Aminoalkylated Phenolic Chalcones: Investigation of Biological Effects on Acetylcholinesterase and Carbonic Anhydrase I and II as Potential Lead Enzyme Inhibitors

Author(s): Cem Yamali*, Halise Inci Gul*, Tahir Cakir, Yeliz Demir, Ilhami Gulcin

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 10 , 2020


DOI : 10.2174/1570180817999200520123510

  Journal Home
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors.

Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4- substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors.

Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes.

Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44±3.17 nM to 43.25±6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76±1.29-31.09±2.7 nM (hCA I) and 6.08 ± 1.18-23.12±4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted.

Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.

Keywords: Mannich, chalcone, carbonic anhydrases, acetylcholinesterase, phenol, hCA I, hCA II.

[1]
Mannich, C.; Krosche, W. Ueber ein Kondensationsprodukt aus formaldehyd, ammoniak und antipyrin. Arch. Pharm. (Berl.), 1912, 250, 647-667.
[http://dx.doi.org/10.1002/ardp.19122500151]
[2]
Bala, S.; Sharma, N.; Kajal, A.; Kamboj, S.; Saini, V. Mannich bases: An important pharmacophore in present scenario. Int. J. Med. Chem., 2014, 2014, 191072
[http://dx.doi.org/10.1155/2014/191072] [PMID: 25478226]
[3]
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]
[4]
Subramaniapillai, S. Mannich reaction: A versatile and convenient approach to bioactive skeletons. J. Chem. Sci., 2013, 125, 467-482.
[http://dx.doi.org/10.1007/s12039-013-0405-y]
[5]
Wilhelm, A.; Kendrekar, P.; Noreljaleel, A.E.; Abay, E.T.; Bonnet, S.L.; Wiesner, L.; de Kock, C.; Swart, K.J.; van der Westhuizen, J.H. Syntheses and in vitro antiplasmodial activity of aminoalkylated chalcones and analogues. J. Nat. Prod., 2015, 78(8), 1848-1858.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00114] [PMID: 26235033]
[6]
Liu, H.R.; Men, X.; Gao, X.H.; Liu, L.B.; Fan, H.Q.; Xia, X.H.; Wang, Q.A. Discovery of potent and selective acetylcholinesterase (AChE) inhibitors: Acacetin 7-O-methyl ether Mannich base derivatives synthesised from easy access natural product naringin. Nat. Prod. Res., 2018, 32(6), 743-747.
[http://dx.doi.org/10.1080/14786419.2017.1340280] [PMID: 28617100]
[7]
Mamedova, G.; Mahmudova, A.; Mamedov, S.; Erden, Y.; Taslimi, P.; Tüzün, B.; Tas, R.; Farzaliyev, V.; Sujayev, A.; Alwasel, S.H.; Gulçin, İ. Novel tribenzylaminobenzolsulphonylimine based on their pyrazine and pyridazines: Synthesis, characterization, antidiabetic, anticancer, anticholinergic, and molecular docking studies. Bioorg. Chem., 2019., 93103313
[http://dx.doi.org/10.1016/j.bioorg.2019.103313] [PMID: 31586711]
[8]
Ling, S.; Yanhua, Z.; Caifang, W.; Haoran, L.; Qiuan, W. Synthesis and acetylcholinesterase inhibitory activity of polymethoxyflavone Mannich base derivatives. Chem. Res. Chin. Univ., 2017, 33(4), 594-597.
[http://dx.doi.org/10.1007/s40242-017-6462-x]
[9]
Liu, H.; Qiang, X.; Song, Q.; Li, W.; He, Y.; Ye, C.; Tan, Z.; Deng, Y. Discovery of 4′-OH-flurbiprofen Mannich base derivatives as potential Alzheimer’s disease treatment with multiple inhibitory activities. Bioorg. Med. Chem., 2019, 27(6), 991-1001.
[http://dx.doi.org/10.1016/j.bmc.2019.01.040] [PMID: 30772129]
[10]
Li, Y.; Qiang, X.; Luo, L.; Yang, X.; Xiao, G.; Zheng, Y.; Cao, Z.; Sang, Z.; Su, F.; Deng, Y. Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties. Bioorg. Med. Chem., 2017, 25(2), 714-726.
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID: 27923535]
[11]
Sosa-Ortiz, A.L.; Acosta-Castillo, I.; Prince, M.J. Epidemiology of dementias and Alzheimer’s disease. Arch. Med. Res., 2012, 43(8), 600-608.
[http://dx.doi.org/10.1016/j.arcmed.2012.11.003] [PMID: 23159715]
[12]
