Synthesis, Characterization and Carbonic Anhydrase Inhibitor Properties of Metal Complexes of 4-sulfamoylbenzoic Acid

Yıl 2026, Cilt: 16 Sayı: 1, 221 - 232, 01.03.2026

Tevfik Emre Kaya , Nagihan Kaya , Şüheda Özkul , Burak Yildiz , Ekrem Tunca , Halil İlkimen

https://doi.org/10.21597/jist.1701182

https://izlik.org/JA85PU95ME

Öz

Six new complexes of 4-sulfamoylbenzoic acid (Hsba) {[Mg(sba)2].2H2O (1), [M(sba)2(H2O)x].yH2O, M = Mn2+, x = 4, y = 2 (2); M = Fe2+ (3), Co2+ (4), x = 4, y = 0; M = Ni2+ (5), Cu2+ (6), x = 2, y = 0} have been prepared. The structures of the metal complexes (1-6) have been proposed based on data obtained from analytic and spectroscopic studies. The structures of the synthesized metal complexes were observed to be linear for 1, octahedral for 2-4, and tetrahedral for 5 and 6. In the next stage of the study, the inhibitory effects of the Mg(Ac)2, FeSO4.7H2O, Mn(Ac)2.4H2O, Co(Ac)2.4H2O, Ni(Ac)2.4H2O, Cu(Ac)2.2H2O, Hsba and synthesized metal complexes (1-6) on hCA I and hCA II isoenzymes were investigated in vitro. In general, the compounds significantly inhibited hCA I and hCA II. It was determined that complex 6 was 2200 times more selective for hCA I, while complex 4 was 8 times more selective for hCA II.

Anahtar Kelimeler

4-sulfamoylbenzoic acid , Metal complexes , Carbonic anhydrase , Esterase acivity , Inhibition

Destekleyen Kurum

Kütahya Dumlupınar University Research Fund

Proje Numarası

2023/31

Teşekkür

We thank to Kütahya Dumlupınar University Research Fund

Synthesis, Characterization and Carbonic Anhydrase Inhibitor Properties of Metal Complexes of 4-sulfamoylbenzoic Acid

https://izlik.org/JA85PU95ME

Öz

Six new complexes of 4-sulfamoylbenzoic acid (Hsba) {[Mg(sba)2].2H2O (1), [M(sba)2(H2O)x].yH2O, M = Mn2+, x = 4, y = 2 (2); M = Fe2+ (3), Co2+ (4), x = 4, y = 0; M = Ni2+ (5), Cu2+ (6), x = 2, y = 0} have been prepared. The structures of the metal complexes (1-6) have been proposed based on data obtained from analytic and spectroscopic studies. The structures of the synthesized metal complexes were observed to be linear for 1, octahedral for 2-4, and tetrahedral for 5 and 6. In the next stage of the study, the inhibitory effects of the synthesized metal complexes on hCA I and hCA II isoenzymes were investigated in vitro. In general, the compounds significantly inhibited hCA I and hCA II. It was determined that the 6 complex was 2200 times more selective for hCA I, while the 4 complex was 8 times more selective for hCA II.

Anahtar Kelimeler

4-sulfamoylbenzoic acid , Metal complexes , Carbonic anhydrase , Esterase acivity , Inhibition

