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Carbonic anhydrase inhibitors: Synthesis of water soluble sulfonamides incorporating a 4-sulfamoylphenylmethylthiourea scaffold, with potent intraocular pressure lowering properties

Casini, Angela, Scozzafava, A, Mincione, F, Menabuoni, L and Supuran, CT 2002. Carbonic anhydrase inhibitors: Synthesis of water soluble sulfonamides incorporating a 4-sulfamoylphenylmethylthiourea scaffold, with potent intraocular pressure lowering properties. Journal of Enzyme Inhibition and Medicinal Chemistry 17 (5) , pp. 333-343. 10.1080/1475636021000010950

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Abstract

Reaction of thiophosgene with 4-aminomethyl-benzenesulfonamide afforded 4-isothiocyanatomethyl-benzenesulfonamide, which by reaction with amines, amino acids and oligopeptides, lead to a series of new sulfonamides incorporating a 4-sulfamoylphenyl-methylthiourea scaffold. These new thioureas showed strong affinities towards isozymes I, II and IV of carbonic anhydrase (CA, EC 4.2.1.1). In vitro inhibitory potency was good (in the low nanomolar range) for the derivatives of: amino-benzoic acids, β -phenyl-serine, α -phenyl-glycine, for those incorporating hydroxy- and mercapto-amino acids (Ser, Thr, Cys and Met), hydrophobic amino acids (Val, Leu, Ile), aromatic amino acids (Phe, His, Trp, Tyr; DOPA); dicarboxylic amino acids as well as di-/tri-/tetrapeptides among others. Such CA inhibitors displayed very good water solubility (in the range of 2-3%) as sodium (carboxylate) salts, with pH values for the solutions obtained of 6.5-7.0. Furthermore, in normotensive rabbits, some of them showed an effective and prolonged intraocular pressure (IOP) lowering when administered topically, as 2% solutions.

Item Type: Article
Status: Published
Schools: Chemistry
Publisher: Informa Healthcare
ISSN: 1475-6366
Last Modified: 04 Jun 2017 08:49
URI: http://orca.cf.ac.uk/id/eprint/85558

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