O-VANİLİN TEMELLİ SCHIFF BAZI LİGANDI İLE YENİ BİR Co(II) KOMPLEKSİNİN SENTEZİ, KARAKTERİZASYONU, BSA BAĞLANMA AKTİVİTESİ VE ADME TAHMİNLERİ

Yıl 2025, Cilt: 11 Sayı: 1, 18 - 27, 30.06.2025

Tolga Göktürk

https://doi.org/10.22531/muglajsci.1629497

Öz

Bu çalışma, o-vanillin bazlı bir Schiff bazı ligandının ve Co(II) kompleksinin sentezi, karakterizasyonu, bovin serum albümini (BSA) ile etkileşimi ve farmakokinetik özelliklerini raporlamaktadır. Ligand (H₂L), izonitrozofenil hidrazin ile o-vanillin arasındaki kondenzasyon reaksiyonu ile sentezlenmiş; Co(II) kompleksi [Co(HL)₂] ise sentezlenen ligandın kobalt(II) asetat monohidrat ile tepkimesiyle hazırlanmıştır. Ligand; elementel analiz, UV-Vis, FTIR, NMR spektroskopisi ile, Co(II) kompleksi ise elementel analiz, UV-Vis, FTIR spektroskopisi, manyetik duyarlılık ölçümü ve kütle spektrometrisi ile karakterize edilmiş ve bu sayede kompleksin oktahedral geometriye sahip olduğu doğrulanmıştır. Co(II) kompleksinin BSA ile bağlanma çalışmaları, statik söndürme mekanizması aracılığıyla orta düzeyde bir bağlanmayı (Kbin= 8.74x10³ M⁻¹) ortaya koymuş; bu durum termodinamik hesaplamalarla (ΔG=–22.49 kJ.mol⁻¹) desteklenmiştir. Ayrıca, ligand da daha düşük bir bağlanma afinitesiyle (Kbin=1.36x10³ M⁻¹) BSA ile etkileşim göstermiştir; bu da metal koordinasyonunun protein etkileşimini önemli ölçüde artırdığını göstermektedir. Co(II) kompleksine ait ADME tahminleri, 651.53 g/mol moleküler ağırlık, 151.54 Ų polar yüzey alanı (TPSA), orta düzeyde esneklik ve iyi düzeyde fizikokimyasal kararlılık gibi umut verici farmakokinetik özellikleri göstermiştir. Bununla birlikte, sınırlı gastrointestinal emilim ve kan-beyin bariyeri geçirgenliğinin olmaması, bu kompleksin periferik tedavi uygulamaları için uygun olabileceğini düşündürmektedir. Gelecek çalışmalarda, bu umut verici Co(II) kompleksi ve Schiff bazı ligandının terapötik etkinliğini ve güvenlik profilini doğrulamak amacıyla ayrıntılı sitotoksisite testleri ve farmakokinetik değerlendirmeler yapılacaktır.

Anahtar Kelimeler

Co(II) Kompleksi , O-Vanilin , Schiff Bazı , BSA Bağlanma , ADME

SYNTHESIS, CHARACTERIZATION, BSA BINDING ACTIVITY AND ADME PREDICTIONS OF A NEW Co(II) COMPLEX WITH O-VANILLIN-BASED SCHIFF BASE LIGAND

Öz

This study reports the synthesis, structural characterization, bovine serum albumin (BSA) binding activity, and pharmacokinetic properties of an o-vanillin-based Schiff base ligand and its Co(II) complex. The ligand (H2L) was synthesized via condensation reaction between isonitrosophenyl hydrazine and o-vanillin, and the Co(II) complex [Co(HL)2] was prepared by reacting the ligand with cobalt(II) acetate monohydrate. The ligand was characterized by elemental analysis, UV-Vis, FTIR, NMR spectroscopy, while Co(II) complex was characterized by elemental analysis, UV-Vis, magnetic susceptibility, FTIR and mass spectrometry, confirming successful complex formation with octahedral geometry. BSA binding studies of Co(II) complex demonstrated moderate binding (Kbin=8.74x103 M-1) via static quenching mechanism, supported by thermodynamic calculations (ΔG=-22.49 kJ.mol-1). The ligand also exhibited BSA binding with a lower affinity (Kbin=1.36x103 M-1), indicating that metal coordination significantly enhances protein interaction. In silico ADME predictions of Co(II) complex indicated promising pharmacokinetics characterized by a molecular weight of 651.53 g/mol, polar surface area (TPSA = 151.54 Ų), moderate flexibility, and reasonable physicochemical stability. However, limited gastrointestinal absorption and lack of blood-brain barrier permeability, suggest potential suitability for peripheral therapeutic applications. Future studies will involve detailed cytotoxicity assays and pharmacokinetic evaluations to validate the therapeutic efficacy and safety profile of this promising Co(II) complex and Schiff base ligand.

