Sulfonamide Complexes Research Articles

Cyclodextrin Complexes of Sulfonamide Carbonic Anhydrase IOnhibitors As Long‐lasting Topically Acting Antiglaucoma Agents

Complexes of several 1,3,4‐thiadiazole‐2‐sulfonamide derivatives possessing strong carbonic anhydrase (CA) inhibitory properties with β‐cyclodextrin and hydroxypropyl‐β‐cyclodextrin were obtained and characterized. Although the investigated CA inhibitors possessed very powerful inhibitory properties against the two CA isozymes involved in aqueous humor production within the eye, i.e., CA II and CA IV, these compounds were topically ineffective as intraocular pressure (IOP) lowering agents in normotensive/hypertensive rabbits, due to their very low water solubility. On the contrary, the cyclodextrin–sulfonamide complexes proved to be effective and long‐lasting IOP lowering agents in the two animal models of glaucoma mentioned above. © 2002 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:2211–2219, 2002

Carbonic anhydrase inhibitors: synthesis of sulfonamides incorporating dtpa tails and of their zinc complexes with powerful topical antiglaucoma properties

Reaction of diethylenetriamino pentaacetic acid (dtpa) dianhydride with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded bis-sulfonamides containing metal-complexing, polyamino-polycarboxylic acid moieties in their molecule. The corresponding mono-sulfonamide derivatives of dtpa were also obtained by an alternative method, from the free acid. Zn(II) complexes of these new sulfonamides were then prepared. Many of these derivatives showed nanomolar affinity towards isozymes I, II and IV of carbonic anhydrase (CA). Some of the best inhibitors were applied as 2% water solutions/suspensions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed.

Docking Substrates to Metalloenzymes

Carbonic Anhydrase (CA) is a metalloenzyme that reversibly catalyzes the interconversion between carbon dioxide and bicarbonate anion. A class of sulfa drugs, sulfonamides, are known to inhibit CA. One approach to identifying important binding and specificity interactions between sulfonamides and CA is to analyze the results from docking studies. Previous docking studies have mainly focused on the encounters of substrates with non-metalloenzymes. Here we report the application of MOE-Dock to the CA II – sulfonamide system. After developing a standard docking protocol for the CA II – sulfonamide system we then used the protocol to determine other CA II – sulfonamide complexes.

Carbonic Anhydrase Inhibitors. Part 91. Metal Complexes of Heterocyclic Sulfonamides as Potential Pharmacological Agents in the Treatment of Gastric Acid Secretion Imbalances

Zinc, magnesium, aluminum and copper complexes of several potent, clinically used carbonic anhydrase (CA) sulfonamide inhibitors, such as acetazolamide, methazolamide, ethoxzolamide and benzolamide were tested for their possible applications as antacids, in experimental animals. Gastric acid secretion parameters 3 days after treatment with these CA inhibitors (2 × 500 mg, twice a day), in dogs with chronic gastric fistulas, led to the observation that the gastric acid parameters BAO (the basal acid output), and MAO (the maximal acid output after stimulation with histamine) were drastically reduced, as compared to the same parameters in animals that did not receive these enzyme inhibitors. These are promising results for the possible use of metal complexes of heterocyclic sulfonamides as treatment alternatives (alone or in combination with other drugs) for gastric acid secretion imbalances.

Carbonic Anhydrase Inhibitors Part 721 Synthesis and AntiglaucomaProperties of Metal Complexes of p‐Fluorobenzolamide

Metal complexes of a heterocyclic sulfonamides possessing very strong carbonic anhydrase (CA) inhibitory properties, i.e., 5-(p-fluorobenzenesulfonylamido)-1,3,4-thiadiazole-2-sulfonamide (p-fluorobenzolamide) were prepared. The new complexes contained metal ions such as Zn(II), Cu(II), Co(II), Ni(II), Cd(II) and Mn(II). The new compounds were characterized by standard physico-chemical procedures, and assayed as inhibitors of three CA isozymes, CA I, II and IV. Very good inhibition has been evidenced both for the parent sulfonamides as well as for the prepared complexes, against all three investigated isozymes. Some of these new complexes as well as the parent sulfonamide, strongly lowered intraocular pressure (IOP) in normotensive rabbits when administered as a 2% solution into the eye.

ChemInform Abstract: Carbonic Anhydrase Inhibitors. Part 52. Metal Complexes of Heterocyclic Sulfonamides: A New Class of Strong Topical Intraocular Pressure‐Lowering Agents in Rabbits.

