İndol-3-Karboksialdehit Tiyosemikarbazon Türevlerinin Sentezi Antioksidan ve Antikolinesteraz özelliklerinin araştırılması

Dört indol-3-karboksialdehit tiyosemikarbazon bileşiği indol-3-karboksialdehit ve tiyosemikarbazit bileşiklerinden Schiff bazı reaksiyonu kullanılarak yüksek verimlerde sentezlenmiştir. 3a ve 3b tiyosemikarbazon yapıları 1HNMR spektroskopisiyle desteklenerek literatür verileriyle uyumlu olduğu kanıtlanmıştır. Bildiğimiz kadarıyla, çalışmamız 3c bileşiğinin sentezi ve 3d bileşiğinin tüm karakterizasyonlarının yapılması açısından ilk bilimsel çalışmadır. 3c ve 3d bileşiklerinin yapıları, FT-IR, yüksek çözünürlüklü kütle spektroskopisi, 1H ve 13CNMR spektroskopileri ile ilk olarak bu çalışmada aydınlatılmıştır. Dahası, sentezlenen 3a-d bileşiklerinin antioksidan özellikleri üç farklı DPPH serbest radikal süpürme, ABTS katyonik radikal süpürme, CUPRAC kuprik iyonunu indirgeme kapasitesi yöntemlerinin uygulanmasıyla belirlenmiştir. Bununla beraber, belirtilen bileşiklerin antikolinesteraz özellikleri, Asetilkolinesteraz (ACh) ve Bütirilkolinesteraz (BCh) enzim inhibisyonu deneyleriyle araştırılmıştır. 3a, 3b ve 3d bileşiklerinin ABTS antioksidan metodu için çok etkili olduğu belirlenmiş ve 3c bileşiğinin antikolinesteraz aktivite alanında kinetik ölçümlerinin yapılarak etki mekanizmasının aydınlatılması konusunda değerli bir hedef molekül olduğu anlaşılmıştır.

Synthesis of Indole-3-Carboxyaldehyde Thiosemicarbazone Derivatives and Investigation of Antioxidant and Anticholinesterase Properties

The synthesis of four indole-3-carboxyaldehyde thiosemicarbazone compounds (3a-d) was achieved viathe Schiff base reaction of the indole-3-carboxyaldehyde and thiosemicarbazides in high yields. Thestructures of thiosemicarbazones 3a and 3b were supported by 1HNMR spectroscopy and confirmedwith the literature data. To the best of our knowledge, our study is the first report for the synthesis ofcompound 3c and literature search revealed that compound 3d was also not fully characterised. Thestructures of compound 3c and 3d were fully characterised by the FT-IR, High Resolution MassSpectrometry (HRMS), 1H and 13CNMR spectroscopy in this work for the first time. Moreover,antioxidant properties of synthesised compounds 3a-d were investigated with the DPPH, ABTS andCUPRAC assays as well as the anticholinesterase properties of designated compounds were determinedby the Acetylcholinesterase (ACh) and Butyrylcholinesterase (BCh) enzyme inhibition assays. Thecompound 3a, 3b and 3d were determined very potent against the ABTS antioxidant assay andcompound 3c was found to be a valuable target molecule for the kinetic measurements to identifymechanism of action in the area of anticholinesterase activity assay.

