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Letters in Drug Design & Discovery

Author(s): Leyla Yurttaş*, Betül Kaya Çavuşoğlu, Halide Edip Temel and Gülşen Akalın Çiftçi

DOI: 10.2174/1570180817999201110114107

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Novel N-(2-Methoxydibenzofuran-3-yl)-2-aryloxyacetamide Derivatives: Synthesis and Biological Investigation

Page: [471 - 479] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: Dibenzofuran ring is a typical heterocyle that is found in many natural sources and its derivatives exhibit a wide scale of biological applications similar to its analog ring systems; furan and benzofuran.

Materials and Methods: Novel N-(2-methoxydibenzofuran-3-yl)-2-aryloxyacetamide derivatives (2a-l) were synthesized and evaluated for their cytotoxic activity against A549 lung cancer and NIH/3T3 mouse embryofibroblast cell lines. The inhibition percentages of cathepsin D, L, acetylcholinesterase (AChE) and butrylcholinesterase (BuChE) enzymes provoked by the compounds were also determined.

Results and Discussion: Most of the compounds exhibited significant cytotoxicity whose IC50 values were identified lower than the tested lowest concentration (<3.90 μg/mL). Compound 2i against cathepsin D and compound 2k against cathepsin L displayed the highest inhibitory activity. Regrettably, the compounds demonstrated very weak AChE and BuChE inhibition.

Conclusion: Compounds 2b, 2c, 2e, 2i and 2k exhibited the highest antiproliferative activity against A549 cell lines with selective profile. However, they did not display satisfying results on tested enzymes.

Keywords: Dibenzofuran, usnic acid, cytotoxicity, cathepsin inhibition, anticholinesterase activity, cytotoxic activity.Dibenzofuran, usnic acid, cytotoxicity, cathepsin inhibition, anticholinesterase activity, cytotoxic activity.

