Synthesis of Azasugar–Sulfonamide conjugates and their Evaluation as Inhibitors of Carbonic Anhydrases: the Azasugar Approach to Selectivity. Issue 18 (10th May 2021)

• Record Type: Journal Article
• Authors: Pratesi, Debora; Sodini, Andrea; Matassini, Camilla; Cardona, Francesca; Angeli, Andrea; Carta, Fabrizio; Ferraroni, Marta; Supuran, Claudiu T.; Goti, Andrea
• Is Part Of: European journal of organic chemistry. Issue 18(2021)
• Page Start: 2604
• Page End: 2614
• Publication Date: 2021-05-10
• Subjects: Azasugars -- Benzenesulfonamides -- Carbonic anhydrases -- Glycomimetics -- Enzyme inhibitors; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.202100250
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: Carbonic Anhydrases (CAs; EC 4.2.1.1) are zinc metalloenzymes which play a pivotal role both in physiological and pathological processes in humans (h). Therefore, modulation of the activity of hCAs represents an appealing target for drug development, which is highly challenging due to the large number of isozymes expressed and the requirement in discovery of selective inhibitors. By following the "sugar approach" and in light of our recent disclosure of two selective hCAs inhibitors based on nitrogen containing glycomimetic–sulfonamide conjugates, twelve new azasugar−benzenesulfonamides have been synthesized. These compounds were prepared by connecting several benzenesulfonamides to a triazole armed azasugar, varying in the chain length and type of linking moiety (ureido, amido or thioureido) to probe their influence on the inhibition profile. The in vitro biological assays highlighted that such structural changes have remarkable effects on the hCAs inhibition profile. Several new compounds behave as selective inhibitors, and four of them are particularly effective on the therapeutically relevant hCAs II and VII isoforms. Abstract : Evolution of the "sugar approach" concept aimed at identifying selective hCAs inhibitors to an "azasugar approach" is presented. The synthesis and biological evaluation of twelve azasugar‐sulfonamide conjugate inhibitors highlighted new interesting candidates for biomedical applications. Three novel compounds behave as selective inhibitors of isoforms hCAs II and VII involved in neuropathic pain.