Carbonic anhydrase inhibitors. Phenacetyl-, pyridylacetyl- and thienylacetyl-substituted aromatic sulfonamides act as potent and selective isoform VII inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 12; pp. 3170 - 3173
• Main Authors: Güzel, Özlen, Innocenti, Alessio, Scozzafava, Andrea, Salman, Aydın, Supuran, Claudiu T.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.06.2009; Elsevier
• Subjects: Acetylation; Biological and medical sciences; Brain Chemistry; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - drug effects; Cytosolic isoform; Epileptogenesis; Humans; Hydrocarbons, Aromatic; Isozyme VII; Medical sciences; Miscellaneous; Neuropharmacology; Pharmacology. Drug treatments; Protein Isoforms; Structure-Activity Relationship; Sulfonamide; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Tail approach; Epileptogenesis; Tail approach; Isozyme VII; Sulfonamide; Carbonic anhydrase; Cytosolic isoform; Enzyme; Isozyme; Epilepsy; Enzyme inhibitor; Lyases; Selectivity; In vitro; Pyridine derivatives; Thiophene derivatives; Structure activity relation; Carbonate dehydratase; Aromatic compound; Chemical synthesis; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.123

K i (hCA I) = 108 nM, K i (hCA II) = 107 nM K i (hCA VII) = 4.7 nM. A series of aromatic/heterocyclic sulfonamides incorporating phenyl(alkyl), halogenosubstituted-phenyl- or 1,3,4-thiadiazole-sulfonamide moieties and thienylacetamido; phenacetamido- and pyridinylacetamido tails were prepared and assayed as inhibitors of cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I, II and VII. The new compounds showed moderate inhibition of the two ubiquitous isoforms I and II ( K Is of 50–390 nM) and excellent inhibitory activity against the brain associated hCA VII ( K Is in the range of 4.7–8.5 nM). Isoform VII highly selective inhibitors are being detected for the first time, with selectivity ratios for inhibiting CA VII over CA II of 11–75, and for inhibiting CA VII over CA I of 10–49, which may be useful for understanding the role of CA VII in epileptogenesis and other physiologic processes.