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Carbonic Anhydrase Inhibitors Drug Design

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Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

Part of the book series: Subcellular Biochemistry ((SCBI,volume 75))

Abstract

Inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti-infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported.

Susan C. Frost and Robert McKenna (eds.). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

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Acknowledgments

Research from C. T. S. laboratory was financed by several grants of the 6th and 7th Framework Programs of the European Union (DeZnIT, Metoxia and Dynano projects) and from R. M. laboratory by a grant from the NIH (GM25154).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA

    Robert McKenna

  2. NEUROFARBA Department, Pharmaceutical Sciences Section, Universita degli Studi di Firenze, Polo Scientifico, Florence, Italy

    Claudiu T. Supuran

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  1. Robert McKenna
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  2. Claudiu T. Supuran
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Correspondence to Claudiu T. Supuran .

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Editors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Susan C. Frost

  2. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Robert McKenna

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McKenna, R., Supuran, C.T. (2014). Carbonic Anhydrase Inhibitors Drug Design. In: Frost, S., McKenna, R. (eds) Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, vol 75. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7359-2_15

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