Selective Carbonic Anhydrase IX and XII Inhibitors Based Around a Functionalized Coumarin Scaffold

30 January 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki’s = 955 nM, 515 nM, 21 nM and 5 nM for CA’s I, II, IX and XII respectively) is highlighted as a novel CA IX and XII inhibitor for further development.


Carbonic anhydrase IX inhibitors
Carbonic anhydrases XII inhibitor
Structure-activity relationship

Supplementary materials

Supplementary Information
1H and 13C NMR Spectra


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