Heterocyclic Sulfonamides Research Articles

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.

Copper complexes with heterocyclic sulfonamides: Synthesis, spectroscopic characterization, microbiological and SOD-like activities: Crystal structure of [Cu(sulfisoxazole) 2(H 2O) 4] · 2H 2O

The synthesis, characterization and comparative biological study of a series of antibacterial copper complexes with heterocyclic sulfonamides were reported. Two kinds of complexes were obtained with the stoichiometries [Cu(L) 2] · H 2O and [Cu(L) 2(H2O) 4] · nH 2O. They were characterized by infrared and electronic spectroscopies and the crystal structure of [Cu(sulfisoxazole) 2(H 2O) 4] · 2H 2O was determined by single crystal X-ray diffraction. It crystallized in the C2/c with Z = 8 monoclinic space group C2/c with Z = 8. The Cu(II) is in a slightly tetragonal distorted octahedron formed by four oxygen atoms from water molecules and two nitrogen atoms from two isoxazole rings. The antimicrobial activity was evaluated for all the synthesized complexes and ligands using the agar dilution test. The results showed that the complexes with five-membered heterocyclic rings were more active than the free sulfonamides while the pyrimidine, pyridine and pyridazine complexes had similar or less activity than the free ligands. In order to find an explanation for this behavior lipophilicity and superoxide dismutase-like activity were tested, showing that the [Cu(sulfamethoxazol) 2(H 2O) 4] · 3H 2O presented the highest antimicrobial potency and a superoxide dismutase-like activity comparable with pharmacological active compounds.

Metal Complexes of Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors

AbstractFor Abstract see ChemInform Abstract in Full Text.

Carbonic Anhydrase Inhibitors. Novel Sulfanilamide/Acetazolamide Derivatives Obtained by the Tail Approach and Their Interaction with the Cytosolic Isozymes I and II, and the Tumor‐Associated Isozyme IX.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamides

The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme VII (hCA VII), has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide and benzolamide), as well as the sulfamate antiepileptic drug topiramate. Inhibition data for the the other physiologically relevant cytosolic isoforms hCA I, hCA II and mCA XIII are also provided for comparison. hCA VII shows a high catalytic activity for the CO 2 hydration reaction, with a k cat of 9.5 × 10 5 s −1 and k cat/ K m of 8.3 × 10 7 M −1 s −1 at pH 7.5 and 20 °C. A very interesting inhibition profile against hCA VII with this series of 32 sulfonamides/sulfamates was observed. hCA VII shows high affinity for all the investigated compounds, with inhibition constants in the range of 0.45–210 nM. Topiramate, ethoxzolamide and benzolamide showed subnanomolar hCA VII inhibitory activity, whereas acetazolamide, methazolamide, dorzolamide and brinzolamide showed K I-s in the range of 2.1–3.5 nM. Dichlorophenamide was slightly less active ( K I of 26.5 nM). A number of heterocyclic or bicyclic aromatic sulfonamides also showed excellent hCA VII inhibitory properties ( K I-s in the range of 4.3–7.0 nM) whereas many monosubstituted or disubstituted benzenesulfonamides were less active ( K I-s in the range of 45–89 nM). The least active hCA VII inhibitors were some substituted benzene-1,3-disulfonamides as well as some halogenated sulfanilamides ( K I-s in the range of 100–210 nM). The inhibition profile of hCA VII is rather different of that of the other cytosolic isozymes, providing thus a possibility for the design of more selective, hCA VII-specific inhibitors. In addition, these data furnish further evidence that hCA VII is the isozyme responsible for the anticonvulsant/antiepileptic activity of sulfonamides and sulfamates.

