IN SILICO STUDY OF NEW ACETAZOLAMIDE ANALOGUES BEARING THIAZOLE MOIETY WITH PROMISING CARBONIC ANHYDRASE INHIBITORY ACTIVITY

HUSSEIN I. ABDULHUSSEIN; NOOR H. NASER

doi:10.22159/ijap.2026v18i1.55957

Authors

HUSSEIN I. ABDULHUSSEIN Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Kufa, Najaf, Iraq https://orcid.org/0009-0003-9858-6811
NOOR H. NASER Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq https://orcid.org/0000-0001-6148-3040

DOI:

https://doi.org/10.22159/ijap.2026v18i1.55957

Keywords:

Cancer, Docking, Carbonic anhydrase, Acetazolamide, Thiazole

Abstract

Objective: Cancer is the second leading cause of death worldwide. Multiple targets can be hit for cancer treatment; carbonic anhydrase enzyme XII is one of these targets because it plays a vital role in the tumour microenvironment.

Methods: ADMETlab 3.0 platform used to predict (absorption, distribution, metabolism, excretion, and toxicity) characteristics, while molecular docking managed by the molecular operating environment program MOE 2015.1.

Results: The molecular docking analysis revealed that all nineteen designed compounds exhibited favourable binding affinities toward carbonic anhydrase enzymes XII (PDB ID: 1JD0) and IX (PDB ID: 3IAI), and most of the designed compounds satisfy the predominant drug-likeness requirements.

Conclusion: Acetazolamide's binding affinity for the carbonic anhydrase enzyme can be enhanced by including a substituted thiazole ring.

References

1. Brown JS, Amend SR, Austin RH, Gatenby RA, Hammarlund EU, Pienta KJ. Updating the Definition of Cancer. Mol Cancer Res. 2023 Nov 1;21(11):1142–1147.

2. Castaneda M, Den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol. 2022 Dec;87:17–31.

3. Ghosh T, Maity TK, Singh J. Evaluation of antitumor activity of stigmasterol, a constituent isolated from Bacopa monnieri Linn aerial parts against Ehrlich Ascites Carcinoma in mice. Orient Pharm Exp Med. 2011 Mar;11(1):41–49.

4. National Center for Health Statistics. National vital statistics report ; v. 70, no. 9 [Internet]. National Center for Health Statistics; 2021 July. Available from: https://stacks.cdc.gov/view/cdc/107021

5. Madriwala B, B.V. S, Jays J. MOLECULAR DOCKING STUDY OF HENTRIACONTANE FOR ANTICANCER AND ANTITUBERCULAR ACTIVITY. Int J Chem Res. 2022 Oct 1;1–4.

6. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May;74(3):229–263.

7. Brennan P, Davey-Smith G. Identifying Novel Causes of Cancers to Enhance Cancer Prevention: New Strategies Are Needed. JNCI J Natl Cancer Inst. 2022 Mar 8;114(3):353–360.

8. Zhu W, Xie L, Han J, Guo X. The Application of Deep Learning in Cancer Prognosis Prediction. Cancers. 2020 Mar 5;12(3):603.

9. Liao C, Liu X, Zhang C, Zhang Q. Tumor hypoxia: From basic knowledge to therapeutic implications. Semin Cancer Biol. 2023 Jan;88:172–186.

10. Weiss F, Lauffenburger D, Friedl P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat Rev Cancer. 2022 Mar;22(3):157–173.

11. Su Z, Dong S, Zhao SC, Liu K, Tan Y, Jiang X, Assaraf YG, Qin B, Chen ZS, Zou C. Novel nanomedicines to overcome cancer multidrug resistance. Drug Resist Updat. 2021 Sept;58:100777.

12. Campestre C, De Luca V, Carradori S, Grande R, Carginale V, Scaloni A, Supuran CT, Capasso C. Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori. Front Microbiol. 2021 Mar 19;12:629163.

13. Pandey V. MODELING OF CARBONIC ANHYDRASE (II) INHIBITORY ACTIVITIES OF SULPHONILAMIDE SCHIFF BASES BY ARTIFICIAL NEURAL NETWORK TRAINED WITH DIFFERENT NUMERICAL TECHNIQUES. Int J Pharm Pharm Sci. 2018 Jan 1;10(1):202.

14. Kciuk M, Gielecińska A, Mujwar S, Mojzych M, Marciniak B, Drozda R, Kontek R. Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies. J Enzyme Inhib Med Chem. 2022 Dec 31;37(1):1278–1298.

15. Li Y, Lei B, Zou J, Wang W, Chen A, Zhang J, Fu Y, Li Z. High expression of carbonic anhydrase 12 (CA12) is associated with good prognosis in breast cancer. Neoplasma. 2019;66(03):420–426.

16. Shin HJ, Rho SB, Jung DC, Han IO, Oh ES, Kim JY. Carbonic anhydrase IX (CA9) modulates tumor-associated cell migration and invasion. J Cell Sci. 2011 Apr 1;124(7):1077–1087.

17. Cuffaro D, Nuti E, Rossello A. An overview of carbohydrate-based carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem. 2020 Jan 1;35(1):1906–1922.

18. Ovung A, Bhattacharyya J. Sulfonamide drugs: structure, antibacterial property, toxicity, and biophysical interactions. Biophys Rev. 2021 Apr;13(2):259–272.

