The design of three dual-tailed sulfonamide series 11a-g, 14a-h and 16a-e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against phar-macologically relevant human (h) CAs isoforms I, II, IV, and VII. Compounds 11a-g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36 - 6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moie-ties within in the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-d and 11g were evaluated for their intraocular pressure (IOP) lower-ing effects in a rabbit model of the glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.