Refractive index modulation in the polyurethane films containing diazo sulfonamide chromophores

The series of photochromic polyurethanes was obtained by modification of precursor polymers prepared from 4,4′-diphenylmethane diisocyanate (MDI), hexamethylene 1,6-diisocyanate (HDI) or toluene 2,4-diisocyanate (TDI) and N, N'-di-(2-hydroxyethyl) aniline. The precursor polymers were functionalized by an azo-coupling reaction to form the polymers with different degrees of functionalization and various heterocyclic sulfonamide groups. Ellipsometric measurements showed a decrease of the refractive index during illumination of thin polymer films with white light. The change of real part of the refractive index was in the range of 0.0033–0.0296 depending on the polymer kind and chromophore content. It was found that photocurrent was generated in the polymer films deposited onto indium tin oxide (ITO) glass plates. For the polyurethanes containing sulfathiazole groups in side chains the current density was up to 180 nA/cm 2. The formation of diffraction grating in the polymer films was easily achieved using linearly polarized laser light (532 nm) in a standard two beam coupling (TBC) system. The diffraction efficiency of the first diffraction beam was dependent on the chromophore content reaching ca. 12% for the derivatives of sulfamethoxazole.

Carbonic anhydrase inhibitors. Inhibition of red blood cell ostrich (Struthio camelus) carbonic anhydrase with a series of aromatic and heterocyclic sulfonamides

The purification of red blood cell carbonic anhydrase (CA, EC 4.2.1.1) from ostrich (scCA) blood is reported, as well as an inhibition study of this enzyme with a series of aromatic and heterocylic sulfonamides. The ostrich enzyme showed a high activity, comparable to that of the human isozyme II, with kcat of 1.2·106 s− 1 and kcat/KM of 1.8·107 M− 1 s− 1, and an inhibition profile quite different from that of the human red blood cell cytosolic isozymes hCA I and II. scCA has generally a lower affinity for sulfonamide inhibitors as compared to hCA I and II. The only sulfonamide which behaved as a very potent inhibitor of this enzyme was ethoxzolamide (KI = 3.9 nM) whereas acetazolamide and sulfanilamide behaved as weaker inhibitors (inhibition constants in the range 303–570 nM). Several other aromatic and heterocyclic sulfonamides, mostly derivatives of sulfanilamide, homosulfanilamide, 4-aminoethylbenzenesulfonamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide, showed good affinities for the ostrich enzyme, with KI values in the range 25–72 nM.

Acyl sulfonamide anti-proliferatives. Part 2: Activity of heterocyclic sulfonamide derivatives

The anti-proliferative activity of acylated heterocyclic sulfonamides is described in Vascular Endothelial Growth Factor-dependent Human Umbilical Vascular Endothelial Cells (VEGF-HUVEC) and in HCT116 tumor cells in a soft agar diffusion assay.

Synthesis of Functionalised Sulfonamides via Microwave Assisted Displacement of PFP‐Sulfonates with Amines

AbstractA convenient microwave assisted synthesis of sulfonamides from PFP‐sulfonates is described. Reaction of various commercially available amines with pentafluorophenyl (PFP) sulfonate esters under microwave irradiation led to the corresponding sulfonamide products in good yields and without the requirement for chromatographic purification. The data shows that a number of functional groups are tolerated in both the amine and sulfonate ester and that the method can be extended to heterocyclic sulfonamides of potential biological interest.

Carbonic anhydrase inhibitors. Novel sulfanilamide/acetazolamide derivatives obtained by the tail approach and their interaction with the cytosolic isozymes I and II, and the tumor-associated isozyme IX

A series of sulfonamides has been obtained by reacting sulfanilamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide with ω-chloroalkanoyl chlorides, followed by replacement of the ω-chlorine atom with secondary amines. Tails incorporating heterocyclic amines belonging to the morpholine, piperidine and piperazine ring systems have been attached to these sulfonamides, by means of an alkanoyl-carboxamido linker containing from two to five carbon atoms. The new derivatives prepared in this way were tested as inhibitors of three carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic isozymes CA I and II, and the catalytic domain of the transmembrane, tumor-associated isozyme CA IX. Several low nanomolar CA I and CA II inhibitors were detected both in the aromatic and heterocyclic sulfonamide series, whereas the best hCA IX inhibitors (inhibition constants in the range of 22–35 nM) all belonged to the acetazolamide-like derivatives.

Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design

The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17–23nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32–56nM. Several low nanomolar (Ki's in the range of 1.3–2.4nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl–sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents.