Anahtar Kelimeler

Co(II) Complex , o-Vanillin , Schiff Base , BSA Binding , ADME

Kaynakça

• Özbağcı, D. İ., Erdağı, S. İ., Aydın, İ., Aydın, R., Zorlu, Y., Arı, F., "A Comparative Study on the Synthesis and Crystal Structures of Ni(II) Complexes Bearing Tetradentate N₂O₂ Donor Schiff Bases: Biomolecular Interactions, Cytotoxicities and Molecular Docking", New Journal of Chemistry, 48(23), 10475-10496, 2024.
• Çalışkan, Ş. G., Genç, O., Erol, F., Sarıkavaklı, N., "Molecular Docking, HOMO-LUMO, Quantum Chemical Computation and Bioactivity Analysis of Vic-Dioxim Derivatives Bearing Hydrazone Group Ligand and Their Ni(II) and Cu(II) Complexes", Gazi University Journal of Science Part A: Engineering and Innovation, 9(3), 299-313, 2022.
• Kaplan, E., Koc, Z. E., Uysal, A., Uba, A. I., Zengin, G., "Elucidation of the Microwave‐Assisted Synthesis and Characterization of Heteronuclear Complexes of Bisbenzimidazole Derivatives and Their Biological Activities by In Vitro and In Silico Assays", Chemical Biology & Drug Design, 104(3), E14605, 2024.
• Varol, M., Varol, T. Ö., "The Role of Metals and Metallodrugs in the Modulation of Angiogenesis", Advances in Metallodrugs: Preparation and Applications in Medicinal Chemistry, 293-318, 2020.
• Kıncal, S., Göktürk, T., Topkaya, C., Güp, R., "Three New Bis (Acylhydrazone) Mononuclear Transition Metal Complexes: Synthesis, Characterizations and DNA Interaction Studies", Mugla Journal of Science and Technology, 9(2), 36-45, 2023.
• Gup, R., Gökçe, C., Aktürk, S., "Copper(II) Complexes with 4-Hydroxyacetophenone-Derived Acylhydrazones: Synthesis, Characterization, DNA Binding and Cleavage Properties", Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 134, 484-492, 2015.
• Khan, E., Gul, Z., Shahzad, A., Jan, M. S., Ullah, F., Tahir, M. N., Noor, A., "Coordination Compounds of 4,5,6,7-Tetrahydro-1H-Indazole with Cu(II), Co(II) and Ag(I): Structural, Antimicrobial, Antioxidant and Enzyme Inhibition Studies", Journal of Coordination Chemistry, 70(24), 4054-4069, 2017.
• Kareem, M. J., Al-Hamdani, A. A. S., Ko, Y. G., Al Zoubi, W., Mohammed, S. G., "Synthesis, Characterization, and Determination Antioxidant Activities for New Schiff Base Complexes Derived from 2-(1H-Indol-3-Yl)-Ethylamine and Metal Ion Complexes", Journal of Molecular Structure, 1231, 129669, 2021
• Sumrra, S. H., Hassan, A. U., Zafar, M. N., Shafqat, S. S., Mustafa, G., Zafar, M. N., Imran, M., "Metal Incorporated Sulfonamides as Promising Multidrug Targets: Combined Enzyme Inhibitory, Antimicrobial, Antioxidant and Theoretical Exploration", Journal of Molecular Structure, 1250, 131710, 2022.
• Topkaya, C., "Experimental Biological Studies of Novel Tetradentate Hydrazone Cu(II) Complexes for Potential Applications in Medicinal Chemistry", Macedonian Journal of Chemistry and Chemical Engineering, 43(1), 2024.
• Bal, W., Sokołowska, M., Kurowska, E., Faller, P., "Binding of Transition Metal Ions to Albumin: Sites, Affinities and Rates", Biochimica et Biophysica Acta (BBA) - General Subjects, 1830(12), 5444–5455, 2013.
• Topală, T., Bodoki, A., Oprean, L., Oprean, R., "Bovine Serum Albumin Interactions with Metal Complexes", Clujul Medical, 87(4), 215–220, 2014.
• Kıncal, S., Topkaya, C., Göktürk, T., Hökelek, T., Güp, R., "Synthesis, Crystal Structure, Hirshfeld Surface Analysis and Interaction Energy and Energy Framework Studies of Novel Hydrazone Derivative Containing Barbituric Acid Moiety", Journal of Chemical Crystallography, 53(1), 81-92, 2023.
