Carbonic anhydrase inhibitors: inhibition of the human transmembrane isozyme XIV with a library of aromatic/heterocyclic sulfonamides.
The first inhibition study of the transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA XIV with a library of aromatic and heteroaromatic sulfonamides synthesized earlier is reported. Most of the inhibitors were sulfanilamide, homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives, to which tails that would induce diverse physicochemical properties have been attached at the amino moiety. Several of these compounds were metanilamide, benzene-1,3-disulfonamide or the 1,3,4-thiadiazole/thiadiazoline-2-sulfonamide derivatives. The tails incorporated in these molecules were of the alkyl/aryl-carboxamido/ sulfonamido-, ureido- or thioureido-types. The sulfanilamides acylated at the 4-amino group with short aliphatic/aromatic moieties incorporating 2-6 carbon atoms showed modest hCA XIV inhibitory activity (K(I)-s in the range of 1.25-4.2 microM) which were anyhow better than that of sulfanilamide (K(I) of 5.4 microM). Better activity showed the homosulfanilamide and 4-aminoethyl-benzenesulfonamide derivatives bearing arylsulfonamido/ureido and thioureido moieties, with K(I)'s in the range of 203-935 nM. The best activity was observed for the heteroaromatic compounds incorporating 1,3,4-thiadiazole/thiadiazoline-2-sulfonamide and 5-arylcarboxamido/sulfonamido moieties, with K(I)'s in the range of 10-85 nM. All these compounds were generally also much better inhibitors of the other two transmembrane CA isozyme, hCA IX and XII. Thus, highly potent hCA XIV inhibitors were detected, but isozyme-specific inhibitors were not discovered for the moment.
Ozensoy
Ozen
O
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Nishimori
Isao
I
Vullo
Daniela
D
Puccetti
Luca
L
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects* / Q000235:genetics; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D007527:Isoenzymes; D008565:Membrane Proteins; D013449:Sulfonamides; D002256:Carbonic Anhydrases; C466621:carbonic anhydrase XIV