Synthesis, Structure–Activity
Relationship
Studies, and X-ray Crystallographic Analysis of Arylsulfonamides as
Potent Carbonic Anhydrase Inhibitors
- Publication date
- Publisher
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) (<i>K</i><sub>i</sub> 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 (<b>I</b> and <b>2a</b>) with hCA II allowed us to elucidate the main
interactions between the inhibitor and specific amino acid residues
within the catalytic site