• Topkaya, C. G., Göktürk, T., Hökelek, T., Cetin, E. S., Kincal, S., Güp, R., "In Vitro DNA Interaction, Topoisomerase I/II Inhibition and Cytotoxic Properties of Polymeric Copper(II) Complex Bridged with Perchlorate Ion Containing N4-Type Schiff Base Ligand", Journal of Molecular Structure, 1266, 133453, 2022.
• Topkaya, C., Aslan, S., Hökelek, T., Göktürk, T., Kıncal, S., Altuntaş, D. B., Güp, R., "Syntheses, Crystal Structures, Hirshfeld Surface Analyses and Electrochemical Etoposide/Camptothecin Sensor Applications of Acetaldehyde Oxime Derivatives", Journal of Molecular Structure, 1265, 133339, 2022.
• Ekennia, A. C., Osowole, A. A., Olasunkanmi, L. O., Onwudiwe, D. C., Olubiyi, O. O., Ebenso, E. E., "Synthesis, Characterization, DFT Calculations and Molecular Docking Studies of Metal(II) Complexes", Journal of Molecular Structure, 1150, 279-292, 2017.
• Özbağcı, D. İ., "Novel Ni(II) Complexes as Minor Groove Binders: Crystal Structures, Biomolecular Interactions, Molecular Docking, and Biological Activities", Applied Organometallic Chemistry, 38(12), E7697, 2024.
• Özbağcı, D. İ., Erdağı, S. İ., Aydın, İ., Aydın, R., Arı, F., Zorlu, Y., "Crystal Structures and Biological Profiles of Novel Tridentate Schiff Bases Nickel(II) Complexes", Applied Organometallic Chemistry, E7860, 2024.
• İnci, D., Aydın, R., Zorlu, Y., "NOO-Type Tridentate Schiff Base Ligand and Its One-Dimensional Cu(II) Coordination Polymer: Synthesis, Crystal Structure, Biomacromolecular Interactions and Radical Scavenging Activities", Inorganica Chimica Acta, 514, 119994, 2021.
• Göktürk, T., "A New Cu(II) Complex with 1,3-Dimethyl-5-Acetyl-Barbituric Acid: Synthesis, Crystal Structure, DNA/BSA Binding Activities, ADME Predictions, and Anticancer Activities", Applied Organometallic Chemistry, 39(1), e70006, 2025.
• Chaudhary, U., Kumar, P., Sharma, P., Chikara, A., Barua, A., Mahiya, K., Subin, J. A., Yadav, P. N., Pokharel, Y. R., "Synthesis of 5-Hydroxyisatin Thiosemicarbazones, Spectroscopic Investigation, Protein-Ligand Docking, and In Vitro Anticancer Activity", Bioorganic Chemistry, 153, 107872, 2024.
• Moroy, G., Martiny, V. Y., Vayer, P., Villoutreix, B. O., Miteva, M. A., "Toward In Silico Structure-Based ADMET Prediction in Drug Discovery", Drug Discovery Today, 17(1-2), 44-55, 2012.
• Göktürk, T., Topkaya, C., Demircan, T., Akgül, S., Hökelek, T., Güp, R., "Novel Benzohydrazide Derivative as a Potential Anticarcinogenic Agent for Breast Cancer: Synthesis, Crystal Structure, In Vitro and In Silico Assessments", Journal of Molecular Structure, 1323, 140673, 2025.
• Alkan, S., Topal, T., Karapınar, E., "Synthesis and Characterization of New Oxime Ligand and Its Cu(II) Complex: DFT Calculations, in Vitro Antibacterial Activity, Drug-Likeness Properties, and Molecular Docking Studies", Russian Journal of Physical Chemistry A, 1-11, 2024.57.
• Coogan, N. T., Chimes, M. A., Raftery, J., Mocilac, P., Denecke, M. A., " Regioselective Synthesis of V-Shaped Bistriazinyl-phenanthrolinesClick to copy article link", Journal of Organic Chemistry, 80, 8684-8693, 2015.
• Göktürk, T., Güp, R., Zengin, T., Hökelek, T., Aksu, E. N., Öztürk, F. S., Sakallı Çetin, E., "Effects of Electron Donating and Withdrawing Substituents on Crystal Structures, Cytotoxicity and In Silico DNA Interactions of Isatinoxime Schiff Base Ligands", Research on Chemical Intermediates, 1-25, 2025.
• Gurusamy, S., Asha, R. N., Sankarganesh, M., Jeyakumar, T. C., Mathavan, A., "Vanillin Based Colorimetric and Fluorometric Chemosensor for Detection of Cu(II) Ion: DFT Calculation, DNA/BSA Interaction and Molecular Docking Studies", Inorganic Chemistry Communications, 143, 109716, 2022.
