One-Pot Procedure for the Synthesis of Asymmetric Substituted Ureido Benzene Sulfonamides as Effective Inhibitors of Carbonic Anhydrase Enzymes

  • J Med Chem. 2022 Jan 13;65(1):824-837. doi: 10.1021/acs.jmedchem.1c01906.
Gioele Vannozzi  1 ,  Daniela Vullo  1 ,  Andrea Angeli  1 ,  Marta Ferraroni  2 ,  Jacob Combs  3 ,  Carrie Lomelino  3 ,  Jacob Andring  3 ,  Robert Mckenna  3 ,  Gianluca Bartolucci  1 ,  Marco Pallecchi  1 ,  Laura Lucarini  4 ,  Silvia Sgambellone  4 ,  Emanuela Masini  4 ,  Fabrizio Carta  1 ,  Claudiu T Supuran  1
Affiliations
  • 1. NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
  • 2. Dipartimento di Chimica " Ugo Schiff", University of Florence, Via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy.
  • 3. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610, United States.
  • 4. NEUROFARBA Department, Section of Pharmacology and Toxicology, University of Florence, Via G. Pieraccini 6, 50139 Florence, Italy.
PMID: 34958217 DOI: 10.1021/acs.jmedchem.1c01906
Abstract

We report a one-pot procedure for the synthesis of asymmetrical ureido-containing benzenesulfonamides based on in situ generation of the corresponding isocyanatobenezenesulfonamide species, which were trapped with the appropriate amines. A library of new compounds was generated and evaluated in vitro for their inhibition properties against a representative panel of the human (h) metalloenzymes carbonic anhydrases (EC 4.2.1.1), and the best performing compounds on the isozyme II (i.e., 7c, 9c, 11g, and 12c) were screened for their ability to reduce the intraocular pressure in glaucomatous rabbits. In addition, the binding modes of 7c, 11f, and 11g were assessed by means of X-ray crystallography.

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