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Quantum chemical QSAR expressions have been developed for a heterogeneous group of 36 sulfonamides which have been shown to lower intraocular pressure in in vivo tests on animals. It was found, using the ACE statistical technique, that the lowering of intraocular pressure correlated non-linearly with K(I) for carbonic anhydrase inhibition and with solubility. Non-linear transformations had to be applied to both the response variable and to solubility. Chemical variables found to be relevant to CA inhibition included the dipole moment vector, the frontier orbital energies, the solvation energy determined by the COSMO model, the electrostatic potential based charges on the atoms of the sulfonamide group, and the size and polarizability of the molecule.

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino or hydroxyl groups with N-tert-butyloxycarbonyl-beta-alanine (Boc-beta-ala; Boc = t-butoxycarbonyl) in the presence of carbodiimide derivatives afforded, after removal of the protecting group, a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic or trifluoromethane sulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Good inhibition was observed against all three isozymes, but especially against CA II and CA IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humour secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% aqueous solutions into the eyes of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the amino acyl groups conferring water solubility to these sulfonamide CA inhibitors, coupled with their strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.

Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of derivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtained by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by conversion of their COOH group into the CONHOH moiety, as mentioned above. The 90 new compounds reported here were assayed as inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of native collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4-carboxyphenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorporate hydrophobic moieties at the P(1') and P(2') sites, whereas the alpha-carbon substituent may be a small and compact moiety (such as H, for the Gly derivatives reported here). Such compounds might lead to the design of collagenase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal keratitis.

Reaction of histamine with tetrabromophthalic anhydride and protection of its imidazole moiety with tritylsulfenyl chloride, followed by hydrazinolysis, afforded N-1-tritylsulfenyl histamine, a key intermediate which was further derivatized at its aminoethyl moiety. Carboxamido derivatives were obtained by reaction of the key intermediate with carboxylic acid anhydrides, acyl chlorides or carboxylic acids in the presence of carbodiimides. Reaction of the same key intermediate with isocyanates, isothiocyanates, cyanamide or dicyandiamide afforded another series of compounds. Deprotection of the above-mentioned intermediates with hydrochloric acid in dioxane afforded two series of compounds, histamine derivatives possessing carboxamido, ureido, thioureido or guanidino moieties in their molecule. The new derivatives were assayed as activators of three carbonic anhydrase (CA) isozymes, hCA I, hCA II (cytosolic forms) and bCA IV (membrane-bound form, h = human, b = bovine isozyme). Efficient activation was observed against all three isozymes, but especially against hCA I and bCA IV, with affinities in the nanomolar range for the best compounds. hCA II was, on the other hand, activatable with affinities around 10-25 nM. This new class of CA activators might lead to the development of drugs/diagnostic agents for the CA deficiency syndrome, a genetic disease of bone, brain and kidneys.

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties have been obtained from the sodium salt of the sulfonamide or from the free sulfonamide in the presence of ammonia, and the following metal ions: Mg(II); Zn(II); Mn(II); Cu(II); Co(II); Ni(II); Be(II); Cd(II); Pb(II); Al(III); Fe(III) and La(III). The original sulfonamide, 5-(3,4-dichlorophenylureido)-1,3,4-thiadiazole-2-sulfonamide and its complexes were assayed for in vitro inhibition of three CA isozymes, CA I, II and IV, some of which play a critical role in ocular fluid secretion. All these compounds (the sulfonamide and its metal complexes) behave as very powerful inhibitors against the three investigated CA isozymes. The parent sulfonamide possesses strong topical pressure lowering effects in rabbits when applied as a 1% solution directly into the eye, but some of its metal complexes, such as the Mg(II); Zn(II); Mn(II) and Cu(II) derivatives, lower intraocular pressure (IOP) in experimental animals much better. Ex vivo data showed a 98.5-99.9% inhibition of CA II and IV in ocular fluids and tissues of the rabbits treated with these agents, proving that the IOP lowering properties are due to CA inhibition. The influence of the different metal ions upon the efficiency of the obtained complexes as pressure lowering drugs are discussed, considering the possibility to design in this way more selective pharmacological agents from this class.