Home Life Sciences Design, synthesis, and biological activity studies of carbonic anhydrase inhibitors
Article
Licensed
Unlicensed Requires Authentication

Design, synthesis, and biological activity studies of carbonic anhydrase inhibitors

  • Delal Erzurum , Derya Osmaniye ORCID logo , Begüm Nurpelin Sağlık ORCID logo , Serkan Levent , Yusuf Özkay and Zafer Asım Kaplancıklı EMAIL logo
Published/Copyright: November 6, 2023
Zeitschrift für Naturforschung C
From the journal Zeitschrift für Naturforschung C Volume 78 Issue 11-12

Abstract

Carbonic anhydrase (CA) enzymes are a common catalytic enzyme in many organisms. Vertebrates and invertebrates have different CA isoforms. Sixteen different isozymes of the α-CA isoform found in vertebrates have been identified so far. The main task of this enzyme is to catalyze the reversible conversion of carbon dioxide into bicarbonate and hydrogen ions in the body. It is widely distributed in many organs and tissues. They are involved in important physiological processes such as pH and CO2 homeostasis, biosynthetic reactions such as gluconeogenesis, lipogenesis, ureagenesis, bone resorption, calcification, tumorigenicity, and electrolyte secretion. As a result of the literature research, it has been determined that the most effective inhibitor of the carbonic anhydrase enzyme is sulfonamides. The R group in the general molecular structure of R-SO2–NH2 generally consists of aromatic or heteroaromatic ring systems. The sulfonamides interact strongly with the Zn2+ ions in the active site of the enzyme. In this study, 10 sulfonamide derivatives were synthesized. Analyses of the obtained compounds are evaluated by using 1H NMR, 13C NMR and HRMS spectroscopic methods. The inhibition effect of the obtained compounds on the carbonic anhydrase enzyme was investigated by means of in vitro kit method. For the selected compounds, docking studies were performed and the enzyme active sites and binding points were determined. It was revealed that the strongest interaction with CA enzymes (CA-I, CA-II, CA-IX, CA-XII) active sites was observed with the compound 2e.

Keywords: carbonic anhydrase; sulfonamide; molecular docking; molecular dynamics
Corresponding author: Zafer Asım Kaplancıklı, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, 26470 Eskişehir, Türkiye, E-mail:

Acknowledgments

As the authors of this study, we thank Anadolu University Faculty of Pharmacy Central Analysis Laboratory for their support and contributions. This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 2111S202.

  1. Research ethics: Not applicable.

  2. Author contributions: Z. A. K. conceived and designed the experiments; D. E. performed the synthesis; B. N. S. performed the activity tests; D. O. and Y. O. performed the molecular docking and molecular dynamic studies; D. E. and S. L. performed analysis studies; D. O., and D. E. wrote the paper. Y. O. and ZAK edited the paper.

  3. Competing interests: The author(s) state(s) no conflict of interest.

  4. Research funding: None declared.

  5. Data availability: Not applicable.

References

1. Supuran, CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 2008;7:168–81. https://doi.org/10.1038/nrd2467.Search in Google Scholar PubMed

2. Alterio, V, Di Fiore, A, DꞌAmbrosio, K, Supuran, CT, De Simone, G. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev 2012;112:4421–68. https://doi.org/10.1021/cr200176r.Search in Google Scholar PubMed

3. Martignoni, M, Groothuis, GMM, de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expet Opin Drug Metabol Toxicol 2006;2:875–94. https://doi.org/10.1517/17425255.2.6.875.Search in Google Scholar PubMed

4. Supuran, CT. Structure-based drug discovery of carbonic anhydrase inhibitors. J Enzym Inhib Med Chem 2012;27:759–72. https://doi.org/10.3109/14756366.2012.672983.Search in Google Scholar PubMed

5. Supuran, CT. Carbonic anhydrases: from biomedical applications of the inhibitors and activators to biotechnological use for CO2 capture. J Enzym Inhib Med Chem 2013;28:229–30. https://doi.org/10.3109/14756366.2013.761876.Search in Google Scholar PubMed

6. Briganti, F, Mangani, S, Scozzafava, A, Vernaglione, G, Supuran, CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? JBIC J Biol Inorg Chem 1999;4:528–36. https://doi.org/10.1007/s007750050375.Search in Google Scholar PubMed

