Multi- and poly-pharmacology of carbonic anhydrase inhibitors.

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.