Graphical Abstract

[1]
Millot, M.; Dieu, A.; Tomasi, S. Dibenzofurans and derivatives from lichens and ascomycetes. Nat. Prod. Rep., 2016, 33(6), 801-811.
[http://dx.doi.org/10.1039/C5NP00134J] [PMID: 26867808]
[2]
Huneck, S.; Yoshimura, I. Identification of lichen substances; Springer: Berlin, Heidelberg, 1996.
[http://dx.doi.org/10.1007/978-3-642-85243-5]
[3]
Molnár, K.; Farkas, E. Current results on biological activities of lichen secondary metabolites: A review. Z. Natforsch. C J. Biosci., 2010, 65(3-4), 157-173.
[http://dx.doi.org/10.1515/znc-2010-3-401] [PMID: 20469633]
[4]
Brisdelli, F.; Perilli, M.; Settlitri, D.; Piovano, M.; Garbarino, J.A.; Nicoletti, M.; Bozzi, A.; Amicosante, G. Celenza, G. Phytother. Res., 2013, 27, 431-437.
[http://dx.doi.org/10.1002/ptr.4739] [PMID: 22628260]
[5]
Sultana, N.; Afolayan, A.J. A new depsidone and antibacterial activities of compounds from Usnea undulata stirton. J. Asian Nat. Prod. Res., 2011, 13(12), 1158-1164.
[http://dx.doi.org/10.1080/10286020.2011.622720] [PMID: 22115039]
[6]
Zambare, V.P.; Christopher, L.P. Biopharmaceutical potential of lichens. Pharm. Biol., 2012, 50(6), 778-798.
[http://dx.doi.org/10.3109/13880209.2011.633089] [PMID: 22471936]
[7]
White, P.A.S.; Oliveira, R.C.M.; Oliveira, A.P.; Serafini, M.R.; Araújo, A.A.S.; Gelain, D.P.; Moreira, J.C.F.; Almeida, J.R.G.S.; Quintans, J.S.S.; Quintans-Junior, L.J.; Santos, M.R.V. Antioxidant activity and mechanisms of action of natural compounds isolated from lichens: A systematic review. Molecules, 2014, 19(9), 14496-14527.
[http://dx.doi.org/10.3390/molecules190914496] [PMID: 25221871]
[8]
Cetin Cakmak, K.; Gülçin, İ. Anticholinergic and antioxidant activities of usnic acid-an activity-structure insight. Toxicol. Rep., 2019, 6, 1273-1280.
[http://dx.doi.org/10.1016/j.toxrep.2019.11.003] [PMID: 31832335]
[9]
Bazin, M.A.; Le Lamer, A.C.; Delcros, J.G.; Rouaud, I.; Uriac, P.; Boustie, J.; Corbel, J.C.; Tomasi, S. Synthesis and cytotoxic activities of usnic acid derivatives. Bioorg. Med. Chem., 2008, 16(14), 6860-6866.
[http://dx.doi.org/10.1016/j.bmc.2008.05.069] [PMID: 18558490]
[10]
Vanga, N.R.; Kota, A.; Sistla, R.; Uppuluri, M. Synthesis and anti-inflammatory activity of novel triazole hybrids of (+)-usnic acid, the major dibenzofuran metabolite of the lichen Usnea longissima. Mol. Divers., 2017, 21(2), 273-282.
[http://dx.doi.org/10.1007/s11030-016-9716-5] [PMID: 28130662]
[11]
Pyrczak-Felczykowska, A.; Narlawar, R.; Pawlik, A.; Guzow-Krzemińska, B.; Artymiuk, D.; Hać, A.; Ryś, K.; Rendina, L.M.; Reekie, T.A.; Herman-Antosiewicz, A.; Kassiou, M. Synthesis of usnic acid derivatives and evaluation of their antiproliferative activity against cancer cells. J. Nat. Prod., 2019, 82(7), 1768-1778.
[http://dx.doi.org/10.1021/acs.jnatprod.8b00980] [PMID: 31282672]
[12]
Mallavadhania, U.V.; Vangaa, N.R.; Raob, K.B.; Jain, N. Synthesis and antiproliferative activity of novel (+)- usnic acid analogues. J. Asian Nat. Prod. Res., 2019, •••, 562-577.
[http://dx.doi.org/10.1080/10286020.2019.1603220]
[13]
Yu, X.; Guo, Q.; Su, G.; Yang, A.; Hu, Z.; Qu, C.; Wan, Z.; Li, R.; Tu, P.; Chai, X. Usnic acid derivatives with cytotoxic and antifungal activities from the lichen Usnea longissima. J. Nat. Prod., 2016, 79(5), 1373-1380.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00109] [PMID: 27186821]
[14]
Huaa, L.P.; Zhanga, Y.Q.; Yea, M.; Xua, W.; Wanga, X.Y.; Fu, Y.H.; Xu, W. Bioactive dibenzofurans from the rattans of Bauhinia championii (Benth.). Benth. Phytochem. Lett., 2018, 24, 154-157.
[http://dx.doi.org/10.1016/j.phytol.2018.02.007]
[15]
Xiang, Y.Q.; Liu, H.X.; Zhao, L.Y.; Xu, Z.F.; Tan, H.B.; Qiu, S.X. Callistemenonone A. A novel dearomatic dibenzofuran-type acylphloroglucinol with antimicrobial activity from Callistemon viminalis. Sci. Rep., 2017, 7(1), 2363.
[http://dx.doi.org/10.1038/s41598-017-02441-5] [PMID: 28539599]
[16]
Kaniwa, K.; Ohtsuki, T.; Yamamoto, Y.; Ishibashi, M. Kehokorins A–C, novel cytotoxic dibenzofurans isolated from the myxomycete Trichia favoginea var. Persimilis. Tetrahedron Lett., 2006, 47, 1505-1508.
