Multi- and polypharmacology of carbonic anhydrase inhibitors

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) have been described in organisms overall in 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 Alzheimer/Parkinson disease management. CAs from pathogenic bacteria, fungi, protozoans, and nematodes have started to be considered as drug targets in recent years, with notable advances being registered. 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 that 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 because drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide, and high-ceiling diuretics) show effective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. SIGNIFICANCE STATEMENT: CAIs have multiple pharmacologic applications, such as diuretics, antiglaucoma, antiepileptic, antiobesity, antiacute mountain sickness, anti-idiopathic intracranial hypertension, and antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations has started to be investigated recently. Parasite carbonic anhydrases are also drug targets for anti-infectives with novel mechanisms of action that can bypass drug resistance to commonly used agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.