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Solution and Solid-State Studies of a Chiral Zinc-Sulfonamide Complex Relevant to Enantioselective Cyclopropanations.

A highly distorted tetrahedron formed by the four nitrogen atoms around zinc in the crystalline zinc-sulfonamide complex 1 may explain its catalytic activity in asymmetric cyclopropanations. The agent is formed by deprotonation of (R,R)-N,N'-cyclohexane-1,2-diyl)bis(n-butanesulfonamide) with diethylzinc and addition of 2,2'-bipyridyl.

Solution and Solid-State Studies of a Chiral Zinc–Sulfonamide Complex Relevant to Enantioselective Cyclopropanations

Solution and Solid-State Studies of a Chiral Zinc–Sulfonamide Complex Relevant to Enantioselective Cyclopropanations

Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV with heterocyclic mercaptans, sulfenamides, sulfonamides and their metal complexes.

A series of sulfenamides, sulfonamides and sulfonamide metal complexes have been prepared starting from 4,5-disubstituted-3-mercapto-1,2,4-triazole derivatives. The heterocyclic mercaptans were oxidized to the corresponding sulfenamides by hypochlorite in the presence of ammonia. The sulfonamides were obtained by oxidation of sulfenamides with potassium permanganate. The Zn(II) and Cu(II) complexes of the new heterocyclic sulfonamides have been prepared via the sodium salt of the ligand. Inhibition of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human, b = bovine) with the prepared compounds has been investigated. Mercaptans were generally less inhibitory than sulfenamides, which in turn behaved as weaker inhibitors than the sulfonamides. The strongest inhibitors were the Zn(II) and Cu(II) complexes of the heterocyclic sulfonamides. Susceptibility to inhibition was generally: hCA II > bCA IV > hCA I. Although none of the obtained simple inhibitors (mercaptans, sulfenamides, sulfonamides) possessed antiglaucoma action when administered directly into the eye in experimental animals, the Zn(II) and Cu(II) complexes of some sulfonamides acted as more efficient intraocular pressure lowering agents as compared to the clinical drug dorzolamide. This constitutes an encouraging result for obtaining novel antiglaucoma drugs from this class of CA inhibitors.

Carbonic Anhydrase Inhibitors. Part 541: Metal Complexes of Heterocyclic Sulfonamides: A New Class of Antiglaucoma Agents

Metal complexes of heterocyclic sulfonamides possessing carbonic anhydrase (CA) inhibitory properties were recently shown to be useful as intraocular pressure (IOP) lowering agents in experimental animals, and might be developed as a novel class of antiglaucoma drugs. Here we report the synthesis of a heterocyclic sulfonamide CA inhibitor and of the metal complexes containing main group metal ions, such as Be(II), Mg(II), Al(III), Zn(II), Cd(II) and Hg(II) and the new sulfonamide as well as 5-amino-1,3,4-thiadiazole-2-sulfonamide as ligands. The new complexes were characterized by standard physico-chemical procedures, and assayed as inhibitors of three CA isozymes, CA I, II and IV. Some of them (but not the parent sulfonamides) strongly lowered IOP in rabbits when administered as a 2% solution into the eye.

Novel aromatic/heterocyclic sulfonamides and their metal complexes as inhibitors of carbonic anhydrase isozymes I, II and IV.

Reaction of five aromatic/heterocyclic sulfonamides containing free amino, groups with 5-nitro-alpha-2-toluenesultone and diethyl pyrocarbonate, respectively, afforded novel inhibitors of the zinc enzyme carbonic anhydrase (CA). Zn(II) complexes of the new sulfonamides were prepared. Excellent inhibition of three CA isozymes (CA I, II and IV respectively) were observed with some of the new sulfonamides, but especially with their Zn(II) complexes. Structure-activity correlations in this series of inhibitors are discussed.

Carbonic Anhydrase Inhibitors. Part 461 Inhibition of Carbonic Anhydrase Isozymes I, II and IV With Trifluoromethylsulfonamide Derivatives and Their Zinc(II) and Copper(II) Complexes

Reaction of aromatic/heterocyclic sulfonamides containing a free amino group with triflic anhydride afforded compounds possessing trifluoromethanesulfonamido moieties in their molecule. The Zn(II) and Cu(II) complexes of these new sulfonamides were prepared and characterized by standard procedures (elemental analysis, spectroscopic, magnetic, thermogravimetric and conductimetric measurements). The new derivatives showed good inhibitory activity against three isozymes of carbonic anhydrase (CA), i.e., CA I, II and IV.