[http://dx.doi.org/10.1016/j.tetlet.2006.01.012]
[17]
Zhao, P.; Guo, R.; Zhang, Y.Y.; Zhang, H.; Yao, G.D.; Lin, B.; Wang, X.B.; Huang, X.X.; Song, S.J. Phenylpropanoid and dibenzofuran derivatives from Crataegus pinnatifida with antiproliferative activities on hepatoma cells. Bioorg. Chem., 2019, 93, 103354.
[http://dx.doi.org/10.1016/j.bioorg.2019.103354] [PMID: 31629256]
[18]
Yempala, Y.; Babu, T.; Gibson, D.; Cassels, B.K. Dibenzofuran annulated 1-azepines: Synthesis and cytotoxicity. Synth. Commun., 2020, 50, 438-445.
[http://dx.doi.org/10.1080/00397911.2019.1703001]
[19]
Takai, M.; Uehara, Y.; Beisler, J.A. Usnic acid derivatives as potential antineoplastic agents. J. Med. Chem., 1979, 22(11), 1380-1384.
[http://dx.doi.org/10.1021/jm00197a019] [PMID: 160461]
[20]
Chen, Y-L.; Chen, I.L.; Tzeng, C.C. Synthesis and cytotoxicity evaluation of certain alpha-methylidene-gamma-butyrolactones bearing coumarin, flavone, xanthone, carbazole, and dibenzofuran moieties. Helv. Chim. Acta, 2000, 83, 989-994.
[http://dx.doi.org/10.1002/(SICI)1522-2675(20000510)83:5<989:AID-HLCA989>3.0.CO;2-E]
[21]
Chen, Y.L.; Chen, P.H.; Chung, C.H.; Li, K.C.; Jeng, H.Y.; Tzeng, C.C. Synthesis and cytotoxicity evaluation of metal-chelator-bearing flavone, carbazole, dibenzofuran, xanthone, and anthraquinone. Helv. Chim. Acta, 2003, 86, 778-786.
[http://dx.doi.org/10.1002/hlca.200390078]
[22]
Love, B.E. Isolation and synthesis of polyoxygenated dibenzofurans possessing biological activity. Eur. J. Med. Chem., 2015, 97, 377-387.
[http://dx.doi.org/10.1016/j.ejmech.2015.01.005] [PMID: 25585873]
[23]
Oramas-Royo, S.; Pantoja, K.D.; Amesty, Á.; Romero, C.; Lorenzo-Castrillejo, I.; Machín, F.; Estévez-Braun, A. Synthesis and antibacterial activity of new symmetric polyoxygenated dibenzofurans. Eur. J. Med. Chem., 2017, 141, 178-187.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.062] [PMID: 29031065]
[24]
Patpi, S.R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar, B.; Murthy, R.; Anjana Devi, T.; Kalivendi, S.V.; Kantevari, S. Design, synthesis, and structure-activity correlations of novel dibenzo[b,d]furan, dibenzo[b,d]thiophene, and N-methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of Mycobacterium tuberculosis. J. Med. Chem., 2012, 55(8), 3911-3922.
[http://dx.doi.org/10.1021/jm300125e] [PMID: 22449006]
[25]
Yurttaş, L.; Abu Mohsen, U.; Ozkan, Y.; Cobanoglu, S.; Levent, S.; Kaplancikli, Z.A. Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1177-1183.
[http://dx.doi.org/10.3109/14756366.2015.1108971] [PMID: 26581445]
[26]
Wang, T.C.; Chen, I.L.; Kuo, D.H. Synthesis and cytotoxic and antiplatelet activities of dibenzofuran- and carbazole-substituted oximes. Helv. Chim. Acta, 2004, 87, 983-990.
[http://dx.doi.org/10.1002/hlca.200490091]
[27]
Albrecht, W.L.; Fleming, R.W.; Horgan, S.W.; Mayer, G.D. Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 8. Bis-basic derivatives of carbazole, dibenzofuran, and dibenzothiophene. J. Med. Chem., 1977, 20(3), 364-371.
[http://dx.doi.org/10.1021/jm00213a011] [PMID: 191610]
[28]
Talontsi, F.M.; Lamshöft, M.; Douanla-Meli, C.; Kouam, S.F.; Spiteller, M. Antiplasmodial and cytotoxic dibenzofurans from Preussia sp. harboured in Enantia chlorantha Oliv. Fitoterapia, 2014, 93, 233-238.
[http://dx.doi.org/10.1016/j.fitote.2014.01.003] [PMID: 24440906]
[29]
Ma, Y.; Wei, H.Y.; Zhang, Y.Z.; Jin, W.Y.; Li, H.L.; Zhou, H.; Cheng, X.C.; Wang, R.L. Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors. Oncotarget, 2017, 8(24), 38466-38481.
[http://dx.doi.org/10.18632/oncotarget.16595] [PMID: 28388567]
[30]
Martel, R.R.; Rochefort, J.G.; Klicius, J.; Dobson, T.A. Anti-inflammatory properties of furobufen. Can. J. Physiol. Pharmacol., 1974, 52(3), 669-673.
[http://dx.doi.org/10.1139/y74-085] [PMID: 4850589]
[31]
Keay, B.A.; Dibble, P.W. Comprehensive Heterocyclic Chemistry II; 2nd ed; Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V., Eds.; Elsevier: Oxford, 1996, pp. 395-436.
