2. Academic Validation
  3. 2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity

2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity

  • Eur J Med Chem. 2022 Jan 15;228:114026. doi: 10.1016/j.ejmech.2021.114026.
Niccolò Chiaramonte 1,  Andrea Angeli 1,  Silvia Sgambellone 2,  Alessandro Bonardi 3,  Alessio Nocentini 3,  Gianluca Bartolucci 1,  Laura Braconi 1,  Silvia Dei 1,  Laura Lucarini 2,  Elisabetta Teodori 1,  Paola Gratteri 3,  Bernhard Wünsch 4,  Claudiu T Supuran 5,  Maria Novella Romanelli 6
Affiliations

Affiliations

  • 1 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
  • 2 University of Florence, Department NEUROFARBA, Section of Pharmacology and Toxicology, Viale Pieraccini 6, 50100, Florence, Italy.
  • 3 University of Florence, Department NEUROFARBA - Section of Pharmaceutical and Nutraceutical Sciences; Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Italy.
  • 4 Institute of Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms University Münster, Corrensstraße 48, D-48149, Münster, Germany.
  • 5 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy. Electronic address: [email protected].
  • 6 University of Florence, Department of Neuroscience, Psychology, Drug Research and Child's Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy. Electronic address: [email protected].
PMID: 34920169 DOI: 10.1016/j.ejmech.2021.114026
Abstract

Targeting Carbonic Anhydrases (CAs) represents a strategy to treat several diseases, from glaucoma to Cancer. To widen the structure-activity relationships (SARs) of our series of piperazines endowed with potent human Carbonic Anhydrase (hCA) inhibition, a new series of chiral piperazines carrying a (2-hydroxyethyl) group was prepared. The Zn-binding function, the 4-sulfamoylbenzoyl moiety, was connected to one piperazine N-atom, while the other nitrogen was decorated with alkyl substituents. In analogy to the approach used for the synthesis of the previously reported series, the preparation of the new compounds started with (R)- and (S)-aspartic acid. A partial racemization occurred during the synthesis. In order to overcome this problem, other chemical strategies were investigated. The inhibitory activity of the new polar derivatives against four hCAs isoforms I, II, IV and IX using a stopped flow CO2 hydrase assay was determined. Some compounds showed potency in the nanomolar range and a preference for inhibiting hCA IX.

Keywords

Carbonic anhydrase; Enantioselectivity; Enzyme inhibitors; Glaucoma; Piperazine.

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