Development of New Aromatic Sulfonamides as Potential Antiglaucoma Agents

Many sulfonamides with the general formula R-SO2NH2 constitute an important class of inhibitors of the zinc enzyme carbonic anhydrase (CA) due to their use in antiglaucoma therapy. Design of new aromatic sulfonamides was carried out using computational methods of theoretical medicinal chemistry as described in our previous works. Of particular interest are the molecular geometries of neutral and anionic species, acidities, and lipophilicities. Synthesis of the so-designed new aromatic sulfonamides was conducted according to published procedures. Antiglaucoma activity was evaluated in both in vitro and in vivo conditions. For determination of the intraocular pressure changes the experiment with adult male Chinchilla was used. In this lecture we present the design and synthesis of novel drug-like aromatic sulfonamides, namely (4-sulfamoyl-N-(3-morpholinopropyl) benzamide, N-(3morpholinopropyl)benzene-1,4-disulfonamide, N-(4-diethylaminoethoxybenzyl)benzene-1,4bis(sulfonamide) and their hydrochloride salts. They exhibited favorable biological, structural, physicochemical and some pharmacokinetic properties comparable to those obtained for therapeutically useful acetazolamide, dorzolamide and brinzolamide. Data obtained allows us to assume, that new aromatic sulfonamides may represent novel class of compounds for the discovery of new effective antiglaucoma drugs.


Introduction
It is estimated 2 out of every 100 people over the age of 65 have glaucoma and half of these people don't know it.
Because there is nowhere in the eye for the fluid to go, pressure in the eye increases.
When the pressure becomes higher than the optic nerve can tolerate, damage to the optic nerve occurs.This damage is called glaucoma.

Normal Fluid Drainage
Fluid is produced in the ciliary body behind the iris, passes into the front of the eye, and then exits through the drainage canals.•The computed pK a values correlate well with the available experimental pK a values found in the literature.

Sulfonamide Inhibitors of CAs
• Aromatic inhibitors 9  13 are in the condensed phase by about 1  2 pK a units less acidic than heteroaromatic inhibitors (dorzolamide, brinzolamide and compound X).
•The calculations showed that methazolamide is also in water solution the most acidic drug of the sulfonamides investigated.Potent systemic antiglaucoma sulfonamides 2  5 are by about 2  4 units more acidic than the parent sulfanilamide.

Lipophilicity
•The compounds studied are only slightly or moderate lipophilic.
•The lipophilicity of the cancerostatic sulfonamides 14 18 is from relatively narrow interval between 0.07 and 1.98.
•The highly active CAI 10  13 are also the most lipophilic compounds among the antiglaucomatics studied.Their lipophilicity is considerably higher than the lipophilicity of the clinically useful topically acting antiglaucoma sulfonamides dorzolamide and brinzolamide  It is therefore probable that the number of hydrogen bond acceptor groups is one of the important factors for designing of highlyactive (K d ≈ nM) inhibitors of carbonic anhydrase.However, the possible differences in the nature of the active site of the various CA isoenzymes can also play important part.
Lipinski parameters of the sulfonamides studied

II
As a prototype of Zn 2+ ion-coordinated complexes the structure and energetics of 46 species, selected from neutral and charged Lewis bases -irregular substrates of CA-with the zinc cation was examined.

Lipophilicity and Solubility
Computed partition coefficients (XLOGP2 method) for drugs studied varied between 0.3 and 1.8.

Compounds are described as slightly lipophilic drugs.
The calculated water solubility of dorzolamide and brinzolamide is comparably low.

Acidity and basicity
The pK a values of the sulfonamides investigated The calculated pK a values of sulfonylamide moiety in the CAI studied are in the range of 7.3 to 9.7 and are characterized as weak organic acids.
Acetazolamide is at physiological pH = 7.4 partially ionized.Details of the three-dimensional hydrogen-bonding network of P10 and P11 with atoms participating in the drawn hydrogen bonds represented by dashed lines.
Synthesis, crystal and molecular structure of two biologically active aromatic sulfonamides and their hydrochloride salts  •The intraocular pressure changes were evaluated in in vivo conditions •The laboratory animals of Chinchilla species were used •The distilled water was used as a control •Measurement apparatus Tono-Pen ® XL •For each compound and each concentration 10 independent assays were carried out anticancer agents o Novel therapy for Alzheimer's disease….C. T. Supuran, Carbonic anhydrases: novel therapeutic applications for inhibitors and activators.Nature Rev. Drug Discov.7 (2008) 168 -181.Sulfonamide Inhibitors of CAs as antiglaucoma agents Mincione F, Scozzafava A, Supuran CT, The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents.Curr Pharm Des.2008;14(7):649-54.•Inhibition of carbonic anhydrase isoforms present in the eyes (CA I, II, IV and XII), study•Allo s i put of desig er's ideas•Useful for identification of a single lead compound•"lo a d li ited to desig er's origi alityDesign and synthesis of new CA inhibitors Remko M, Garaj V, Thermodynamics of binding of Zn 2+ to carbonic anhydrase inhibitors.Mol.Phys.2003; 101:2357- 2368.BenchmarksMolecular structure, pK a , lipophilicity, solubility and absorption of biologically active aromatic and heterocyclic sulfonamides M. Remko, J. Mol.Struct., Theochem, 2010 −311+G d,p opti ized structures of the sulfo a ides i estigated ΔE bac-opt = 130 kJ/mole (2H4N) ΔE bac-opt = 142 kJ/mole (1CIL) Dorzolamide

•
30 (I-3), the tail extension strategy Extended tail of this derivative contains diethylaminoethoxybenzyl moiety and exploit the strategy of enhanced hydrophobic interactions between hydrophobic moieties of both active site of enzyme and inhibitor.In vitro assay -IC 50
Experimental potent cancerostatic sulfonamides (14 -19)The pKa values of the sulfonamides studied.pKiand pKd are corresponding inhibition and dissociation constants against hCA II, respectivelyNo.
a Range of log P values obtained by three theoretical methods (ALOGPS,KoWWIN, XLogP2)