Aromatic Sulfonamides Research Articles

Aromatic Sulfonamides Containing a Condensed Piperidine Moiety as Potential Oxidative Stress-Inducing Anticancer Agents

A 30-membered piperidine ring-fused aromatic sulfonamide library was synthetized, including N-arylsulfonyl 1,2,3,4-tetrahydroquinolines, 1,2,3,4-tetrahydroisoquinolines and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles. The compounds induced oxidative stress and glutathione depletion in HT168 melanoma and K562 leukemia cells and in micromolar concentrations exerted cytotoxic effects. Among the tested sulfonamides, compounds 21, 22, 23, 35 and 41 exhibited 100% cytotoxic effects with low (< 10 µM) EC50 values on K562 cells. The cytotoxicity of lead compound 22 was investigated in 24 different cancer cell lines, and it was found to be active against leukemia, melanoma, glioblastoma, and liver, breast and lung cancer cells, as confirmed by classical biochemical and holographic microscopic analyses.

Inhibition of tumor-associated human carbonic anhydrase isozymes IX and XII by a new class of substituted-phenylacetamido aromatic sulfonamides

Here, we investigate 28 structurally new sulfonamides and their subsequent testing for enzyme inhibition of cytosolic and tumor-associated carbonic anhydrases (CAs, EC 4.2.1.1). The compounds showed very potent inhibition of four physiologically relevant human (h) CA isoforms, namely hCA I, II, IX and XII. Interestingly, the KI values were in the nanomolar range for the tumor-associated hCA IX and hCA XII. Docking studies have revealed details regarding the very favorable interactions between the scaffolds of this new class of inhibitors and the active sites of the investigated CA isoforms. As there are reported cases of tumors overexpressing both CA II and IX, such potent inhibitors for the two isoforms as those detected in this work, may have applications for targeting more than one CA present in tumors.

The extremo-α-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium azorense is highly inhibited by sulfonamides

The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered extremophilic bacterium Sulfurihydrogenibium azorense (SazCA) is the most effective CA known to date. Here we investigated the inhibition profile of this enzyme with a series of aromatic and heterocyclic sulfonamides, and one sulfamate. Many clinically used sulfonamides, such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulpiride were low nanomolar/subnanomolar SazCA inhibitors (KIs in the range of 0.9–10.8nM) whereas simple aromatic derivatives were less effective as SazCA inhibitors. The inhibition profile of SazCA is slightly different from that of the related enzyme from S. yellostonense (SspCA), investigated earlier by our groups.

Synthesis and Characterization of Half‐Sandwich Ruthenium Complexes Containing Aromatic Sulfonamides Bearing Pyr­id­inyl Rings: Catalysts for Transfer Hydrogenation of Acetophenone Derivatives

AbstractN‐(Quinoline‐8‐yl‐aryl)benzenesulfonamides 1–6 were successfully synthesized by the reaction of 8‐aminoquinoline and various benzenesulfonyl chlorides. Then, half‐sandwich ruthenium complexes 7–12 were prepared from the reactions of 1–6 with [RuCl2(p‐cymene)]2. The synthesized compounds were characterized by NMR and FTIR spectroscopy and elemental analysis, and compounds 8 and 9 were further analyzed by X‐ray diffraction. The complexes were screened for their efficiency as catalysts in the transfer hydrogenation of acetophenone derivatives to phenylethanols in the presence of KOH with 2‐propanol (as hydrogen source) at 82 °C, and they all showed good activity. Complexes 10 and 12 were the most active (turnover frequency values: 703 and 734 h–1, respectively).

Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1' position. Structure-activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R(6) substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R(6) substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

ChemInform Abstract: Access to Sultams by Rhodium(III)‐Catalyzed Directed C—H Activation.

AbstractAcylated aromatic sulfonamides undergo cyclization reaction with symmetrical or unsymmetrical internal alkynes to yield aryl sultams.

SYNTHESIS, CHARACTERIZATION, THERMAL AND ANTIBACTERIAL STUDY OF A NOVEL SULFONAMIDE DERIVATIVE, W-[(E)-PYRIDIN-3-YLMETHYLIDENE]BENZENESULFONAMIDE, AND ITS CO(II), CU(II) AND ZN(II) COMPLEXES