Molecular complexes of sulfonamides. 3. Structure of 5-methoxysulfadiazine (form II) and its 1∶1 complex with acetylsalicylic acid

The X-ray structure of the biologically most active polymorph (Form II) of 5-methoxysulfadiazine (1) and that of the 1∶1 complex between this sulfonamide and acetylsalicylic acid (2) are reported. The polymorph1 is monoclinic, space groupP21/c witha=13.086(2) A,b=5.583(1) A,c=17.222(3) A, β=99.98(1)°,Z=4 and occurs as centrosymmetric hydrogen bonded (N−H...N) dimers in the crystal. This arrangement differs from that observed in other polymorphs of the drug. Complex2 is triclinic,\(P\bar 1\),a=8.102(1)A,b=12.033(1) A,c=12.170(2) A, α=111.67(1)°, β=93.77(1)°, γ=103.82(1)°,Z=2. Complexation involves linear intermolecular hydrogen bonds, N−H...O=C and N...O−H, between the amide group and pyrimidinyl N atom of the sulfonamide and the carboxylic group of the acetylsalicylic acid. On complexation to form2, neither molecular component undergoes any major structural change.

Structural comparison of sulfodiimine and sulfonamide inhibitors in their complexes with zinc enzymes.

The three-dimensional structure of (L(-)-2-carboxy-3-phenylpropyl) methylsulfodiimine in its complex with the zinc metalloenzyme carboxypeptidase A has been determined at 2.25-A resolution by x-ray crystallographic methods. This is the first example of a sulfodiimine-containing inhibitor binding to a zinc enzyme, and the structure of the enzyme-inhibitor complex reveals that the tetrahedral sulfodiimine group coordinates to the active site zinc ion in unidentate fashion. The zinc-coordinated nitrogen atom of the sulfodiimine group is also within hydrogen bonding distance to active site base Glu-270; presumably, the sulfodiimine is ionized and accepts a hydrogen bond from protonated Glu-270. The other sulfodiimine nitrogen accepts a hydrogen bond from Arg-127, and the inhibitor binds as a possible analogue of the tetrahedral transition state (or intermediate) in a promoted water pathway for peptide hydrolysis. The unidentate sulfodiimine-zinc binding mode observed in this enzyme-inhibitor complex is reminiscent of that observed in sulfonamide complexes with the zinc metalloenzyme carbonic anhydrase II, and the structural features of sulfodiimine- and sulfonamide-zinc interactions exhibit important similarities among recently determined structures of enzyme-inhibitor complexes: ionized nitrogens bind to zinc in each structure, and these nitrogens are engaged in hydrogen bond interactions with neighboring enzyme residues.

Molecular complexes of sulfonamides. 2.1:1 complexes between drug molecules: sulfadimidine-acetylsalicylic acid and sulfadimidine-4-aminosalicylic acid

The preparation and crystal structures of the 1:1 complexes sulfadimidine-acetylsalicylic acid (I) and sulfadimidine-4-aminosalicylic acid (II) are described. Each complex unit is maintained by two intermolecular hydrogen bonds, namely N-H⋯O=C and N⋯H-O, involving the N atom of the sulfonamide group and one pyrimidine N atom of the sulfonamide and the carboxylic group of the acid. Molecular parameters for protonated complexed aspirin, as found in I, are reported for the first time and reveal a significantly different conformation from that of the uncomplexed aspirin molecule. The structure of the 4-aminosalicylic acid molecule does not change significantly on complexation with sulfadimidine. Variation in the hydrogen bonded N⋯O distances in these complexes and their analogs is discussed.

1H NMR and UV-vis spectroscopic characterization of sulfonamide complexes of nickek(II)-carbonic anhydrase. Resonance assignments based on NOE effects

The binding of acetazolamide, p-fluorobenzenesulfonamide, p-toluenesulfonamide, and sulfanilamide to nickel(II)-substituted carbonic anhydrase II has been studied by 1H NMR and electronic absorption spectroscopies. These inhibitors bind to the metal ion forming 1:1 complexes and their affinity constants were determined. The 1H NMR spectra of the formed complexes show a number of isotropically shifted signals corresponding to the histidine ligands. The complexes with benzene-sulfonamides gave rise to very similar 1H NMR spectra. The NMR data suggest that these aromatic sulfonamides bind to the metal ion altering its coordination sphere. In addition, from the temperature dependence of the 1H NMR spectra of the p-fluorobenzenesulfonamide adduct, a conformational change is suggested. The T 1 values of the meta-like protons of the coordinated histidines have been measured and resonance assignments based on NOE experiments were performed.