PDF

___

Alley, M.C., Hollingshead, M.G., Pacula-Cox, C.M., Waud, W.R., Hartley, J.A., Howard, P.W., Gregson, S.J., Thurston, D.E. and Sausville, E.A., 2004. A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity. Cancer Research, 64, 6700-6706.
Antholine, W., Knight, J., Whelan, H. and Petering, D.H., 1977. Studies of the Reaction of 2-Formylpyridine Thiosemicarbazone and Its Iron and Copper Complexes with Biological Systems. Molecular Pharmacology, 13, 89–98.
Apak, R., Güçlü, K., Özyürek, M. and Karademir, S.E.. 2004. Novel Total Antioxidant Capacity Index for Dietary Polyphenols and Vitamins C and E, Using Their Cupric Ion Reducing Capability in the Presence of Neocuproine: CUPRAC Method. Journal of Agriculture and Food Chemistry, 52, 7970-81.
Blois, M.S.. 1958. Antioxidant Determinations by the Use of a Stable Free Radical. Nature, 181, 1199-200.
Đilović, I., Rubčić, M., Vrdoljak, V., Pavelić, S.K., Kralj, M., Piantanida, I. and Cindric, M., 2008. Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity. Bioorganic & Medicinal Chemistry, 16, 5189- 98.
Ellman, G.L., Courtney, K.D., Andres, V. and Featherstone, R.M., 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7, 88-95.
Garoufis, A., Hadjikakou, S.K. and Hadjiliadis, N., 2009. Palladium coordination compounds as anti-viral, antifungal, anti-microbial and anti-tumor agents. Coordination Chemistry Reviews, 253, 1384-97.
Gözler, B., Gözler, T., Freyer, A.J. and Shamma, M., 1988. Some Unusual Pavine and Isopavine Alkaloids from Roemeria refracta. Journal of Natural Products, 51, 760-4.
Gust, R., Ott, I., Posselt, D. and Sommer, K., 2004. Development of Cobalt(3,4-diarylsalen) Complexes as Tumor Therapeutics. Journal of Medicinal Chemistry, 47, 5837-46.
Haribabu, J., Tamizh, M.M., Balachandran, C., Arun, Y., Bhuvanesh, N.S.P., Endo, A. and Karvembu, R. 2018. Synthesis, structures and mechanistic pathways of anticancer activity of palladium(ii) complexes with indole-3-carbaldehyde thiosemicarbazones. New Journal of Chemistry, 42, 10818-32.
Havoundjian, H., Reed, G.F., Paul, S.M. and Skolnick, P., 1987. Protection against the lethal effects of pentobarbital in mice by a benzodiazepine receptor inverse agonist, 6,7-dimethoxy-4-ethyl-3- carbomethoxy-beta-carboline. The Journal of Clinical Investigation, 79, 473-7.
Hosseini-Yazdi, S.A., Mirzaahmadi, A., Khandar, A.A., Eigner, V., Dušek, M., Mahdavi, M., Soltani, S., Lotfipour, F. and White, J., 2017. Reactions of copper(II), nickel(II), and zinc(II) acetates with a new water-soluble 4-phenylthiosemicarbazone Schiff base ligand: Synthesis, characterization, unexpected cyclization, antimicrobial, antioxidant, and anticancer activities. Polyhedron, 124, 156-65.
Hu, K., Yang, Z., Pan, S-S., Xu, H. and Ren, J., 2010. Synthesis and antitumor activity of liquiritigenin thiosemicarbazone derivatives. European Journal of Medicinal Chemistry, 45, 3453-8.
Hu, W., Zhou, W., Xia, C. and Wen, X., 2006. Synthesis and anticancer activity of thiosemicarbazones. Bioorganic & medicinal chemistry letters, 16, 2213—2218.
Husain, K., Bhat, A.R. and Azam, A., 2008. New Pd(II) complexes of the synthesized 1-N-substituted thiosemicarbazones of 3-indole carboxaldehyde: characterization and antiamoebic assessment against E. histolytica. European journal of medicinal chemistry, 43, 2016-2028.
