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Synthesis of Azasugar–Sulfonamide conjugates and their Evaluation as Inhibitors of Carbonic Anhydrases: the Azasugar Approach to Selectivity
Author(s) -
Pratesi Debora,
Sodini Andrea,
Matassini Camilla,
Cardona Francesca,
Angeli Andrea,
Carta Fabrizio,
Ferraroni Marta,
Supuran Claudiu T.,
Goti Andrea
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202100250
Subject(s) - chemistry , sulfonamide , carbonic anhydrase , moiety , combinatorial chemistry , biochemistry , enzyme , isozyme , in vitro , drug discovery , stereochemistry
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.