2. Academic Validation
  3. N-aryl-N'-ureido-O-sulfamates as potent and selective inhibitors of hCA VB over hCA VA: Deciphering the binding mode of new potential agents in mitochondrial dysfunctions

N-aryl-N'-ureido-O-sulfamates as potent and selective inhibitors of hCA VB over hCA VA: Deciphering the binding mode of new potential agents in mitochondrial dysfunctions

  • Bioorg Chem. 2020 Jul;100:103896. doi: 10.1016/j.bioorg.2020.103896.
Giulio Poli 1,  Murat Bozdag 2,  Emanuela Berrino 3,  Andrea Angeli 2,  Tiziano Tuccinardi 1,  Fabrizio Carta 2,  Claudiu T Supuran 4
Affiliations

Affiliations

  • 1 University of Pisa, Department of Pharmacy, Via Bonanno 6, 56126 Pisa, Italy.
  • 2 University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
  • 3 University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: [email protected].
  • 4 University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: [email protected].
PMID: 32413627 DOI: 10.1016/j.bioorg.2020.103896
Abstract

N-aryl-N'-ureido-O-sulfamates (AUSs) were recently reported as new class of Carbonic Anhydrase Inhibitors (CAIs), endowed of high potency and selectivity against hCA VII and XII. In this work, we extended the investigational study on this new class of CAIs profiling them against the mitochondrial CA isoforms hCA VA and VB. The results revealed a very interesting selectivity profile, with dramatic selectivity against hCA VB over the VA isoform observed for all the analyzed compounds 2-22. On derivative 15, selected as one of the most promising among the series, molecular modeling studies were conducted, highlighting the importance of small residue substitution between the two isoforms in substantially changing the tail orientation and interaction with the enzymes.

Keywords

Carbonic anhydrase; Carbonic anhydrase inhibitors; Mitochondrial CAs; Mitochondrial dynamics; N-Aryl-N′-ureido-O-sulfamates; Obesity; Selectivity.

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