ABSTRACT The novel aromatic sulfonamide ligand, N -[( E )-pyridin-3-ylmethylidene]benzenesulfonamide (PMBS) was synthesized along with its Cu(II), Co(II) and Zn(II) complexes of MLCl 2 type. The characterization of the complexes and the ligand was done by physical methods like elemental analysis, UV-VIS spectra, 1 H-NMR, IR and conductance studies. Additionally, the thermal degradation pattern was examined by TG/DT analysis. Antimicrobial activities are studied with both gram negative Pseudomonas aeruginosa, Salmonella typhi, Eschericia coli and gram positive bacteria Bacillus subtilus, Staphylococcus aureus, Staphylococcus epidermis, Streptococcus pneumonia. Key Words: N -[( E )-pyridin-3-ylmethylidene]benzenesulfonamide (PMBS), Escherichia coli, Salmonella typhi, Bacillus subtilus, Staphylococcus aureus . INTRODUCTION Sulfonamide derivatives form a scaffold in a number of pharmacologically active compounds. Their toxicity is attributed to SO 2 NH moiety. Among the pharmacological properties, antibacterial is the most important one. Sulfonamides inhibit the biosynthesis of tetrahydrofolate in the bacteria, which is a co-factor for the bacterial DNA and RNA synthesis. Deficiency of tetrahydrofolate, decreases the production of new DNA and RNA, ultimately resulting in the bacterial decay. Sulfonamides mimic the substrate for the enzymes and thus block their active sites by reacting with them first instead of the substrate

Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease

An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO2 hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo.

Mucoadhesive 4-carboxybenzenesulfonamide-chitosan with antibacterial properties

The mucoadhesive property of chitosan, especially in an acidic (<pH 6.0) environment, was increased by conjugating an aromatic sulfonamide group at the C2-N position of chitosan. Four different feeding ratios of 4-carboxybenzensulfonamide (4-CBS) to chitosan in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride as a coupling agent were investigated. The 0.2:1 (w/w) ratio 4-CBS:chitosan revealed a 20-fold stronger mucoadhesion to mucin type II than the native chitosan in the simulated gastric fluid (SGF; pH 1.2), and a swelling ratio after 1h in water, SGF and simulated intestinal fluid (pH 7.4) of about 2.9-, 3.0- and 3.4-fold higher than that of chitosan, respectively. In tissue culture, the 4-CBS-chitosan, like chitosan, were found to be non-cytotoxic to the Vero, KB, MCF-7 and NCI-H187 cell lines but showed potential antibacterial activity against Escherichia coli and Staphlyococcus aureus as model Gram-negative and Gram-positive bacteria, respectively.

Synthesis and Extraction Properties Toward Metal Cations of 4,6-Dialkoxy-benzene-1,3-disulfonic Acid Bis-dimethylamide

N,N-disubstituted sulfonamide between sulfonyl chlorides and tertiary amines was discovered.Four aromatic sulfonamides were synthesized in dichloromethane or acetone by using 4,6-dialkoxy-benzene-1,3-disulfonyl dichlorides and 2,4,6-tris(dimethylaminomethyl)phenol as the starting materials.The purified products were characterized by IR,1H NMR,elemental analysis and MS.Aromatic sulfonamides were then applied as the extraction reagents for Ca2+,Pb2+ and some transition metal cations.The primary results showed that the aromatic sulfonamides have better extraction capability for Ca2+.

Synthesis and characterization of SiO2-supported ruthenium complexes containing aromatic sulfonamides: as catalysts for transfer hydrogenation of acetophenone

3-Amino-N-aryl-benzenesulfonamides (1–3) were successfully synthesized by the reaction of m-phenylenediamine and various benzenesulfonyl chlorides. Then, a series of ruthenium complexes (4–6) were prepared from the reaction of [RuCl2(p-cymene)]2 and 1–3. Finally, SiO2-supported Ru(II) complexes (7–9) were prepared by an impregnation method. The synthesized compounds and materials were characterized by different methods such as NMR, FT-IR, TG/DTA, nitrogen adsorption–desorption (BET), SEM and EDX. Also, the solid state structures of 4–6 were determined by single-crystal X-ray diffraction. 4–9 were used as catalysts for the transfer hydrogenation of acetophenone. 4–9 showed good catalytic activity and so the effects of the different groups were also examined. For the transfer hydrogenation of acetophenone, 7–9 had similar activity to 4–6. However, the longer lifetime of 7–9 makes them more advantageous than the non-supported catalysts (4–6) in terms of catalytic cycle. Therefore, the effect of SiO2 was investigated as a catalyst and the results show that excess silicon(IV) oxide was a surprisingly active catalyst for the hydrogenation of acetophenone under these conditions.

Chemoselective nitration of aromatic sulfonamides with tert-butyl nitrite

A methodology for the efficient conversion of aromatic sulfonamides into their mono-nitro derivatives using tert-butyl nitrite is reported. The reaction exhibits a high degree of chemoselectivity for sulfonamide functionalized aryl systems, even in the presence of other sensitive or potentially reactive functionalities.

