Benzenesulfonamide Derivatives as Selective Carbonic Anhydrase Inhibitors: SAR and Antibacterial Potential

References

[1] Meldrum NU, Roughton FJW. Carbonic anhydrase. Its preparation and properties. J Physiol. 1933;80(2):113–142.

[2] Supuran CT. Structure and function of carbonic anhydrases. Biochem J. 2016;473(14):2023–2032.

[3] Alterio V, Di Fiore A, D'Ambrosio 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(8):4421–4468.

[4] Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008;7(2):168–181.

[5] Krishnamurthy VM, Kaufman GK, Urbach AR, et al. Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding. Chem Rev. 2008;108(3):946–1051.

[6] Capasso C, Supuran CT. An overview of the alpha-, beta- and gamma-carbonic anhydrases from bacteria: can bacterial carbonic anhydrases shed new light on evolution of bacteria?. J Enzyme Inhib Med Chem. 2015;30(2):325–332.

[7] Pastorekova S, Parkkila S, Pastorek J, Supuran CT. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzyme Inhib Med Chem. 2004;19(3):199–229.

[8] Supuran CT. Carbonic anhydrase inhibitors. Bioorg Med Chem Lett. 2010;20(12):3467–3474.

[9] Supuran CT, Scozzafava A. Carbonic anhydrases as targets for medicinal chemistry. Bioorg Med Chem. 2007;15(13):4336–4350.

[10] Thiry A, Dogné JM, Masereel B, Supuran CT. Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol Sci. 2006;27(11):566–573.

[11] Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov. 2011;10(10):767–777.

[12] Nocentini A, Supuran CT. Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery. Expert Opin Drug Discov. 2019;14(11):1175–1197.

[13] Winum JY, Rami M, Scozzafava A, Montero JL, Supuran CT. Carbonic anhydrase IX: a new druggable target for the design of antitumor agents. Med Res Rev. 2008;28(3):445–463.

[14] Looking toward the rim of the active site cavity of druggable human carbonic anhydrase isoforms. J Enzyme Inhib Med Chem. 2020.

[15] A decade of tail-approach based design of selective as well as potent tumor-associated carbonic anhydrase inhibitors. Bioorg Med Chem. 2022.

[16] Alterio V, Di Fiore A, D'Ambrosio K, De Simone G, Supuran CT. Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site. J Med Chem. 2014.

[17] Sulfonamide inhibitors of human carbonic anhydrases designed through a three-tails approach: improving ligand/isoform matching and selectivity of action. J Med Chem. 2020.

[18] The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII. J Enzyme Inhib Med Chem. 2022.

[19] Wilkinson BL, Bornaghi LF, Houston TA, Innocenti A, Supuran CT, Poulsen SA. Carbonic anhydrase inhibition with benzenesulfonamides and tetrafluorobenzenesulfonamides obtained via click chemistry. ACS Med Chem Lett. 2014.

[20] Pacchiano F, Carta F, McDonald PC, et al. Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem. 2011;54(6):1896–1902.

[21] Lou Y, McDonald PC, Oloumi A, et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res.

[22] Discovery of benzenesulfonamides with potent human carbonic anhydrase inhibitory and effective anticonvulsant action: design, synthesis, and pharmacological assessment. J Med Chem. 2017.

[23] Pastorekova S, Supuran CT. Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas. Expert Opin Ther Pat. 2018;28(10):709–712.

[24] A Phase 1 study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. Am J Clin Oncol. 2020.

[25] Phase I. clinical trials of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. Cancer Res (AACR Abstract). 2020.

[26] Inhibition of carbonic anhydrases IX/XII by SLC-0111 boosts cisplatin effects in hampering head and neck squamous carcinoma cell growth and invasion. J Exp Clin Cancer Res. 2022.

[27] Vullo D, Del Prete S, Osman SM, et al. Sulfonamide inhibition studies of the β-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. Bioorg Med Chem Lett.

[28] Nishimori I, Vullo D, Innocenti A, Scozzafava A, Mastrolorenzo A, Supuran CT. Carbonic anhydrase inhibitors: cloning, characterization, and inhibition studies of a new beta-carbonic anhydrase from Mycobacterium tuberculosis. J Med Chem.

[29] Click-tailed benzenesulfonamides as potent bacterial carbonic anhydrase inhibitors for targeting Mycobacterium tuberculosis and Vibrio cholerae. Bioorg Med Chem. 2019.

