Carbonic anhydrase inhibitors: ureido and thioureido derivatives of aromatic sulfonamides possessing increased affinities for isozyme I. A novel route to 2,5-disubstituted-1,3,4-thiadiazoles via thioureas, and their interaction with isozymes I, II and IV.
Reaction of 12 aromatic sulfonamides containing a free amino group with cyanate or thiocyanate in the presence of acid afforded the corresponding urea/thiourea derivatives which were assayed as inhibitors of three isozymes of carbonic anhydrase (CA), i.e., CA I, II and IV. Oxidation of the obtained thioureas with iodine in acidic medium afforded symmetrical 2,5-bis(substituted-phenyl)-1,3,4-thiadiazole derivatives possessing sulfonamido groups on the aromatic ring, via a new synthesis of the heterocyclic moiety. Good inhibition of all these three CA isozymes was observed with the new compounds, but a novel finding was that the ureas/thioureas reported here had an increased affinity for the slow isozyme CA I, which generally is less sensitive to inhibition by sulfonamides when compared to the rapid isozymes CA II and IV. The disubstituted-1,3,4-thiadiazoles on the other hand were better inhibitors of CA II than CA IV and especially CA I, similarly to the large majority of aromatic/heterocyclic sulfonamides. Some of the new compounds could constitute good lead molecules for developing more selective CA I inhibitors.
Scozzafava
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Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Firenze, Italia. scoz@risc1.lrm.fi.cnr.it
Supuran
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D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D013830:Thiadiazoles; D002256:Carbonic Anhydrases; D013890:Thiourea