Beta and Gamma Amino Acid-Substituted Benzenesulfonamides as Inhibitors of Human Carbonic Anhydrases

• Main Authors: Benas Balandis (Author), Tomas Šimkūnas (Author), Vaida Paketurytė-Latvė (Author), Vilma Michailovienė (Author), Aurelija Mickevičiūtė (Author), Elena Manakova (Author), Saulius Gražulis (Author), Sergey Belyakov (Author), Visvaldas Kairys (Author), Vytautas Mickevičius (Author), Asta Zubrienė (Author), Daumantas Matulis (Author)
• פורמט: ספר
• יצא לאור: MDPI AG, 2022-04-01T00:00:00Z.
• נושאים: article
• גישה מקוונת: Connect to this object online.
• Notes: 10.3390/ph15040477; 1424-8247
• Keywords: carbonic anhydrase inhibitor; benzenesulfonamide; fluorescent thermal shift assay; X-ray crystallography; intrinsic thermodynamics of binding; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 4, p 477 (2022)

A series of novel benzenesulfonamide derivatives were synthesized bearing <i>para</i>-<i>N</i> β,γ-amino acid or <i>para</i>-<i>N</i> β-amino acid and thiazole moieties and their binding to the human carbonic anhydrase (CA) isozymes determined. These enzymes are involved in various illnesses, such as glaucoma, altitude sickness, epilepsy, obesity, and even cancer. There are numerous compounds that are inhibitors of CA and used as pharmaceuticals. However, most of them bind to most CA isozymes with little selectivity. The design of high affinity and selectivity towards one CA isozyme remains a significant challenge. The beta and gamma amino acid-substituted compound affinities were determined by the fluorescent thermal shift assay and isothermal titration calorimetry for all 12 catalytically active human carbonic anhydrase isozymes, showing the full affinity and selectivity profile. The structures of several compounds were determined by X-ray crystallography, and the binding mode in the active site of CA enzyme was shown.