4‑Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki–Miyaura Reaction, Enzyme Inhibition, and X‑ray Crystallographic Studies

Benzenesulfonamides
bearing various substituted (hetero)­aryl rings
in the para-position were prepared by palladium nanoparticle-catalyzed
Suzuki–Miyaura cross-coupling reactions and evaluated as human
carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA
I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition
against hCA I isoform, whereas the other cytosolic isoenzyme, hCA
II, was strongly affected. The major part of these new derivatives
acted as potent inhibitors of the tumor-associated isoform hCA XII.
An opposite trend was observed for phenyl, naphthyl, and various heteroaryl
substituted benzenesulfonamides which displayed subnanomolar hCA IX
inhibition while poorly inhibiting the other tumor-associated isoform
hCA XII. The inhibition potency and influence of the partially restricted
aryl–aryl bond rotation on the activity/selectivity were rationalized
by means of X-ray crystallography of the adducts of hCA II with several
4-arylbenzenesulfonamides.