Proje Numarası

2023/31

Kaynakça

• Abou-Zeid, Y. M., Abou-Ouf, A. A., & Ragab, H. (1962). Sulfamoylbenzoic acids of expected antituberculous activity. Bulletin of the Faculty of Pharmacy (Cairo University), 1(1), 169-175.
• Adeva-Andany, M. M., Fernández-Fernández, C., Sánchez-Bello, R., Donapetry-García, C., & Martínez-Rodríguez, J. (2015). The role of carbonic anhydrase in the pathogenesis of vascular calcification in humans. Atherosclerosis, 241(1), 183-191.
• Alkan Alkaya, Z., İlkimen, H., Yenikaya, C., Tunca, E., Bülbül, M., Tunç, T., & Sarı, M. (2018). Synthesis and characterization of Cu(II) complexes of 2-amino-6-sulfamoylbenzothiazole and their inhibition studies on carbonic anhydrase isoenzymes. Polyhedron, 151, 199-205.
• Alterio, V., Di Fiore, A., D’Ambrosio, K., Supuran, C. T., & De Simone, G. (2012). Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms? Chemical Reviews, 112, 4421-4468.
• Angeli, A. & Supuran, C. T. (2023). Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), 2166503.
• Barton, V., Ward, S. A., Chadwick, J., Hill, A., & O'Neill, P. M. (2010). Rational design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics. Journal of Medicinal Chemistry, 53(11), 4555-4559.
• Bertucci, A., Innocenti, A., Zoccola, D., Scozzafava, A., Tambutte, S., & Supuran, C. T. (2009). Carbonic anhydrase inhibitors. Inhibition studies of a coral secretory isoform by sulfonamides. Bioorganic & Medicinal Chemistry, 17(14), 5054-5058.
• Buza, A., Türkeş, C., Arslan, M., Demir, Y., Dincer, B., Nixha, A. R., & Beydemir, Ş. (2025). Novel benzenesulfonamides containing a dual triazole moiety with selective carbonic anhydrase inhibition and anticancer activity. RSC Medicinal Chemistry, 16, 324-345.
• Cetin, A., Korkmaz, A., Erdoğan, E., & Kösemen, A., (2019). A study on synthesis, optical properties and surface morphological of novel conjugated oligo-pyrazole films. Materials Chemistry and Physics, 222(15), 37-44.
• Ciuhaudu, G., Roscovanu, A., & Cutui, M. (1968). Photometric determination of arsenic using a new reagent: the silver salt of p-sulfamylbenzoic acid. Chimie Analytique (Paris), 50(9), 489-493.
• Curreli, F., Zhang, H., Zhang, X., Pyatkin, I., Victor, Z., Altieri, A., & Debnath, A. K. (2011). Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid. Bioorganic & Medicinal Chemistry, 19(1), 77-90.
• Dedeoglu, N., DeLuca, V., Isik, S., Yildirim, H., Kockar, F., Capasso, C., & Supuran, C. T. (2015). Sulfonamide inhibition study of the β-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans. Bioorganic & Medicinal Chemistry Letters, 25(11), 2291-2297.
• Facsko, G., & Nemes, M. (1973). Polarographic determination of mercury(II) complex-bound with the sodium salt of 4-sulfonamidobenzoic acid in strong alkaline medium. Revue Roumaine de Chimie, 18(11), 1971-1982.
• Facsko, G., & Nemes, M. (1974). Amperometric titration of mercury(II) in strongly alkaline medium with thioacetamide. Revue Roumaine de Chimie, 19(1), 141-144.
• Ganesh, T., Jiang, J., & Dingledine, R. (2014). Development of second generation EP2 antagonists with high selectivity. European Journal of Medicinal Chemistry, 82, 521-535.
• García-Llorca, A., Carta, F., Supuran, C. T., & Eysteinsson, T. (2024). Carbonic anhydrase, its inhibitors and vascular function. Frontiers in Molecular Biosciences, 11, 1338528.
• Gaur, J. N., Mehrotra, R. C., Palrecha, M. M., Jain, D. S., Kumar, A., & Gupta, C. M. (1968). Polarographic studies on formation constants of some complexes of lead, cadmium, and indium with organic ligands. Journal of the Polarographic Society, 14(4), 122-129.
• Geary, W. J. (1971). The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coordination Chemistry Reviews, 7, 81-121
• Goeres, E., & Schwarz, J. (1967). Anticonvulsive action of benzenesulfonamides on animals. Acta Biologica et Medica Germanica, 19(6), 1061-1062.
• Gulec, Ö., Bilgiçli, A. T., Tüzün, B., Taslimi, P., Günsel, A., Gülçin, İ., Arslan, M., & Yarasir M. N. (2024). Peripheral (E)‐2‐[(4‐hydroxybenzylidene)‐3,4‐dihydronaphthalen‐1(2H)‐one)]‐coordinated phthalocyanines with improved enzyme inhibition properties and photophysicochemical behaviors. Archiv der Pharmazie, 357, e2400209.
• Guseinov, G. A., Musaev, F. N., & Usubaliev, B.T. (1984). Crystal structure of Na[Zn(p-H2NSO2C6H4COO)3.H2O]. Koordinatsionnaya Khimiya, 10(8), 1108-1112.
• Haapasalo, J., Nordfors, K., Haapasalo, H., & Parkkila, S. (2020). The expression of carbonic anhydrases II, IX and XII in brain tumors. Cancers, 12, 1723.
• Ilkimen H. (2024). Cu(II) complexes of 5-sulfamoylbenzoic acid derivatives: synthesis and characterization. Polyhedron, 257, 117019.
• Ilkimen, H., Salün, S. G., & Yenikaya, C. (2020). Synthesis and characterization of Fe(III) metal complexes of sulfamoyl benzoic acid derivatives. Eurasia Journal of Mathematics-Engineering Natural & Medical Sciences, 7(8), 108-116.