[http://dx.doi.org/10.1016/B978-008096518-5.00047-2]
[32]
Xu, Z.; Zhao, S.; Lv, Z.; Feng, L.; Wang, Y.; Zhang, F.; Bai, L.; Deng, J. Benzofuran derivatives and their anti-tubercular, anti-bacterial activities. Eur. J. Med. Chem., 2019, 162(15), 266-276.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.025] [PMID: 30448416]
[33]
Lukevits, É.; Demicheva, L. Biological activity of furan derivatives. Chem. Heterocycl. Compd., 1993, 29, 243-267.
[http://dx.doi.org/10.1007/BF00531499]
[34]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[35]
Liu, W.J.; Xu, B.H.; Ye, L.; Liang, D.; Wu, H.L.; Zheng, Y.Y.; Deng, J.K.; Li, B.; Liu, H.F. Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells. Am. J. Physiol. Renal Physiol., 2015, 308(6), F639-F649.
[http://dx.doi.org/10.1152/ajprenal.00383.2014] [PMID: 25587119]
[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]
Desai, N.C.; Kotadiya, G.M. Facile synthesis of pyrazole encompassing pyridyl oxadiazoles using conventional and microwave techniques. Curr. Org. Chem., 2014, 18, 2561-2570.
[http://dx.doi.org/10.2174/138527281819141028114856]
[38]
Shou, Q.; Banbury, L.K.; Renshaw, D.E.; Lambley, E.H.; Mon, H.; Macfarlane, G.A.; Griesser, H.J.; Heinrich, M.M.; Wohlmuth, H. Biologically active dibenzofurans from Pilidiostigma glabrum, an endemic Australian Myrtaceae. J. Nat. Prod., 2012, 75(9), 1612-1617.
[http://dx.doi.org/10.1021/np300433r] [PMID: 22934671]
[39]
Kaplancikli, Z.A.; Yurttaş, L.; Turan-Zitouni, G.; Özdemir, A.; Özic, R.; Ulusoylar-Yildirim, Ş. Synthesis, antimicrobial activity and cytotoxicity of some new carbazole derivatives. J. Enzyme Inhib. Med. Chem., 2012, 27(6), 868-874.
[http://dx.doi.org/10.3109/14756366.2011.622273] [PMID: 21999633]
[40]
Paniraj, A.S.; Lokanath-Rai, K.M.; Prasanna, V.B.; Goud, P.S.K.; Vadiraj, S.G.; Boseb, P.; Kumari, N.S. Synthesis, characterization and biological activity of some new 5-halo-4, 6-dimethoxy-2-(alkoxy or aryloxy) pyrimidines. Pharma Chem., 2011, 3, 63-72.
[41]
Peña-Morán, O.A.; Villarreal, M.L.; Álvarez-Berber, L.; Meneses-Acosta, A.; Rodríguez-López, V. Cytotoxicity, post-treatment recovery, and selectivity analysis of naturally occurring podophyllotoxins from Bursera fagaroides var. fagaroides on breast cancer cell lines. Molecules, 2016, 21(8), 1013.
[http://dx.doi.org/10.3390/molecules21081013] [PMID: 27527135]
[42]
Sun, H.; Lou, X.; Shan, Q.; Zhang, J.; Zhu, X.; Zhang, J.; Wang, Y.; Xie, Y.; Xu, N.; Liu, S. Proteolytic characteristics of cathepsin D related to the recognition and cleavage of its target proteins. PLoS One, 2013, 8(6), e65733.
[http://dx.doi.org/10.1371/journal.pone.0065733] [PMID: 23840360]
[43]
Vidak, E.; Javoršek, U.; Vizovišek, M.; Turk, B. Cysteine cathepsins and their extracellular roles: Shaping the microenvironment. Cells, 2019, 8(3), E264.
[http://dx.doi.org/10.3390/cells8030264] [PMID: 30897858]
[44]
Lankelma, J.M.; Voorend, D.M.; Barwari, T.; Koetsveld, J.; Van der Spek, A.H.; De Porto, A.P.; Van Rooijen, G.; Van Noorden, C.J. Cathepsin L, target in cancer treatment? Life Sci., 2010, 86(7-8), 225-233.
[http://dx.doi.org/10.1016/j.lfs.2009.11.016] [PMID: 19958782]
[45]
Xie, Y.S.; Kumar, D.; Bodduri, V.V.; Tarani, P.S.; Zhao, B.X.; Miao, J.Y.; Shin, D.S. Microwave-assisted parallel synthesis of benzofuran-2-carboxamide derivatives bearing anti-inflammatory, analgesic and antipyretic agents. Tetrahedron Lett., 2014, 55(17), 2796-2800.
[http://dx.doi.org/10.1016/j.tetlet.2014.02.116]
[46]
Lark, M.W.; Stroup, G.B.; James, I.E.; Dodds, R.A.; Hwang, S.M.; Blake, S.M.; Lechowska, B.A.; Hoffman, S.J.; Smith, B.R.; Kapadia, R.; Liang, X.; Erhard, K.; Ru, Y.; Dong, X.; Marquis, R.W.; Veber, D.; Gowen, M. A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat. Bone, 2002, 30(5), 746-753.
[http://dx.doi.org/10.1016/S8756-3282(02)00675-0] [PMID: 11996914]
[47]
Drug-Likeness and molecular property prediction. Available at: https://molsoft.com/mprop/2020.
[48]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]