Coumarin carbonic anhydrase inhibitors from natural sources

Abstract

Coumarins constitute a relatively new class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), possessing a unique inhibition mechanism, acting as "prodrug inhibitors." They undergo the hydrolysis of the lactone ring mediated by the esterase activity of CA. The formed 2-hydroxy-cinnamic acids thereafter bind within a very particular part of the enzyme active site, at its entrance, where a high variability of amino acid residues among the different mammalian CA isoforms is present, and where other inhibitors classes were not seen bound earlier. This explains why coumarins are among the most isoform-selective CA inhibitors known to date among the many chemotypes endowed with such biological activity. As coumarins are widespread secondary metabolites in some bacteria, plants, fungi, and ascidians, many such compounds from various natural sources have been investigated for their CA inhibitory properties and for possible biomedical applications, mainly as anticancer agents targeting hypoxic tumours.

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

“…All the synthesised compounds show a propyl substituent in the position 8 or 9 of the coumarin and psoralen nucleus, respectively. As in previously reported derivatives, a methylene carboxylic group was placed in position 3 of the chromene which may lead to the formation of a bidentate chelator of the Zn 2+ ion in the catalytic pocket, due to the hCA esterase activity 32 , 34 , 63 on the dihydropyranone ring, as illustrated in Figure 2 .…”

“… (a) Esterase activity of carbonic anhydrase on compound EMAC10157g 34 . (b, c) Oral bioavailability radar profile.…”

Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivatives

“…Carbonic anhydrase (CAs) isoforms are overexpressed in the synovium of RA patients and there is the interaction between various CAs subtypes and arthritis-like diseases, so carbonic anhydrase inhibitors have been paid more and more attention in the development of anti-RA drugs 30 . Coumarin derivative is a kind of suicided CAIs, which is hydrolysed by esterase CA activity and binds to the active site of carbonic anhydrase, so coumarin has a unique and new carbonic anhydrase inhibition mechanism 31 , 32 . 3-(4-aminophenyl)-coumarin derivatives are derived from 3-arylcoumarin, and the positional isomer structure of 3-arylcoumarin is similar to that of flavonoids and isoflavones.…”

Coumarin‐Thiourea Hybrids Show Potent Carbonic Anhydrase IX and XIII Inhibitory Action

“…[19,20] Several natural coumarins were reported to be potent inhibitors of CA XIII. [21] Thioureas are molecules which possess the fragment NHC (=S)NH. They have also been known to display diverse biological profiles like anticancer, anti-inflammatory, antimicrobial and antiplatelet.…”