Zhang, X.; Song, Q.; Cao, Z.; Li, Y.; Tian, C.; Yang, Z.; Zhang, H.; Deng, Y. Design, synthesis and evaluation of chalcone Mannich base derivatives as multifunctional agents for the potential treatment of Alzheimer’s disease. Bioorg. Chem., 2019, 87, 395-408.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.043] [PMID: 30921741]
[13]
Supuran, C.T.; Mugelli, A. Polypharmacology of carbonic anhydrase inhibitors; Pharmadvances, 2019, pp. 14-38.
[14]
Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J., 2016, 473(14), 2023-2032.
[http://dx.doi.org/10.1042/BCJ20160115] [PMID: 27407171]
[15]
Supuran, C.T.; Scozzafava, A. Carbonic anhydrases as targets for medicinal chemistry. Bioorg. Med. Chem., 2007, 15(13), 4336-4350.
[http://dx.doi.org/10.1016/j.bmc.2007.04.020] [PMID: 17475500]
[16]
Biçer, A.; Taslimi, P.; Yakalı, G.; Gülçin, I.; Serdar Gültekin, M.; Turgut Cin, G. Synthesis, characterization, crystal structure of novel bis-thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes. Bioorg. Chem., 2019, 82, 393-404.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.001] [PMID: 30428418]
[17]
Karioti, A.; Carta, F.; Supuran, C.T. Phenols and polyphenols as carbonic anhydrase inhibitors. Molecules, 2016, 21(12), 1649-1676.
[http://dx.doi.org/10.3390/molecules21121649] [PMID: 27918439]
[18]
Innocenti, A.; Vullo, D.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase inhibitors: interactions of phenols with the 12 catalytically active mammalian isoforms (CA I-XIV). Bioorg. Med. Chem. Lett., 2008, 18(5), 1583-1587.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.077] [PMID: 18242985]
[19]
Huyut, Z.; Beydemir, Ş.; Gülçin, İ. Inhibitory effects of some phenolic compounds on the activities of carbonic anhydrase: from in vivo to ex vivo. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1234-1240.
[http://dx.doi.org/10.3109/14756366.2015.1117459] [PMID: 26670706]
[20]
Bilginer, S.; Unluer, E.; Gul, H.I.; Mete, E.; Isik, S.; Vullo, D.; Ozensoy-Guler, O.; Beyaztas, S.; Capasso, C.; Supuran, C.T. Carbonic anhydrase inhibitors. Phenols incorporating 2- or 3-pyridyl-ethenylcarbonyl and tertiary amine moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase. J. Enzyme Inhib. Med. Chem., 2014, 29(4), 495-499.
[http://dx.doi.org/10.3109/14756366.2013.806497] [PMID: 23808805]
[21]
Gul, H.I.; Yazici, Z.; Tanc, M.; Supuran, C.T. Inhibitory effects of benzimidazole containing new phenolic Mannich bases on human carbonic anhydrase isoforms hCA I and II. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1540-1544.
[http://dx.doi.org/10.3109/14756366.2016.1156675] [PMID: 26985571]
[22]
Tugrak, M.; Gul, H.I.; Bandow, K.; Sakagami, H.; Gulcin, I.; Ozkay, Y.; Supuran, C.T. Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors. Bioorg. Chem., 2019., 90103095
[http://dx.doi.org/10.1016/j.bioorg.2019.103095] [PMID: 31288135]
[23]
Yamali, C.; Gul, H.I.; Sakagami, H.; Supuran, C.T. Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases. J. Enzyme Inhib. Med. Chem., 2016, 31(Suppl. 4), 125-131.
[24]
Yamali, C.; Gul, H.I.; Ozgun, D.O.; Sakagam, H.; Umemura, N.; Kazaz, C.; Gul, M. Synthesis and cytotoxic activities of difluoro-dimethoxy chalcones. Anticancer. Agents Med. Chem., 2017, 17(10), 1426-1433.
[http://dx.doi.org/10.2174/1871520617666170327123909] [PMID: 28356013]
[25]
Yamali, C.; Ozmen Ozgun, D. Gul, H. I., Sakagami, H., Kazaz, C., Okudaira, N. Synthesis and structure elucidation of 1-(2,5/3,5-difluorophenyl)-3-(2,3/2,4/2,5/3,4-dimethoxyphenyl)-2-propen-1-ones as anticancer agents. Med. Chem. Res., 2017, 26(9), 2015-2023.
[http://dx.doi.org/10.1007/s00044-017-1911-0]
[26]
Badr, G.; Gul, H.I.; Yamali, C.; Mohamed, A.A.M.; Badr, B.M.; Gul, M.; Abo Markeb, A.; Abo El-Maali, N. Curcumin analogue 1,5-bis(4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)penta-1,4-dien-3-one mediates growth arrest and apoptosis by targeting the PI3K/AKT/mTOR and PKC-theta signaling pathways in human breast carcinoma cells. Bioorg. Chem., 2018, 78, 46-57.