7. Supuran, CT, Scozzafava, A. Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat 2000;10:575–600. https://doi.org/10.1517/13543776.10.5.575.Search in Google Scholar

8. Supuran, CT, De Simone, G. Carbonic anhydrases as biocatalysts, theory to medical and industrial applications, 1st ed. US: Elsevier; 2015.10.1016/B978-0-444-63258-6.00001-9Search in Google Scholar

9. Maren, TH. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol Rev 1967;47:595–781. https://doi.org/10.1152/physrev.1967.47.4.595.Search in Google Scholar PubMed

10. Supuran, CT, Scozzafava, A, Conway, J, editors. Carbonic anhydrase. Boca Raton: CRC Press; 2004.10.4324/9780203475300Search in Google Scholar

11. Göcer, H, Akıncıoğlu, A, Göksu, S, Gülçin, İ. Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arab J Chem 2017;10:398–402. https://doi.org/10.1016/j.arabjc.2014.08.005.Search in Google Scholar

12. Aydin, F, Kahraman, Z, Türkoğlu, E, Kuzu, M, Severoğlu, Z. In vitro antioxidant activity and carbonic anhydrase inhibitory features of Ferula communis extracts. Int J Agr Environ Food Sci 2021;5:592–8. https://doi.org/10.31015/jaefs.2021.4.19.Search in Google Scholar

13. Gao, BB, Clermont, A, Rook, S, Fonda, SJ, Srinivasan, VJ, Wojtkowski, M, et al.. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007;13:181–8. https://doi.org/10.1038/nm1534.Search in Google Scholar PubMed

14. Supuran, C. Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr Pharmaceut Des 2008;14:641–8. https://doi.org/10.2174/138161208783877947.Search in Google Scholar PubMed

15. Ke, T, Wang, J, Swenson, ER, Zhang, X, Hu, Y, Chen, Y, et al.. Effect of acetazolamide and Gingko biloba on the human pulmonary vascular response to an acute altitude ascent. High Alt Med Biol 2013;14:162–7. https://doi.org/10.1089/ham.2012.1099.Search in Google Scholar PubMed PubMed Central

16. Wong, CM, Marcocci, L, Liu, L, Suzuki, YJ. Cell signaling by protein carbonylation and decarbonylation. Antioxidants Redox Signal 2010;12:393–404. https://doi.org/10.1089/ars.2009.2805.Search in Google Scholar PubMed PubMed Central

17. Du, AL, Du, AL, Ren, HM, Du, AL, Ren, HM, Lu, CZ, et al.. Carbonic anhydrase III is insufficient in muscles of myasthenia gravis patients. Autoimmunity 2009;42:209–15. https://doi.org/10.1080/08916930802668610.Search in Google Scholar PubMed

18. Liu, C, Wei, Y, Wang, J, Pi, L, Huang, J, Wang, P. Carbonic anhydrases III and IV autoantibodies in rheumatoid arthritis, systemic lupus erythematosus, diabetes, hypertensive renal disease, and heart failure. Clin Dev Immunol 2012;2012:1–6. https://doi.org/10.1155/2012/354594.Search in Google Scholar PubMed PubMed Central

19. De Simone, G, Supuran, C. Antiobesity carbonic anhydrase inhibitors. Curr Top Med Chem 2007;7:879–84. https://doi.org/10.2174/156802607780636762.Search in Google Scholar PubMed

20. Kivelä, J, Parkkila, S, Parkkila, AK, Rajaniemi, H. A low concentration of carbonic anhydrase isoenzyme VI in whole saliva is associated with caries prevalence. Caries Res 1999;33:178–84. https://doi.org/10.1159/000016514.Search in Google Scholar PubMed

21. De Simone, G, Scozzafava, A, Supuran, CT. Which carbonic anhydrases are targeted by the antiepileptic sulfonamides and sulfamates? Chem Biol Drug Des 2009;74:317–21. https://doi.org/10.1111/j.1747-0285.2009.00857.x.Search in Google Scholar PubMed

22. Ruusuvuori, E, Li, H, Huttu, K, Palva, JM, Smirnov, S, Rivera, C, et al.. Carbonic anhydrase isoform VII acts as a molecular switch in the development of synchronous gamma-frequency firing of hippocampal CA1 pyramidal cells. J Neurosci 2004;24:2699–707. https://doi.org/10.1523/jneurosci.5176-03.2004.Search in Google Scholar