19. Shukralla AA, Dolan E, Delanty N. Acetazolamide: Old drug, new evidence? Epilepsia Open. 2022 Sept;7(3):378–392.

20. T. Chhabria M, Patel S, Modi P, S. Brahmkshatriya P. Thiazole: A Review on Chemistry, Synthesis and Therapeutic Importance of its Derivatives. Curr Top Med Chem. 2016 Sept 2;16(26):2841–2862.

21. De Santana TI, Barbosa MDO, Gomes PATDM, Da Cruz ACN, Da Silva TG, Leite ACL. Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur J Med Chem. 2018 Jan;144:874–886.

22. Dong J, Wang NN, Yao ZJ, Zhang L, Cheng Y, Ouyang D, Lu AP, Cao DS. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. J Cheminformatics [Internet]. Springer Science and Business Media LLC; 2018 Dec [cited 2025 July 8];10(1). Available from: https://jcheminf.biomedcentral.com/articles/10.1186/s13321-018-0283-x

23. Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. Oxford University Press (OUP); 2021 July 2;49(W1):W5–W14.

24. Al-Gburi K, Naser NH, Jasmi M. DESIGN AND COMPUTATIONAL ANALYSIS OF NEW ISATIN-IMINE HYBRIDS AS SELECTIVE HDAC6 INHIBITORS. Int J Appl Pharm. Innovare Academic Sciences Pvt Ltd; 2025 May 7;214–227.

25. Wei Y, Palazzolo L, Ben Mariem O, Bianchi D, Laurenzi T, Guerrini U, Eberini I. Investigation of in silico studies for cytochrome P450 isoforms specificity. Comput Struct Biotechnol J. 2024 Dec;23:3090–3103.

26. Shah R, Alharbi A, Hameed AM, Saad F, Zaky R, Khedr AM, El-Metwaly N. Synthesis and Structural Elucidation for New Schiff Base Complexes; Conductance, Conformational, MOE-Docking and Biological Studies. J Inorg Organomet Polym Mater. 2020 Sept;30(9):3595–3607.

27. Aloufi BH. Structure-based Multi-targeted Molecular Docking and Molecular Dynamic Simulation Analysis to Identify Potential Inhibitors against Ovarian Cancer. J Biochem Technol. 2022;13(2):29–39.

28. Alibeg AAA, Hussein TS. In Silico Study of New Isatin- Sulfonamide Derivatives as Carbonic Anhydrase Inhibitors. Wiad Lek. 2024 Oct 30;77(10):2027–2032.

29. Ononamadu CJ, Abdalla M, Ihegboro GO, Li J, Owolarafe TA, John TD, Tian Q. In silico identification and study of potential anti-mosquito juvenile hormone binding protein (MJHBP) compounds as candidates for dengue virus - Vector insecticides. Biochem Biophys Rep. 2021 Dec;28:101178.

30. Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW. 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. 2001 Aug 14;98(17):9545–9550.

31. Arsianti AA, Astuty H, Fadilah F, Bahtiar A, Tanimoto H, Kakiuchi K. Design and screening of gallic acid derivatives as inhibitors of malarial dihydrofolate reductase by in silico docking. Asian J Pharm Clin Res. 2017 Feb 1;10(2):330.

32. Ward SE, Davis A, editors. The Handbook of Medicinal Chemistry: Principles and Practice [Internet]. 2nd ed. The Royal Society of Chemistry; 2023 [cited 2025 Aug 6]. Available from: https://books.rsc.org/books/monograph/2061/

33. Williams J, Siramshetty V, Nguyễn ÐT, Padilha EC, Kabir Md, Yu KR, Wang AQ, Zhao T, Itkin M, Shinn P, Mathé EA, Xu X, Shah P. Using in vitro ADME data for lead compound selection: An emphasis on PAMPA pH 5 permeability and oral bioavailability. Bioorg Med Chem. 2022 Feb;56:116588.

34. Klimoszek D, Jeleń M, Dołowy M, Morak-Młodawska B. Study of the Lipophilicity and ADMET Parameters of New Anticancer Diquinothiazines with Pharmacophore Substituents. Pharmaceuticals. 2024 June 3;17(6):725.

35. Sohlenius-Sternbeck AK, Terelius Y. Evaluation of ADMET Predictor in Early Discovery Drug Metabolism and Pharmacokinetics Project Work. Drug Metab Dispos. 2022 Feb;50(2):95–104.

36. Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, Yin M, Zeng X, Wu C, Lu A, Chen X, Hou T, Cao D. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021 July 2;49(W1):W5–W14.

37. Konyar D, Okur H, Arslan Z. MOLECULAR DOCKING STUDIES OF COX INHIBITORS ON WILD-TYPE RAS. Ank Univ Eczacilik Fak Derg [Internet]. 2021 Oct 22 [cited 2025 Aug 6]; Available from: https://dergipark.org.tr/en/doi/10.33483/jfpau.1008048

38. Barua H, Bhagat N, Toraskar (Mrs.) M. P. STUDY OF BINDING INTERACTIONS OF HUMAN CARBONIC ANHYDRASE XII. Int J Curr Pharm Res. 2016 Dec 31;9(1):118.