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Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.

Abstract
Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.
AuthorsFrancesco Mincione, Francesca Benedini, Stefano Biondi, Alessandro Cecchi, Claudia Temperini, Giuseppe Formicola, Ilaria Pacileo, Andrea Scozzafava, Emanuela Masini, Claudiu T Supuran
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 11 Pg. 3216-21 (Jun 01 2011) ISSN: 1464-3405 [Electronic] England
PMID21549597 (Publication Type: Journal Article)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Carbonic Anhydrase Inhibitors
  • Protein Isoforms
  • Sulfonamides
  • Thiophenes
  • Nitric Oxide
  • dorzolamide
Topics
  • Animals
  • Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Glaucoma (drug therapy)
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nitric Oxide (chemistry)
  • Ocular Hypertension (drug therapy)
  • Protein Isoforms (chemical synthesis, chemistry, pharmacology)
  • Rabbits
  • Sulfonamides (chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Thiophenes (chemistry, pharmacology, therapeutic use)

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