23. Aspatwar, A, Tolvanen, MEE, Ortutay, C, Parkkila, S. Carbonic anhydrase related protein VIII and its role in neurodegeneration and cancer. Curr Pharmaceut Des 2010;16:3264–76. https://doi.org/10.2174/138161210793429823.Search in Google Scholar PubMed

24. Battke, C, Kremmer, E, Mysliwietz, J, Gondi, G, Dumitru, C, Brandau, S, et al.. Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII. Cancer Immunol Immunother 2011;60:649–58. https://doi.org/10.1007/s00262-011-0980-z.Search in Google Scholar PubMed

25. Pastorekova, S, Parkkila, S, Zavada, J. Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem 2006;42:167–216.10.1016/S0065-2423(06)42005-9Search in Google Scholar

26. Guler, O, Simone, G, Supuran, C. Drug design studies of the novel antitumor targets carbonic anhydrase IX and XII. Curr Med Chem 2010;17:1516–26. https://doi.org/10.2174/092986710790979999.Search in Google Scholar PubMed

27. De Simone, G, Supuran, CT. Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochim Biophys Acta Protein Proteonomics 2010;1804:404–9. https://doi.org/10.1016/j.bbapap.2009.07.027.Search in Google Scholar PubMed

28. Halmi, P, Parkkila, S, Honkaniemi, J. Expression of carbonic anhydrases II, IV, VII, VIII and XII in rat brain after kainic acid induced status epilepticus. Neurochem Int 2006;48:24–30. https://doi.org/10.1016/j.neuint.2005.08.007.Search in Google Scholar PubMed

29. Lehtonen, J, Shen, B, Vihinen, M, Casini, A, Scozzafava, A, Supuran, CT, et al.. Characterization of CA XIII, a novel member of the carbonic anhydrase isozyme family. J Biol Chem 2004;279:2719–27. https://doi.org/10.1074/jbc.m308984200.Search in Google Scholar PubMed

30. Nagelhus, EA, Mathiisen, TM, Bateman, AC, Haug, FM, Ottersen, OP, Grubb, JH, et al.. Carbonic anhydrase XIV is enriched in specific membrane domains of retinal pigment epithelium, Müller cells, and astrocytes. Proc Natl Acad Sci USA 2005;102:8030–5. https://doi.org/10.1073/pnas.0503021102.Search in Google Scholar PubMed PubMed Central

31. Shah, GN, Ulmasov, B, Waheed, A, Becker, T, Makani, S, Svichar, N, et al.. Carbonic anhydrase IV and XIV knockout mice: roles of the respective carbonic anhydrases in buffering the extracellular space in brain. Proc Natl Acad Sci USA 2005;102:16771–6. https://doi.org/10.1073/pnas.0508449102.Search in Google Scholar PubMed PubMed Central

32. Chakravarty, S, Kannan, KK. Drug-protein interactions. J Mol Biol 1994;243:298–309. https://doi.org/10.1006/jmbi.1994.1655.Search in Google Scholar PubMed

33. Sippel, KH, Robbins, AH, Domsic, J, Genis, C, Agbandje-McKenna, M, McKenna, R. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design. Acta Crystallogr Sect F Struct Biol Cryst Commun 2009;65:992–5. https://doi.org/10.1107/s1744309109036665.Search in Google Scholar

34. Andring, JT, Fouch, M, Akocak, S, Angeli, A, Supuran, CT, Ilies, MA, et al.. Structural basis of nanomolar inhibition of tumor-associated carbonic anhydrase IX: x-ray crystallographic and inhibition study of lipophilic inhibitors with acetazolamide backbone. J Med Chem 2020;63:13064–75. https://doi.org/10.1021/acs.jmedchem.0c01390.Search in Google Scholar PubMed

35. Whittington, DA, Waheed, A, Ulmasov, B, Shah, GN, Grubb, JH, Sly, WS, et al.. Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci USA 2001;98:9545–50. https://doi.org/10.1073/pnas.161301298.Search in Google Scholar PubMed PubMed Central