• Kavitha, B., Sravanthi, M., Reddy, P. S., "DNA Interaction, Docking, Molecular Modelling and Biological Studies of o-Vanillin Derived Schiff Base Metal Complexes", Journal of Molecular Structure, 1185, 153-167, 2019.
• Singh, A., Maiti, S. K., Gogoi, H. P., Barman, P., "Purine-Based Schiff Base Co(II), Cu(II), and Zn(II) Complexes: Synthesis, Characterization, DFT Calculations, DNA Binding Study, and Molecular Docking", Polyhedron, 230, 116244, 2023.
• Kumar, S., Devi, J., Dubey, A., Kumar, D., Jindal, D. K., Asija, S., Sharma, A., "Co(II), Ni(II), Cu(II) and Zn (II) Complexes of Schiff Base Ligands: Synthesis, Characterization, DFT, In Vitro Antimicrobial Activity and Molecular Docking Studies", Research on Chemical Intermediates, 49(3), 939-965, 2023.
• Schägger, H., Von Jagow, G., "Tricine-Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis for the Separation of Proteins in the Range from 1 to 100 kDa", Analytical Biochemistry, 166(2), 368-379, 1987.
• Parsekar, S. U., Velankanni, P., Sridhar, S., Haldar, P., Mate, N. A., Banerjee, A., Antharjanam, P. K., Koley, A. P., Kumar, M., "Protein Binding Studies with Human Serum Albumin, Molecular Docking and In Vitro Cytotoxicity Studies Using HeLa Cervical Carcinoma Cells of Cu(II)/Zn(II) Complexes Containing a Carbohydrazone Ligand", Dalton Transactions, 49(9), 2947-2965, 2020.
• Daina, A., Michielin, O., Zoete, V., "SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules", Scientific Reports, 7(1), 42717, 2017.
• Saghatforoush, L. A., Chalabian, F., Aminkhani, A., Karimnezhad, G., Ershad, S., "Synthesis, Spectroscopic Characterization and Antibacterial Activity of New Cobalt(II) Complexes of Unsymmetrical Tetradentate (OSN₂) Schiff Base Ligands", European Journal of Medicinal Chemistry, 44(11), 4490–4495, 2009.
• Bengi, K., Maddikayala, S., Pulimamidi, S. R., "DNA Binding, Cleavage, Docking, Biological and Kinetic Studies of Cr(III), Fe(III), Co(II) and Cu(II) Complexes with Ortho-Vanillin Schiff Base Derivative", Applied Organometallic Chemistry, 36(1), e6451, 2022.
• Refat, M. S., El-Sayed, M. Y., Adam, A. M. A., "Cu(II), Co(II) and Ni(II) Complexes of New Schiff Base Ligand: Synthesis, Thermal and Spectroscopic Characterizations", Journal of Molecular Structure, 1038, 62–72, 2013.
• Bahron, H., Khaidir, S. S., Tajuddin, A. M., Ramasamy, K., Yamin, B. M., "Synthesis, Characterization and Anticancer Activity of Mono- and Dinuclear Ni(II) and Co(II) Complexes of a Schiff Base Derived from o-Vanillin", Polyhedron, 161, 84–92, 2019.
• Gönül, İ., Fakı, E., Ay, B., Köse, M., Serin, S., "Cobalt(II), Nickel(II) and Copper(II) Complexes of a Schiff Base Ligand: Synthesis, Structural Characterization and Luminescence Properties", Transition Metal Chemistry, 43, 73–81, 2018.
• Venkatesh, G., Vennila, P., Kaya, S., Ahmed, S. B., Sumathi, P., Siva, V., Kamal, C., "Synthesis and Spectroscopic Characterization of Schiff Base Metal Complexes, Biological Activity, and Molecular Docking Studies", ACS Omega, 9(7), 8123-8138, 2024.
• Ahmadi, R. A., Hasanvand, F., Bruno, G., Rudbari, H. A., Amani, S., "Synthesis, Spectroscopy, and Magnetic Characterization of Copper(II) and Cobalt(II) Complexes with 2-Amino-5-Bromopyridine as Ligand", Russian Journal of Coordination Chemistry, 39, 867-871, 2013.
• Göktürk, T., Topkaya, C. G., Hökelek, T., Güp, R., "Serendipitous Synthesis of an Octahedral Ni(II) Complex: Single Crystal Structure, Hirshfeld Surface and Voids Analysis", Journal of Structural Chemistry, 65(1), 15-27, 2024.
