4-[ N-(Substituted 4-pyrimidinyl)amino]benzenesulfonamides as inhibitors of carbonic anhydrase isozymes I, II, VII, and XIII

• Published in: Bioorganic & medicinal chemistry 2010-11, Vol.18 (21), p.7413-7421
• Main Authors: Sūdžius, Jurgis, Baranauskienė, Lina, Golovenko, Dmitrij, Matulienė, Jurgita, Michailovienė, Vilma, Torresan, Jolanta, Jachno, Jelena, Sukackaitė, Rasa, Manakova, Elena, Gražulis, Saulius, Tumkevičius, Sigitas, Matulis, Daumantas
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Benzenesulfonamide; Benzenesulfonamides; Binding Sites; Biological and medical sciences; Calorimetry; Carbonic Anhydrase I - antagonists & inhibitors; Carbonic Anhydrase I - genetics; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - genetics; Carbonic Anhydrase II - metabolism; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrase isozymes I, II, VII, and XIII; Carbonic Anhydrases - chemistry; Carbonic Anhydrases - genetics; Carbonic Anhydrases - metabolism; Crystallography, X-Ray; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Isothermal titration calorimetry; Lyases; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein Structure, Tertiary; Pyrimidine; Pyrimidines - chemistry; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thermal shift assay; ThermoFluor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.011

A series of 4-[ N-(substituted 4-pyrimidinyl)amino]benzenesulfonamides were designed and synthesised. Their binding potencies as inhibitors of selected recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII were measured using isothermal titration calorimetry and the thermal shift assay. To determine the structural features of inhibitor binding, the crystal structures of several compounds in complex with hCA II were determined. Several compounds exhibited selectivity towards isozymes I, II, and XIII, and some were potent inhibitors of hCA VII.