Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations

Herein
we report the synthesis of two series of benzenesulfonamide
containing compounds that incorporate the phenyl-1,2,3-triazole moieties.
We explored the insertion of appropriate linkers, such as ether, thioether,
and amino type, into the inner section of the molecules with the intent
to confer additional flexibility. All obtained compounds were screened
in vitro as inhibitors of the physiologically relevant human (h) isoforms
of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of
them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors,
whereas they did not potently inhibit hCA I. Computational and X-ray
crystallographic studies of the enzyme–inhibitor adducts helped
us to rationalize the obtained results. Some of the sulfonamides reported
here showed significant intraocular pressure lowering activity in
an animal model of glaucoma.