• Bozbey, I., Uslu, H., Türkmenoğlu, B., Özdemir, Z., Karakurt, A., Levent, S., "Conventional and Microwave Prompted Synthesis of Aryl (Alkyl) Azole Oximes, 1H-NMR Spectroscopic Determination of E/Z Isomer Ratio and HOMO-LUMO Analysis", Journal of Molecular Structure, 1251, 132077, 2022.
• March, R., Clegg, W., Coxall, R. A., Cucurull-Sánchez, L., Lezama, L., Rojo, T., González-Duarte, P., "Synthesis, Characterisation and Magnetic Properties of Cobalt(II) Complexes with Picolinic Acid Derivatives: The Crystal and Molecular Structures of [Co(Mec₅h₃ncoo)₂(H₂O)₂] and [CoCl₂(C₅H₄NCOOPr)₂]", Inorganica Chimica Acta, 353, 129–138, 2003.
• Shebl, M., "Synthesis, Spectral and Magnetic Studies of Mono- and Bi-Nuclear Metal Complexes of a New Bis (Tridentate NO2) Schiff Base Ligand Derived from 4,6-Diacetylresorcinol and Ethanolamine", Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 73(2), 313-323, 2009.
• Adeleke, A. A., Islam, M. S., Omondi, B., "Silver(I) Pyridinyl Complexes with Benzothiazole, Thiophene, and Furan Moieties: DNA/Protein‐Binding, Antibacterial, Antioxidant, and Anticancer Studies", Archiv der Pharmazie, 356(1), 2200308, 2023.
• Özbağcı, D. İ., "5-Chloroanthranilic Acid Schiff Base: Crystal Structure, DNA/BSA Interactions, Molecular Docking and Antioxidant Activity", Hacettepe Journal of Biology and Chemistry, 53(1), 17-28.
• Patel, R., Maurya, N., Parray, M. U. D., Farooq, N., Siddique, A., Verma, K. L., Dohare, N., "Esterase Activity and Conformational Changes of Bovine Serum Albumin Toward Interaction with Mephedrone: Spectroscopic and Computational Studies", Journal of Molecular Recognition, 31(11), E2734, 2018.
• Raja, D. S., Paramaguru, G., Bhuvanesh, N. S., Reibenspies, J. H., Renganathan, R., Natarajan, K., "Effect of Terminal N-Substitution in 2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde Thiosemicarbazones on the Mode of Coordination, Structure, Interaction with Protein, Radical Scavenging and Cytotoxic Activity of Copper(II) Complexes", Dalton Transactions, 40(17), 4548-4559, 2011.
• Maurya, N., Maurya, J. K., Singh, U. K., Dohare, R., Zafaryab, M., Moshahid Alam Rizvi, M., Kumari, M., Patel, R., "In Vitro Cytotoxicity and Interaction of Noscapine with Human Serum Albumin: Effect on Structure and Esterase Activity of HSA", Molecular Pharmaceutics, 16(3), 952-966, 2019.
• Göktürk, T., Zengin, T., Hökelek, T., Topkaya, C. G., Güp, R., "Synthesis, Crystal Structure, Hirshfeld Surface Analysis, DNA/BSA Interaction and Molecular Docking Studies of 2-(6-(4-Chlorophenyl)-1,2,4-Triazin-3-Yl) Quinoline", Journal of Molecular Structure, 1292, 136128, 2023.
• Gurusamy, S., Sankarganesh, M., Revathi, N., Asha, R. N., Mathavan, A., "Synthesis and Structural Investigation of o-Vanillin Scaffold Schiff Base Metal Complexes: Biomolecular Interaction and Molecular Docking Studies", Journal of Molecular Liquids, 369, 120941, 2023.
• Liang, J., Cheng, Y., Han, H., "Study on the Interaction Between Bovine Serum Albumin and CdTe Quantum Dots with Spectroscopic Techniques", Journal of Molecular Structure, 892(1-3), 116-120, 2008.
• Lee, J., Beers, J. L., Geffert, R. M., Jackson, K. D., "A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment", Biomolecules, 14(1), 99, 2024.
• Wu, D., Chen, Q., Chen, X., Han, F., Chen, Z., Wang, Y., "The Blood–Brain Barrier: Structure, Regulation, and Drug Delivery", Signal Transduction and Targeted Therapy, 8(1), 217, 2023.