Kamal, A., Rao, M.V., Laxman, N., Ramesh. G. and Reddy, G.S.K., 2002. Recent Developments in the Design, Synthesis and Structure-Activity Relationship Studies of Pyrrolo[2,1-c][1,4]benzodiazepines as DNAInteractive Antitumour Antibiotics. Current Medicinal Chemistry - Anti-Cancer Agents, 2, 215-254.
Liu, L., Yang, J., Zhao, Z., Shi, P. and Liu, X., 2010. Solventfree synthesis of indole-based thiosemicarbazones under microwave irradiation. Journal of Chemical Research, 34, 57-60.
de Oliveira, R.B., de Souza-Fagundes, E.M. de, Soares, R.P.P., Andrade, A.A., Krettli, A.U. and Zani, C.L., 2008. Synthesis and antimalarial activity of semicarbazone and thiosemicarbazone derivatives. European Journal of Medicinal Chemistry, 43, 1983-8.
Palanimuthu, D., Poon, R., Sahni, S., Anjum, R., Hibbs, D., Lin, H-Y., Bernhardt, V.P., Kalinowski, D.S. and Richardson, D.R., 2017. A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer’s disease. European journal of medicinal chemistry, 139, 612—632.
Pavan, F.R., Maia, Pedro da, S., Leite, S.R.A., Deflon, V.M., Batista, A.A., Sato, D.N., Franzblau, G.S. and Leite, Q.F.C., 2010. Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: Anti – Mycobacterium tuberculosis activity and cytotoxicity. European Journal of Medicinal Chemistry, 45, 1898- 905.
Pchalek, K., Jones, A.W., Wekking, M.M.T. and Black, D.S., 2005. Synthesis of activated 3-substituted indoles: an optimised one-pot procedure. Tetrahedron, 61, 77- 82.
Piri, Z., Moradi-Shoeili, Z. and Assoud, A., 2017. New copper(II) complex with bioactive 2–acetylpyridine4N-p-chlorophenyl thiosemicarbazone ligand: Synthesis, X-ray structure, and evaluation of antioxidant and antibacterial activity. Inorganic Chemistry Communications, 84, 122-6.
Refat, M.S. and El-Metwaly, N.M., 2012. Spectral, thermal and biological studies of Mn(II) and Cu(II) complexes with two thiosemicarbazide derivatives. Spectrochimica Acta Part A, Molecular and biomolecular spectroscopy, 92, 336—346.
Rogolino, D., Cavazzoni, A., Gatti, A., Tegoni, M., Pelosi, G., Verdolino, V., Fumarola, C., Cretella, D., Petronini, G.P. and Carcelli, M., 2017. Anti-proliferative effects of copper(II) complexes with hydroxyquinolinethiosemicarbazone ligands. European Journal of Medicinal Chemistry, 128, 140-153.
Salas, P.F., Herrmann, C. and Orvig, C., 2013. Metalloantimalarials. Chemical Reviews, 113, 3450- 92.
Shahabadi, N., Kashanian, S. and Darabi, F., 2010. DNA binding and DNA cleavage studies of a water soluble cobalt(II) complex containing dinitrogen Schiff base ligand: The effect of metal on the mode of binding. European Journal of Medicinal Chemistry, 45, 4239- 45.
Silva, C.M., da Silva, D.L., da Modolo, L.V., Alves, R.B., Resende, M.A., de Martins, C.V.B. and de Fatima, A. 2011. Schiff bases: A short review of their antimicrobial activities. Journal of Advanced Research, 2(1), 1-8.
Re, R., Pellegrini, N., Proteggente, A., Pannala, A., Yang, M. and Rice-Evans, C., 1999. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Biology and Medicine, 26, 1231-7.
Yu, Y., Kalinowski, D.S., Kovacevic, Z., Siafakas, A.R., Jansson, P.J., Stefani, C., Lovejoy, D.B., Sharpe, P.S., Bernhardt, P.V. and Richardson, D.R., 2009. Thiosemicarbazones from the Old to New: Iron Chelators That Are More Than Just Ribonucleotide Reductase Inhibitors. Journal of Medicinal Chemistry, 52(17), 5271-94.
Zhang, H-J., Qian, Y., Zhu, D-D., Yang, X-G. and Zhu, H-L., 2011. Synthesis, molecular modeling and biological evaluation of chalcone thiosemicarbazide derivatives as novel anticancer agents. European journal of medicinal chemistry, 46, 4702—4708.