Carbonic anhydrase inhibitors : Synthesis and inhibition studies against mammalian isoforms I-XV with a series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 20; pp. 9113 - 9120
• Main Authors: GÜZEL, Ozlen, INNOCENTI, Alessio, SCOZZAFAVA, Andrea, SALMAN, Aydin, PARKKILA, Seppo, HILVO, Mika, SUPURAN, Claudiu T
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.10.2008
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - classification; Carbonic Anhydrases - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrazines - chemistry; Indoles - chemistry; Isoenzymes - antagonists & inhibitors; Isoenzymes - classification; Isoenzymes - metabolism; Lyases; Medical sciences; Mice; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Organic hydrazide; Nitrogen heterocycle; Isozyme; Isoforms CA I-CA XV; Lyases; Selectivity; Structure activity relation; CA XIV-selective inhibitor; Bicyclic compound; Aromatic compound; Chemical synthesis; Human; Indole-5-sulfonamide; Sulfonamide; Enzyme; Rodentia; Benzene derivatives; Enzyme inhibitor; In vitro; Vertebrata; Mammalia; Mouse; Carbonic anhydrase; Animal; Carbonate dehydratase; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.09.032

A series of 2-(hydrazinocarbonyl)-3-substitutedphenyl-1H-indole-5-sulfonamides possessing various 2-, 3- or 4- substituted phenyl groups with methyl-, halogeno- and methoxy- functionalities, as well as the perfluorophenyl moiety have been synthesized and evaluated as inhibitors of 13 catalytically active, mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, that is, CA I-CA XV (of human (h) or murine (m) origin). The new compounds were ineffective inhibitors of isozymes hCA III, hCA IV, hCA VA, hCA VB, hCA VI and mCA XIII, moderate inhibitors of hCA I, hCA VII, hCA IX and mCA XV, and excellent, low-nanomolar inhibitors of hCA II and hCA XIV. The substitution pattern of the aromatic group in the 3-position of the indole ring influenced biological activity and isozyme inhibition profiles in this series of sulfonamides. Some of the best and most selective hCA XIV and mCA XV inhibitors ever reported have been identified in this study.