Mono-/dihydroxybenzoic acid esters and phenol pyridinium derivatives as inhibitors of the mammalian carbonic anhydrase isoforms I, II, VII, IX, XII and XIV.
Using hydroxy-/dihydroxybenzoic acids as leads, a series of methyl, ethyl and iso-propyl esters of 4-hydroxy-benzoic acid, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dihydroxybenzoic acids and of coumaric acid, were obtained and investigated for the inhibition of six mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, that is, the cytosolic CA I, II and VII, and the transmembrane CA IX, XII and XIV, many of which are established drug targets. Other compounds incorporating phenol/catechol moieties were obtained from dopamine by reaction with fluorescein isothiocyanate or with 2,4,6-trisubstituted pyrylium salts. Some aminophenols were also derivatized in a similar manner, by using pyrylium salts. Many of these compounds showed increased inhibitory action compared to the lead compounds from which they were obtained, with efficacy in the submicromolar range against most investigated CA isoforms. As phenols are a class of less investigated CA inhibitors (CAIs) compared to the sulfonamides, and their mechanism of inhibition is less well understood, compounds of the type designed here may be helpful in gaining more insights into these phenomena.
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy. fabrizio.carta@unifi.it
Fabrizio
F
Carta
Daniela
D
Vullo
Alfonso
A
Maresca
Andrea
A
Scozzafava
Claudiu T
CT
Supuran
D000818:Animals; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D004952:Esters; D062385:Hydroxybenzoates / Q000737:chemistry* / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D019800:Phenol / Q000737:chemistry*; D011485:Protein Binding; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D002257:Carbonic Anhydrase Inhibitors; D004952:Esters; D062385:Hydroxybenzoates; D007527:Isoenzymes; D011726:Pyridinium Compounds; D019800:Phenol; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; C477051:carbonic anhydrase VI; C477378:carbonic anhydrase XII; C466621:carbonic anhydrase XIV