[http://dx.doi.org/10.1016/j.bioorg.2018.03.006] [PMID: 29533214]
[27]
Gul, H.I.; Yamali, C.; Yesilyurt, F.; Sakagami, H.; Kucukoglu, K.; Gulcin, I.; Gul, M.; Supuran, C.T. Microwave-assisted synthesis and bioevaluation of new sulfonamides. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 369-374.
[http://dx.doi.org/10.1080/14756366.2016.1254207] [PMID: 28260401]
[28]
Gul, H.I.; Yamali, C.; Gunesacar, G.; Sakagami, H.; Okudaira, N.; Uesawa, Y.; Kagaya, H. Cytotoxicity, apoptosis, and QSAR studies of phenothiazine derived methoxylated chalcones as anticancer drug candidates. Med. Chem. Res., 2018, 27(10), 2366-2378.
[http://dx.doi.org/10.1007/s00044-018-2242-5]
[29]
Gul, H.I.; Yamali, C.; Bulbuller, M.; Kirmizibayrak, P.B.; Gul, M.; Angeli, A.; Bua, S.; Supuran, C.T. Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes. Bioorg. Chem., 2018, 78, 290-297.
[http://dx.doi.org/10.1016/j.bioorg.2018.03.027] [PMID: 29621641]
[30]
Gul, H.I.; Yamali, C.; Sakagami, H.; Angeli, A.; Leitans, J.; Kazaks, A.; Tars, K.; Ozgun, D.O.; Supuran, C.T. New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors. Bioorg. Chem., 2018, 77, 411-419.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.021] [PMID: 29427856]
[31]
Verpoorte, J.A.; Mehta, S.; Edsall, J.T. Esterase activities of human carbonic anhydrases B and C. J. Biol. Chem., 1967, 242(18), 4221-4229.
[PMID: 4964830]
[32]
Sarı, Y.; Aktaş, A.; Taslimi, P.; Gök, Y.; Gulçin, İ. Novel N-propylphthalimide- and 4-vinylbenzyl-substituted benzimidazole salts: Synthesis, characterization, and determination of their metal chelating effects and inhibition profiles against acetylcholinesterase and carbonic anhydrase enzymes. J. Biochem. Mol. Toxicol., 2018, 32(1)
[http://dx.doi.org/10.1002/jbt.22009] [PMID: 29149534]
[33]
Yamali, C.; Gul, H.I.; Ece, A.; Taslimi, P.; Gulcin, I. Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes. Chem. Biol. Drug Des., 2018, 91(4), 854-866.
[http://dx.doi.org/10.1111/cbdd.13149] [PMID: 29143485]
[34]
Lineweaver, H.; Burk, D. The determination of enzyme dissociation constants. J. Am. Chem. Soc., 1934, 56, 658-666.
[http://dx.doi.org/10.1021/ja01318a036]
[35]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[36]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. 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]
[37]
Ozgun, D.O.; Yamali, C.; Gul, H.I.; Taslimi, P.; Gulcin, I.; Yanik, T.; Supuran, C.T. Inhibitory effects of isatin Mannich bases on carbonic anhydrases, acetylcholinesterase, and butyrylcholinesterase. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1498-1501.
[http://dx.doi.org/10.3109/14756366.2016.1149479] [PMID: 26928426]
[38]
Li, Y.; Qiang, X.; Luo, L.; Yang, X.; Xiao, G.; Liu, Q.; Ai, J.; Tan, Z.; Deng, Y. Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-β-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer’s disease. Eur. J. Med. Chem., 2017, 126, 762-775.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.009] [PMID: 27951485]
[39]
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., 94103477
[http://dx.doi.org/10.1016/j.bioorg.2019.103477] [PMID: 31818478]
[40]
Yamali, C.; Tugrak, M.; Gul, H.I.; Tanc, M.; Supuran, C.T. The inhibitory effects of phenolic Mannich bases on carbonic anhydrase I and II isoenzymes. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1678-1681.
[http://dx.doi.org/10.3109/14756366.2015.1126715] [PMID: 26808123]
[41]
Inci Gul, H.; Yamali, C.; Tugce Yasa, A.; Unluer, E.; Sakagami, H.; Tanc, M.; Supuran, C.T. Carbonic anhydrase inhibition and cytotoxicity studies of Mannich base derivatives of thymol. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1375-1380.
[http://dx.doi.org/10.3109/14756366.2016.1140755] [PMID: 26850788]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 10
Year: 2020
Published on: 11 October, 2020
Page: [1283 - 1292]
Pages: 10
DOI: 10.2174/1570180817999200520123510
Price: $65

Article Metrics

PDF: 13
HTML: 1



Most Downloaded Article(s)