Carbonic anhydrase inhibitors: Perfluoroalkyl/aryl-substituted derivatives of aromatic/heterocyclic sulfonamides as topical intraocular pressure-lowering agents with prolonged duration of action

Reaction of perfluoroalky/arylsulfonyl chlorides or perfluoroalkyl/arylcarbonyl chlorides with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded compounds with the general formula C(x)F(y)Z-A-SO2NH2, where Z = SO2NH, SO3, CONH, or CO2 and A = aromatic/heterocyclic moiety. The sulfonyl chlorides used in synthesis included: CF3SO2Cl, n-C4F9SO2Cl, n-C8F17SO2Cl, and C6F5SO2Cl, whereas the acyl chlorides were C8F17COCl and C6F5COCl. A total of 25 different sulfonamides have been derivatized by means of the above-mentioned perfluorosulfonyl/acyl halides. These new series of sulfonamides showed strong affinities toward isozymes I, II, and TV of carbonic anhydrase (CA). For a given sulfonamide derivatized by the above procedures, inhibitory power was greater for the alkyl/arylsulfonylated compounds, as compared to the corresponding perfluoroalky/arylcarbonylated ones. In vitro inhibitory activity generally increased with the number of carbon atoms in the molecule of the acylating/sulfonylating agent, with a maximum for the perfluorophenylsulfonylated and perfluorobenzoylated derivatives. Some of the prepared CA inhibitors displayed very good water solubility (in the range of 2%) and strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomatous rabbit eye, as 2% water solutions. The good water solubility of these new classes of CA inhibitors, correlated with the neutral pH of their solutions used in the ophthalmologic applications, makes them attractive candidates for developing novel types of antiglaucoma drugs devoid of unpleasant ocular side effects.