Carbonic anhydrase inhibitors: the first QSAR study on inhibition of tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides

QSAR study on the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isoenzyme has been made using a large pool of distance-based topological indices : W, Sz, PI, 0χ, 1χ, 2χ, 0χv, 1χv, and 2χv. A combined set of 32 aromatic and heterocyclic compounds, including the six clinically used derivatives: acetazolamide, methazolamide, ethoxyzolamide, dichlorophenamide, dorzolamide, and brinzolamide are used for this purpose. The results have shown that the inhibition of the tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides can be modeled excellently in multiparametric regression after introduction of indicator parameters. The predictive power of the models is discussed using probable error of correlation (PE), variance-inflation factor (VIF), and cross-validation parameters: PRESS, SSY, r2cv, SPRESS, and PSE. This is the first report on QSAR study on inhibition of tumor-associated isoenzyme IX.

In Vitro Inhibition Effects of some New Sulfonamide Inhibitors on Human Carbonic Anhydrase I and II

A new series of aromatic and heterocyclic sulfonamides, including six new derivatives, 2-(3-cyclohexene-1-carbamido)-1,3,4-thiadiazole-5-sulfonamide (CCTS), 4-(3-cyclohexene-1-carbamido) methyl-benzenesulfonamide (CCBS), 2-(9-octadecenoylamido)-1,3,4-thiadiazole-5-sulfonamide (ODTS), 2-(4,7,10-trioxa-tetradecanoylamido)-1,3,4-thiadiazole-5-sulfonamide (TDTS), 2-(coumarine-3-carbamido)-1,3,4-thiadiazole-5-sulfonamide (COTS) and 2-(8-methoxycoumarine-3-carbamido)-1,3,4-thiadiazole-5-sulfonamide (MCTS), has been investigated. These sulfonamides were assayed for inhibition of human carbonic anhydrase I (hCA-I) and human carbonic anhydrase II (hCA-II) which were purified by affinity chromatography.

Carbonic anhydrase inhibitors: the first QSAR study on inhibition of tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides

QSAR study on the tumor-associated transmembrane carbonic anhydrase IX (CA IX) isoenzyme has been made using a large pool of distance-based topological indices : W, Sz, PI, 0χ , 1χ , 2χ , 0χ v , 1χ v , and 2χ v . A combined set of 32 aromatic and heterocyclic compounds, including the six clinically used derivatives: acetazolamide, methazolamide, ethoxyzolamide, dichlorophenamide, dorzolamide, and brinzolamide are used for this purpose. The results have shown that the inhibition of the tumor-associated isoenzyme IX with aromatic and heterocyclic sulfonamides can be modeled excellently in multiparametric regression after introduction of indicator parameters. The predictive power of the models is discussed using probable error of correlation (PE), variance-inflation factor (VIF), and cross-validation parameters: PRESS, SSY, r 2 cv, S PRESS, and PSE. This is the first report on QSAR study on inhibition of tumor-associated isoenzyme IX.

Carbonic anhydrase inhibitors: aromatic and heterocyclic sulfonamides incorporating adamantyl moieties with strong anticonvulsant activity

A series of aromatic/heterocyclic sulfonamides incorporating adamantyl moieties were prepared by reaction of aromatic/heterocyclic aminosulfonamides with the acyl chlorides derived from adamantyl-1-carboxylic acid and 1-adamantyl-acetic acid. Related derivatives were obtained from the above-mentioned aminosulfonamides with adamantyl isocyanate and adamantyl isothiocyanate, respectively. Some of these derivatives showed good inhibitory potency against two human CA isozymes involved in important physiological processes, CA I, and CA II, of the same order of magnitude as the clinically used drugs acetazolamide and methazolamide. The lipophilicity of the best CA inhibitors was determined and expressed as their experimental log k ′ IAM and theoretical ClogP value. Their lipophilicity was propitious with the crossing of the blood-brain barrier (log k ′ IAM > 1.35). The anticonvulsant activity of some of the best CA inhibitors reported here has been evaluated in a MES test in mice. After intraperitoneal injection (30 mg kg −1), compounds A8 and A9 exhibited a high protection against electrically induced convulsions (>90%). Their ED 50 was 3.5 and 2.6 mg kg −1, respectively.

