Sulfonamides incorporating 2-carboxy-benzenecarboxamido (phthaloyl) moieties in their molecules were prepared by reaction of phthalic anhydride with aromatic/heterocyclic sulfonamides in mild conditions. Another closely related series of derivatives was prepared by reaction of the same reagents in more energetic conditions, when the corresponding phthalimides were obtained. Some of these compounds showed very good in vitro carbonic anhydrase (CA) isozymes I, II and IV inhibitory properties, with affinities for the enzymes in the low nanomolar range for the best inhibitors. Some of the potent CA inhibitors reported here have been formulated as sodium salts, in aqueous solutions for topical administration as antiglaucoma agents, in normotensive/glaucomatous rabbits. Only the derivatives possessing good water solubility, showed effective and longer lasting topical intraocular pressure (IOP) lowering than dorzolamide and brinzolamide, two clinically used topical antiglaucoma drugs. All the in vivo effective new compounds belonged to the first series of derivatives, whereas the corresponding phthalimides, although stronger in vitro CA inhibitors were devoid of topical IOP lowering properties, probably due to their unproper physico-chemical properties.