A general synthetic route to pentaamminecobalt(III) complexes of N-bonded amides, ureas, carbamates, sulfinamides, sulfonamides and sulfamate

A general synthetic procedure for preparing stable cobalt(III) complexes containing selectively nitrogen-bonded ambidentate molecules e.g. amides, ureas, carbamates, sulfinamides, sulfonamides and sulfamate, is described. The method relies on the superior acidity of the nitrogen-bonded, relative to the oxygen-bonded, isomer and this is attributed to much better resonance stabilization of the anionic ligand while N-bonded. Thus the method should be applicable to complexes of other metal ions.

Preparation, Spectral Properties and Biological Activity of Cu(II), Zn(II) and Cd(II) Chelates of 8-Hydroxyquinoline-5-sulfonamides

The complexes of some quinolinol sulfonamides with Cu(II), Zn(II), and Cd(II) have been synthesized and formulated as [Cu(L)2(H2O)2] and [M(L)2]nH2O, M = Zn(II), or Cd(II), n = 0—3 and L = anion of the corresponding ligand. Their structures have been suggested by elemental analysis, electronic and IR spectroscopy, and conductivity measurements. It was found that the sulfonamide ligands are monobasic bidentate ON donors of the quinolinol group. Consequently, the Zn(II) and Cd(II) complexes are formulated as tetrahedral, whereas in Cu(II) complexes a distorted octahedral environment of the metal ion is proposed. It was proven that the metal chelates inhibit and actively affect the germination of wheat seed.

Structure-Activity Relationships of Sulfonamide Drugs and Human Carbonic Anhydrase C: Modeling of Inhibitor Molecules into the Receptor Site of the Enzyme with an Interactive Computer Graphics Display

We have analyzed the molecular interaction of 28 sulfonamide inhibitors with human carbonic anhydrase C (HCAC) using an interactive computer graphic display. Small aromatic sulfonamides gain most of their inhibitory power towards HCAC from the interaction of hydrogen bond acceptors at the para or meta positions with hydrophilic residues of the enzyme. Additional coordinated water molecules stabilize the complexes of heterocyclic sulfonamides (i.e., thiophenes, 1,3-thiazoles, and 1,3,4-thiadiazoles) with HCAC. We propose two different modes of binding of the heterocyclic ring with respect to the active site cleft: the heterocyclic sulfur atom of a 3,4-unsubstituted thiophene approaches the oxygen atom of a coordinated water molecule (sulfur “out”), whereas in 3,4-unsubstituted 1,3,4-thiadiazoles, the sulfur is in contact with a hydrophobic part of the receptor site (sulfur “in”). This proposal is consistent with crystallographic evidence. Sulfonamides with two aromatic or heterocyclic rings also interact with a hydrophobic pocket of the enzyme located >10 Å away from the active site metal Zn2+. We also discuss the possibility that the relative inactivity of thiazide diuretics is due to the steric interaction of the ortho chlorine atom with the enzyme receptor cavity.

Evidence for direct metal-nitrogen binding in aromatic sulfonamide complexes of cadmium (II)-substituted carbonic anhydrases by cadmium-113 nuclear magnetic resonance.

113Cd NMR has been used to study the nature of the metal-sulfonamide interaction in complexes of 113Cd-substituted carbonic anhydrases and the aromatic sulfonamides benzenesulfonamide and Neoprontosil. The 113Cd chemical shifts of the complexes exhibit negligible dependence on the isotopic composition of the sulfonamide nitrogen. However, benzenesulfonamide and Neoprontosil, when 90% 15N-enriched at the sulfonamide nitrogen, each split the 113Cd resonance into a doublet (J113Cd-15N approximately or equal to 200 Hz). This constitutes evidence for metal-nitrogen bonds in these complexes. The chemical shifts of the complexes (approximately 390 ppm) and their pH independence from pH 7.0 to 10.0 suggest the sulfonamides are bound in the anionic form. The resonance Raman (RR) spectra of 15N-labeled and unlabeled Neoprontosil have been obtained to clarify the report of anomalous Neoprontosil binding in the nonionized form [Petersen, R. L., Li, T.-Y., McFarland, J. T., & Watters, K. L. (1977) Biochemistry 16, 726]-a report based on the assignment of a band at approximately 900 cm-1 to a sulfonamide S-N stretching vibration. We find the frequencies of Raman bands observed in the range 800-1700 cm-1 to be virtually identical for the 15N-labeled and unlabeled molecules, indicating that none of the bands can be assigned to a S-N stretching vibration. The RR data unambiguously show the report of Petersen et al. (1977) is based on the misassignment of the band at approximately 900 cm-1.