl)-N-methylcarbamates and aryl N-(arylsulfonylmethyl)-N-methylcarbamates. Recl. Trav. Chim. Pays Bas, 1971, 90, 1307-1319.
[http://dx.doi.org/10.1002/recl.19710901204]
[29]
de los Ríos, C. Cholinesterase inhibitors: a patent review (2007 - 2011). Expert Opin. Ther. Pat., 2012, 22(8), 853-869.
[http://dx.doi.org/10.1517/13543776.2012.701619] [PMID: 22764681]
[30]
Fallah, A.; Mohanazadeh, F.; Safavi, M. Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE. Med. Chem. Res., 2020, 29, 341-355.
[http://dx.doi.org/10.1007/s00044-019-02475-6]
[31]
Mahar Doan, K.M.; Humphreys, J.E.; Webster, L.O.; Wring, S.A.; Shampine, L.J.; Serabjit-Singh, C.J.; Adkison, K.K.; Polli, J.W. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther., 2002, 303(3), 1029-1037.
[http://dx.doi.org/10.1124/jpet.102.039255] [PMID: 12438524]
[32]
Ghose, A.K.; Ott, G.R.; Hudkins, R.L. Technically extended multiparameter optimization (TEMPO): an advanced robust scoring scheme to calculate central nervous system druggability and monitor lead optimization. ACS Chem. Neurosci., 2017, 8(1), 147-154.
[http://dx.doi.org/10.1021/acschemneuro.6b00273] [PMID: 27741392]
[33]
Arnott, J.A.; Planey, S.L. The influence of lipophilicity in drug discovery and design. Expert Opin. Drug Discov., 2012, 7(10), 863-875.
[http://dx.doi.org/10.1517/17460441.2012.714363] [PMID: 22992175]

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