• Ilkimen, H., Turken, N., & Gulbandilar, A. (2021). Synthesis, characterization, antimicrobial and antifungal activity studies of two novel aminopyridine-sulfamoylbenzoic acid salts and their Cu(II) complexes. Journal of the Iranian Chemical Society, 18(8), 1941-1946.
• Ilkimen, H., Yenikaya, C., Sarı, M., Bülbül, M., Tunca, E., & Süzen, Y. (2013). Synthesis and characterization of a proton transfer salt between dipicolinic acid and 2-amino-6-methylbenzothiazole and its complexes, and their inhibition studies on carbonic anhydrase isoenzymes. Polyhedron, 61, 56-64.
• Innocenti, A., Hall, R .A., Schlicker, C., Scozzafava, A., Steegborn, C., Muehlschlegel, F. A., & Supuran, C. T. (2009). Carbonic anhydrase inhibitors. Inhibition and homology modeling studies of the fungal β-carbonic anhydrase from Candida albicans with sulfonamides. Bioorganic & Medicinal Chemistry, 17(13), 4503-4509.
• Krall, N., Pretto, F., Decurtins, W., Bernardes, G. J. L., Supuran, C. T., & Neri, D. (2014). A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors. Angewandte Chemie, International Edition, 53(16), 4231-4235.
• Lee, J., Vinh, N.B., Drinkwater, N., Yang, W., Sivaraman, K. K., Schembri, L. S., Gazdik, M., Grin, P. M., Butler, G. S., Overall, C. M., Charman, S. A., McGowan, S., & Scammells, P. J. (2019). Novel human aminopeptidase n inhibitors: discovery and optimization of subsite binding interactions. Journal of Medicinal Chemistry, 62(15), 7185-7209.
• Lineweaver, H., & Burk, D. (1934). The Determination of Enzyme Dissociation Constants. Journal of the American Chemical Society, 56, 658-666.
• Muller, A. (1918). Studien über die Komplexbildung von Uranylverbindungen. Zeitschrift für anorganische und allgemeine Chemie, 103, 55-68.
• Nakamoto, K. (1997). Infrared and raman spectra of inorganic and coordination compounds. 5th ed., New York: Wiley-Interscience.
• Neri, D., & Supuran, C. T. (2011). Interfering with pH regulation in tumours as a therapeutic strategy. Nature Reviews Drug Discovery, 10, 767-777.
• Parmaksız, R., & Tunca, E. (2024). Immobilization of carbonic anhydrase on bentonite – chitosan composite and determination of its kinetic parameters and CO2 removal capacity. Materials Today Communications, 40, 109673.
• Pirkes, S. B., Arsen'ev, V. S., Savina, E. N., Khudzik, L. B., Kulikova, L. K., Lapitskaya, A. V., Baranova, T. A., Zakharova, T. V., & Buchkova, R. T. (1984a). Synthesis and biological activity of some carboxylates of rare earth elements. Khimiko-Farmatsevticheskii Zhurnal, 18(12), 1466-1468.
• Pirkes, S. B., Lapitskaya, A. V., Vaistub, T. G., Baranova, T. A., Chulkevich, A. K., & Fainleib, A. M. (1984b). p-Sulfamidobenzoates of lanthanides and yttrium. Zhurnal Neorganicheskoi Khimii, 29(10), 2488-2491.
• Singh, S., & Supuran, C. T. (2014). 3D-QSAR CoMFA studies on sulfonamide inhibitors of the Rv3588c β-carbonic anhydrase from Mycobacterium tuberculosis and design of not yet synthesized new molecules. Journal of Enzyme Inhibition and Medicinal Chemistry, 29(3), 449-455.
• Song, Z. J., Wu, X. F., Zhou, Z. Y., Zhang, J. J., Pan, Y. Y., Dong, X., Pang, X., Xie, Y. P., Sun, J., & Zhang, Y. (2025). Design, synthesis, and evaluation of carboxylic acid-substituted celecoxib isosteres as potential anti-inflammatory agents. European Journal of Medicinal Chemistry, 286, 117286.
• Supuran, C. T. (2008). Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery, 7, 168-181.
• Tanimukai, H., Inui, M., Hariguchi, S., & Kaneko, J. (1965). Antiepileptic property of inhibitors of carbonic anhydrase. Biochemical Pharmacology, 14(6), 961-970.
• Tunca, E., Bülbül, M., İlkimen, H., Saygılı Canlıdinç, R., & Yenikaya, C. (2020). Investigation of the effects of the proton transfer salts of 2‑aminopyridine derivatives with 5‑sulfosalicylic acid and their Cu(II) complexes on cancer‑related carbonic anhydrases: CA IX and CA XII. Chemical Papers, 74, 2365-2374.
• Verpoorte, J.A., Mehta, S., & Edsall, J.T. (1967). Esterase activities of human carbonic anhydrases B and C. Journal of Biological Chemistry, 242, 4221-4229.
• Vullo, D., Innocenti, A., Nishimori, I., Pastorek, J., Scozzafava, A., Pastorekova, S., & Supuran, C. T. (2005). Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides-a new target for the design of antitumor and antiglaucoma drugs? Bioorganic & Medicinal Chemistry Letters, 15(4), 963-969.
• Vullo, D., Voipio, J., Innocenti, A., Rivera, C., Ranki, H., Scozzafava, A., Kaila, K., & Supuran, C. T. (2005). Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamides. Bioorganic & Medicinal Chemistry Letters, 15(4), 971-976.
• Winum, J. Y., Dogne, J. M., Casini, A., de Leval, X., Montero, J. L., Scozzafava, A., Vullo, D., Innocenti, A., & Supuran, C. T. (2005). Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties. Journal of Medicinal Chemistry, 48(6), 2121-2125.
• Zollinger, H., & Wittwer, C. (1956). Complex dyes. I. Principles of the effect of sulfonamido and methylsulfonyl groups in dyes. Hammett's σ values and solvation effects. Helvetica Chimica Acta, 39, 347-356.