title: Carbonic anhydrase inhibitors drug design.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA, rmckenna@ufl.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D057930:Click Chemistry; D003374:Coumarins / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D013449:Sulfonamides; D002256:Carbonic Anhydrases