Emerging role of carbonic anhydrase inhibitors

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) was clinically exploited for decades, as most modern diuretics were obtained considering as lead molecule acetazolamide, the prototypical CA inhibitor (CAI). The discovery and characterization of multiple human CA (hCA) isoforms, 15 of which being known today, led to new applications of their inhibitors. They include widely clinically used antiglaucoma, antiepileptic and antiobesity agents, antitumor drugs in clinical development, as well as drugs for the management of acute mountain sickness and idiopathic intracranial hypertension (IIH). Emerging roles of several CA isoforms in areas not generally connected to these enzymes were recently documented, such as in neuropathic pain, cerebral ischemia, rheumatoid arthritis, oxidative stress and Alzheimer's disease. Proof-of-concept studies thus emerged by using isoform-selective inhibitors, which may lead to new clinical applications in such areas. Relevant preclinical models are available for these pathologies due to the availability of isoform-selective CAIs for all human isoforms, belonging to novel classes of compounds, such as coumarins, sulfocoumarins, dithiocarbamates, benzoxaboroles, apart the classical sulfonamide inhibitors. The inhibition of CAs from pathogenic bacteria, fungi, protozoans or nematodes started recently to be considered for obtaining anti-infectives with a new mechanism of action. Carbonic anhydrase (CA, EC 4.2.1.1) was discovered in 1933 by Meldrum and Roughton [1] during experiments on the transport of CO2/bicarbonate in the blood, being noted that the large amounts of metabolically generated CO2 and its relatively low hydration rate at the physiological pH, implicated that an efficient catalyst must interconvert the two species [1,2]. This catalyst was indeed demonstrated to be a metalloenzyme, subsequently denominated by the two researches CA. Krebs and Roughton [3] later defined it as a 'tool in studying the mechanism of reactions involving H2CO3, CO2 or HCO3', which is role that this enzyme still has today after thousands of valuable studies that have been performed worldwide. Furthermore, it has been ascertained that in humans, as in most vertebrates, at least 15 different CA isoforms belonging to the alpha-class are widespread in many organs, tissues and cells, being involved in a multitude