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.