[30] Inhibition of bacterial α-, β- and γ-class carbonic anhydrases with selenazoles incorporating benzenesulfonamide moieties. J Enzyme Inhib Med Chem. 2019.

[31] An overview of novel antimicrobial carbonic anhydrase inhibitors. Expert Opin Ther Pat. 2023.

[32] Maresca A, Temperini C, Vu H, et al. Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. J Am Chem Soc. 2009;131(8):3057–3062.

[33] Maresca A, Supuran CT. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J Med Chem. 2010;53(2):612–618.

[34] Maresca A, Scozzafava A, Supuran CT. 7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones i and II in the low nanomolar/subnanomolar range. Bioorg Med Chem Lett. 2010;20(24):7255–7258.

[35] Scozzafava A, Menabuoni L, Mincione F, Briganti F, Mincione G, Supuran CT. Carbonic anhydrase inhibitors: synthesis of schiff bases of hydroxybenzaldehydes with aromatic sulfonamides, and their reactions with arylsulfonyl isocyanates. Eur J Med Chem / J Enzyme Inhib. 2000.

[36] Inhibition studies of bacterial, fungal and protozoan β-class carbonic anhydrases with Schiff bases incorporating sulfonamide moieties. Bioorg Med Chem. 2015.

[37] Carbonic anhydrase inhibitors: Schiff's bases of aromatic and heterocyclic sulfonamides and their metal complexes. J Enzyme Inhib Med Chem.

[38] Sulfonamide diuretic azosemide as an efficient carbonic anhydrase inhibitor. J Mol Struct. 2022.

[39] Carta F, Aggarwal M, Maresca A, et al. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo. J Med Chem.

[40] Discovery of new selenoureido analogues of 4-(4-fluorophenylureido)benzenesulfonamide as carbonic anhydrase inhibitors. ACS Med Chem Lett. 2017.

[41] Design and synthesis of some new benzoylthioureido benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem. 2022.

[42] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26.

[43] Supuran CT, Scozzafava A, Casini A. Carbonic anhydrase inhibitors: the development of topically acting carbonic anhydrase inhibitors as anti-glaucoma agents. Med Res Rev. 2003;23(2):146–189.

@article{1723904,
      author = {Karan Kumar Gupta, Swarup J. Chatterjee},
      title = {Benzenesulfonamide Derivatives as Selective Carbonic Anhydrase Inhibitors: SAR and Antibacterial Potential},
      journal = {Iconic Research And Engineering Journals},
      year = {2026},
      volume = {10},
      number = {4},
      pages = {1399-1411},
      issn = {2456-8880},
      url = {https://www.irejournals.com/formatedpaper/1723904.pdf},
      abstract = {Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and a proton, a reaction central to respiration, pH homeostasis, ion transport and several pathological processes including glaucoma, epilepsy, tumour progression and bacterial survival in host tissue. The primary sulfonamide group (–SO2NH2) remains the most validated zinc-binding pharmacophore for CA inhibition, and the last two decades of medicinal chemistry have been dominated by the “tail approach,” in which a constant benzenesulfonamide zinc-anchor is decorated with a chemically diverse “tail” that projects into the enzyme’s variable rim and hydrophobic/hydrophilic halves, thereby tuning potency and isoform selectivity among the fifteen catalytically active human CA isoforms. This review synthesises the historical development, catalytic mechanism, and structure-based rationale of the tail approach, and critically discusses eight representative tail chemotypes — aromatic amide, ureido, Schiff base, azo, 1,2,3-triazole (click), reduced Schiff base, coumarin and thioureido — that have been most extensively explored for engineering selectivity between physiologically essential off-target isoforms (CA I, CA II) and tumour-associated or pathogen-derived isoforms (CA IX, CA XII, and bacterial β-/γ-class enzymes). Comparative isoform properties, in-silico/ADMET-guided design considerations, and the translational status of tail-modified sulfonamides — exemplified by the clinical-stage agent SLC-0111 — are summarised. We highlight persisting challenges in achieving absolute isoform selectivity, off-target physiological inhibition, and antimicrobial resistance pressure, and outline future directions including multi-tailed ligands, click-chemistry diversification and structure-guided antibacterial CA-inhibitor design, of direct relevance to the rational design of new tail-modified benzenesulfonamide derivatives.},
      keywords = {carbonic anhydrase inhibitors; benzenesulfonamide; tail approach; isoform selectivity; carbonic anhydrase IX; antibacterial agents; click chemistry; drug design},
      month = {October},
  }