Polypharmacology of carbonic anhydrase inhibitors

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Carbonic anhydrases (CAs, EC are widespread metalloenzymes all over the phylogenetic tree, with 16 different isoforms present in mammals. CAs are efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and are inhibited by several classes of compounds such as the sulfonamides and their isosteres, sulfamates and sulfamides. A large number of clinically used drugs/agents in clinical development show significant inhibitory activity against the human (h) CA isoforms. Such compounds have applications as diuretics and antiglaucoma drugs, anticonvulsants, with some derivatives in clinical development as anticancer agents/diagnostic tools, or as antiobesity drugs. Several drugs originally discovered for other targets, such as such as the antiepileptics topiramate, zonisamide, and lacosamide; the sulfonamide coxibs (celecoxib, valdecoxib and paricoxib), or the protein kinase inhibitors pazopanib, imatinib and nilotinib, also show significant inhibition of many pharmacologically relevant CA isoforms. This polypharmacology of the CA inhibitors (CAIs) thus affords for novel applications for these drugs, such as for example the antiobesity action of topiramate and zonisamide (thought to be due to inhibition of two mitochondrial CA isoforms) or the antitumor activity of most sulfonamides and also coxibs and kinase inhibitors, which strongly inhibit the tumor-associated isoforms CA IX and XII. Novel applications of CAIs have also emerged in the treatment of rheumatoid arthritis, neuropathic pain and cerebral ischemia, considering the off-target activity/polypharmacology of well-known, clinically used drugs targeting these enzymes.