Kinetics of refractive index changes in polymeric photochromic films

AbstractMethacrylate copolymers containing, in side chain azobenzene groupings with heterocyclic sulfonamide substituents: N‐(2,6‐dimethylpyrimidin‐4‐yl)sulfamoyl (sulfisomidine) and N‐(5‐methylisoxazol‐3‐yl) sulfamoyl (sulfamethoxazole) were investigated. The materials undergo reversible trans‐cis isomerisation during illumination with light. This results in changes of dipole moment, polarizability and refractive index. Ellipsometric measurements showed a distinct decreasing refractive index during illumination with light corresponding to absorption band (ca. 450 nm). Depending on the polymer, the change of real part of refractive index in spin‐coated films was between 0.016 and 0.031. The dynamics of growth and decay of refractive index changes, was described by biexponential function approach.

Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides.

The first inhibition study of the mitochondrial isozyme carbonic anhydrase (CA) V (of murine origin) with a series of aromatic and heterocyclic sulfonamides is reported. Inhibition data of the cytosolic isozymes CA I and CA II and the membrane-bound isozyme CA IV with these inhibitors are also provided for comparison. Several low nanomolar CA V inhibitors were detected (KI values in the range of 4-15 nM), most of them belonging to the acylated sulfanilamide, ureido-benzenesulfonamide, 1,3,4-thiadiazole-2-sulfonamide, and aminobenzolamide type of compounds. The clinically used inhibitors acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and topiramate on the other hand were less effective CA V inhibitors, showing inhibition constants in the range of 47-63 nM. Some of the investigated sulfonamides, such as the ureido-benzenesulfonamides and the acylated sulfanilamides showed higher affinity for CA V than for the other isozymes, CA II included, which is a remarkable result, since most compounds investigated up to now inhibited the cytosolic isozyme CA II better. These results prompt us to hypothesize that the selective inhibition of CA V, or the dual inhibition of CA II and CA V, may lead to the development of novel pharmacological applications for such sulfonamides, for example in the treatment or prevention of obesity, by inhibiting CA-mediated lipogenetic processes.

Carbonic Anhydrase Inhibitors: Schiff's Bases of Aromatic and Heterocyclic Sulfonamides and their Metal Complexes

Schiff's bases were obtained from aromatic/heterocyclic sulfonamides and amino-sulfonamide derivatives, such as sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and 5-amino-1,3,4-thiadiazole-2-sulfonamide. Metal complexes of some of these Schiff's bases, incorporating Zn(II), Co(II), Ni(II) and Cu(II) ions, were also prepared and tested as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more specifically the red blood cell isozymes I and II. The Schiff's bases behaved as medium potency CA I and CA II inhibitors, whereas their metal complexes showed a highly enhanced potency, with several low nanomolar CA II inhibitors detected.

Designing of Novel Carbonic Anhydrase Inhibitors and Activators

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide spread enzymes, present in mammals in at least 14 different isoforms: some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), while others are membrane-bound (CA IV, CA IX, CA XII and CA XIV); CA V is mitochondrial, and CA VI is secreted in the saliva. Three acatalytic forms are also known (CARP VIII, CARP X and CARP XI). Several important physiological and physio-pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped in the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, constituting thus interesting leads for developing novel antitumor therapies. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes will be dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation for this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II--activator adducts, X-ray crystallographic studies have also been reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators will be discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiologic relevance of CA activation will also be addressed, together with the recent pharmacological applications of blood CA isozymes activators, as potential memory enhancing drugs.

Refractive index modulation in polymeric photochromic films

AbstractPhotochromic properties of methylacrylate monomers and polymers containing azobenzene groups with heterocyclic sulfonamide functionalities viz sulfisomidyne (4-amino-N-[2,6-dimethylpyrimidyn-4-yl]benzenesulfonamide) and sulfamethoxazole (4-amino-N-[5-methylisoxazol-3-yl]benzenesulfonamide) substituents were investigated. On illumination with light the azobenzene group underwent trans-cis isomerisation, which was manifested by a drop in the absorbance of the maximum absorption peak at ca. 450 nm and by decrease in refractive index.Quantum chemical calculations showed significant differences in UV-VIS spectra, dipole moments, polarizability and refractive index between both cis and trans form of the chromophoric monomers.The illumination of spin-coated polymer films during ellipsometry measurements resulted in a change in refractive index within the range of 0.014 to 0.025. The dynamics of growth and decay of refractive index changes, was described by biexponential functions approach.