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Chemistry. 2018 Nov 9. doi: 10.1002/chem.201805039. [Epub ahead of print]

Phosphorus versus Sulfur: Discovery of Benzenephosphonamidates as Versatile Sulfonamide-Mimic Chemotypes Acting as Carbonic Anhydrase Inhibitors.

Author information

1
Department NEUROFARBA-Pharmaceutical and nutraceutical section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
2
Department NEUROFARBA-Pharmaceutical and nutraceutical section, University of Firenze, via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.

Abstract

The first zinc-binding group (ZBG) to have been identified as inhibitor of the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1) was the sulfonamide. From then on several classes of zinc-binders have been described. This work reports the benzenephosponamidates as a new chiral aromatic sulfonamide-mimic ZBG able to meet the requirements for effectively binding the enzyme active site. Several low micromolar CA I, II, VII, IX inhibitors were thus detected. Kinetic studies, QM-polarized ligand docking, and MM-GBSA in silico methods were used to characterize this newly identified CA inhibitor chemotype.

KEYWORDS:

MM-GBSA; QPLD; carbonic anhydrase; inhibition; metallo-enzymes; phosphonamidate; zinc-binder

PMID:
30411821
DOI:
10.1002/chem.201805039

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