Synthesis, structure-activity relationship studies, and X-ray crystallographic analysis of arylsulfonamides as potent carbonic anhydrase inhibitors.
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Gitto R, Damiano FM, Mader P, De Luca L, Ferro S, Supuran CT, Vullo D, Brynda J, Rezacova P, Chimirri A
Synthesis, structure-activity relationship studies, and X-ray crystallographic analysis of arylsulfonamides as potent carbonic anhydrase inhibitors.
J Med Chem. 2012 Apr 26;55(8):3891-9. doi: 10.1021/jm300112w. Epub 2012 Apr 6.
- PubMed ID
- 22443141 [ View in PubMed]
- Abstract
A series of arylsulfonamides has been synthesized and investigated for the inhibition of some selected human carbonic anhydrase isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV) (K(i) values from 4.8 to 61.7 nM), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. On the basis of biochemical data, we herein discussed structure-affinity relationships for this series of arylsulfonamides, suggesting a key role for alkoxy substituents in CA inhibition. Furthermore, X-ray crystal structures of complexes of two active inhibitors (I and 2a) with hCA II allowed us to elucidate the main interactions between the inhibitor and specific amino acid residues within the catalytic site.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 14 Ki (nM) 41 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details Acetazolamide Carbonic anhydrase 7 Ki (nM) 2.5 N/A N/A Details Topiramate Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Topiramate Carbonic anhydrase 2 Ki (nM) 10 N/A N/A Details Zonisamide Carbonic anhydrase 1 Ki (nM) 56 N/A N/A Details Zonisamide Carbonic anhydrase 14 Ki (nM) 5250 N/A N/A Details Zonisamide Carbonic anhydrase 2 Ki (nM) 35 N/A N/A Details Zonisamide Carbonic anhydrase 7 Ki (nM) 117 N/A N/A Details Zonisamide Carbonic anhydrase 9 Ki (nM) 5.1 N/A N/A Details