Probing Molecular Interactions between Human Carbonic Anhydrases (hCAs) and a Novel Class of Benzenesulfonamides

On the basis of X-ray crystallographic
studies of the complex of
hCA II with 4-(3,4-dihydro-1H-isoquinoline-2-carbonyl)­benzenesulfonamide
(3) (PDB code 4Z1J), a novel series of 4-(1-aryl-3,4-dihydro-1H-isoquinolin-2-carbonyl)­benzenesulfonamides (23–33) was designed. Specifically, our idea was
to improve the selectivity toward druggable isoforms through the introduction
of additional hydrophobic/hydrophilic functionalities. Among the synthesized
and tested compounds, the (R,S)-4-(6,7-dihydroxy-1-phenyl-3,4-tetrahydroisoquinoline-1H-2-carbonyl)­benzenesulfonamide (30) exhibited
a remarkable inhibition for the brain-expressed hCA VII (Ki = 0.20 nM) and selectivity over wider distributed hCA
I and hCA II isoforms. By enantioselective HPLC, we solved the racemic
mixture and ascertained that the two enantiomers (30a and 30b) are equiactive inhibitors for hCA VII. Crystallographic
and docking studies revealed the main interactions of these inhibitors
into the carbonic anhydrase (CA) catalytic site, thus highlighting
the relevant role of nonpolar contacts for this class of hCA inhibitors.