36. Maestro, 10.6. New York, NY, USA: Schrödinger, LLC; 2020.Search in Google Scholar

37. Schrödinger. LigPrep version 3.8. New York, NY, USA: Schrödinger, LLC; 2020.Search in Google Scholar

38. Schrödinger. Glide version 7.1. New York, NY, USA: Schrödinger, LLC; 2020.Search in Google Scholar

39. Liu, X, Shi, D, Zhou, S, Liu, H, Liu, H, Yao, X. Molecular dynamics simulations and novel drug discovery. Expet Opin Drug Discov 2018;13:23–37. https://doi.org/10.1080/17460441.2018.1403419.Search in Google Scholar PubMed

40. M-DI Tools. Schrödinger release 2018-3: prime, (2018). New York, NY: Schrödinger, LLC; 2020.Search in Google Scholar

41. S Release. 1: Desmond molecular dynamics system, version 3.7. New York, NY, DE Shaw Research; 2014. Maestro-desmond interoperability tools, version, 3.Search in Google Scholar

42. Saral, A, Sudha, P, Muthu, S, Sevvanthi, S, Sangeetha, P, Selvakumari, S. Vibrational spectroscopy, quantum computational and molecular docking studies on 2-chloroquinoline-3-carboxaldehyde. Heliyon 2021;7:e07529. https://doi.org/10.1016/j.heliyon.2021.e07529.Search in Google Scholar PubMed PubMed Central

43. Osmaniye, D, Evren, AE, Karaca, Ş, Özkay, Y, Kaplancıklı, ZA. Novel thiadiazol derivatives; design, synthesis, biological activity, molecular docking and molecular dynamics. J Mol Struct 2023;1272:134171. https://doi.org/10.1016/j.molstruc.2022.134171.Search in Google Scholar

44. Khezri, A, Karimi, A, Yazdian, F, Jokar, M, Mofradnia, SR, Rashedi, H, et al.. Molecular dynamic of curcumin/chitosan interaction using a computational molecular approach: emphasis on biofilm reduction. Int J Biol Macromol 2018;114:972–8. https://doi.org/10.1016/j.ijbiomac.2018.03.100.Search in Google Scholar PubMed

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/znc-2023-0102).

Received: 2023-07-26
Accepted: 2023-10-14
Published Online: 2023-11-06
Published in Print: 2023-11-27

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Research Articles
  3. Crystal structure of phloridzin and its distribution changes in flowering and fruiting stage of Malus rockii
  4. Evaluation of maceration, microwave, ultrasound-assisted extraction methods on free, esterified and bound phenolic profile and antioxidant activity of black rice
  5. Dietary flavonoid myricetin 3-O-galactoside suppresses α-melanocyte stimulating hormone-induced melanogenesis in B16F10 melanoma cells by regulating PKA and ERK1/2 activation
  6. A new alkaloid from Portulaca oleracea L. with its anti-inflammatory activity
  7. Terpenoid compounds from the fruits of Solanum virginianum
  8. Design, synthesis, and biological activity studies of carbonic anhydrase inhibitors
  9. Design, synthesis and apoptotic effects of novel benzoxazole compounds
  10. Corrigendum
  11. Corrigendum to: Proximate analysis and fatty acid, mineral and soluble carbohydrate profiles of some brown macroalgae collected from Türkiye coasts
https://doi.org/10.1515/znc-2023-0102
Keywords for this article
carbonic anhydrase; sulfonamide; molecular docking; molecular dynamics

Articles in the same Issue

  1. Frontmatter
  2. Research Articles
  3. Crystal structure of phloridzin and its distribution changes in flowering and fruiting stage of Malus rockii
  4. Evaluation of maceration, microwave, ultrasound-assisted extraction methods on free, esterified and bound phenolic profile and antioxidant activity of black rice
  5. Dietary flavonoid myricetin 3-O-galactoside suppresses α-melanocyte stimulating hormone-induced melanogenesis in B16F10 melanoma cells by regulating PKA and ERK1/2 activation
  6. A new alkaloid from Portulaca oleracea L. with its anti-inflammatory activity
  7. Terpenoid compounds from the fruits of Solanum virginianum
  8. Design, synthesis, and biological activity studies of carbonic anhydrase inhibitors
  9. Design, synthesis and apoptotic effects of novel benzoxazole compounds
  10. Corrigendum
  11. Corrigendum to: Proximate analysis and fatty acid, mineral and soluble carbohydrate profiles of some brown macroalgae collected from Türkiye coasts
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 30.12.2025 from https://www.degruyterbrill.com/document/doi/10.1515/znc-2023-0102/html
Scroll to top button