Synthesis, characterization and catalytic properties of novel palladium(II) complexes containing aromatic sulfonamides: effective catalysts for the oxidation of benzyl alcohol

In this article, N‐(2‐aminophenyl)arylsulfonamides (1–5) were successfully synthesized by the reaction of o‐phenylenediamine and various benzenesulfonyl chlorides. The Schiff base derivatives (1a–f; 4e) of those compounds were obtained using different aldehydes. Then, a series of neutral‐four coordinate Pd(II) complexes (6–10) were prepared from the reaction of Pd(OAc)2 and 1–5. On the other hand, when we tried to synthesize Pd(II) complexes containing Schiff base/sulfonamide ligands, two different situations were observed. Generally, when an electron‐donating group was attached to the imine fragment (1a–d) except for 1f, the Schiff base hydrolyzed and 6 was isolated. When an electron‐withdrawing group was attached to the imine fragment (1e, 4e), neutral four‐coordinate Pd(II) complexes (11–13) bearing Schiff base/sulfonamide ligands were isolated. The synthesized compounds were characterized by FT‐IR, elemental analysis and NMR spectroscopy. The complexes were used as a catalyst in the oxidation reaction of benzyl alcohol to benzaldehyde in the presence of H5IO6 in acetonitrile. All complexes showed satisfactory catalytic activity. The highest catalytic activity was obtained with 9. Copyright © 2012 John Wiley &amp; Sons, Ltd.

Aromatic sulfonyl hydrazides and sulfonyl hydrazones: antimicrobial activity and physical properties

A series of novel aromatic sulfonamide derivatives (1–7) were synthesized and characterized by elemental analyses, FT-IR, 1H NMR, 13C NMR, and LC/MS techniques. The compounds’ quantum mechanical descriptors, surface area, and molecular volume were calculated. All the synthesized compounds were evaluated in vitro as antimicrobial agents against representative strains of gram-positive and gram-negative bacteria and as antifungal agents for yeast by both the disc diffusion and minimal inhibition concentration methods for comparison. All the bacteria and fungi studied were screened against some commercial antibiotics to compare with our chemicals’ zone diameters. Quantitative structure–activity relationship studies with multiple linear regression analysis were applied to find the correlation between the different calculated molecular descriptors of the synthesized compounds and biological activity.

A QSAR Study on Novel Series of Carbonic Anhydrase Inhibitors hCA IX—Tumor-Associated (Hypoxia)

This paper presents results of QSAR (Quantitative Structure Activity Relationship) studies realized with the PRECLAV (Property Evaluation by Class Variables) software. The database contains 66 derivatives of aromatic benzene sulfonamides incorporating 1, 3, 5-triazine moieties, fluorophenyl sulfamates, S-substituted-2-mercaptobenzenesulfonamide and diazenylbenzenesulfonamides with clinically used CA inhibitors. For each molecule over 3600 descriptors were calculated using programs MOPAC, PRECLAV and DRAGON. A heuristic algorithm selects the best multiple linear regression (MLR) equation showed that the correlation between the observed values and the calculated values of activity is very good (N = 66, Se = 0.263, r(2) = 0.884, F = 92.98, r(2)(cv) = 0.859, Q = 0.794). The virtual molecular fragments that lead to a significant increase of the inhibitor activity of hCA IX are C(3)H(2)N(5)Cl, NH(2), C(6)H(4), C(3)H(5)N(6), COOH, and C(3)HN(6). The virtual fragment--HO, C(5)H(2)NO, C(3)HN(6), leads to a significant decrease of the inhibitor activity value. With a view to external validation, the calibration set includes 50 molecules (Se = 0.256, r(2) = 0.885, F = 69.501, r(2)(cv) = 0.852) and the validation set includes 16 molecules (Se = 0.111, r(2) = 0.87, F = 93.984). Identification of molecules in validation set with high estimated value of inhibitory activity of hCA IX is correct enough to have practical value, even if the calibration/validation set contains aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties and fluor phenyl sulfamates derivatives with very different chemical structures.

In Silico Modeling of Carbonic Anhydrase Inhibitor hCA IX-Tumor Associated (Hypoxia)

From two QSAR studies realized with the PRECLAV computer program, the database of the series of aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties derivative, give without outliers N = 59, Se = 0.2858, r2 = 0.8734, rCV2 = 0.8444, F = 74.5237. The virtual molecular fragments that lead to a significant increase of the inhibitor activity of CA IX are C3H2N5Cl, NH2, C3H5N6, CHO2, and C3HN6. The virtual fragment OH, C5H2NO, N atom, CHO2, C3HN6 leads to a significant decrease of the inhibitor activity value. The CA IX inhibitor activity is favorably influenced by the size of the molecule. With a view to external validation, the calibration set includes 46 molecules (Se = 0.234, r2 = 0.9114, F = 84.3447, rCV2 = 0.8872) and the validation set includes 13 molecules (Se = 0.279, r2 = 0.8741, F = 56.9143, rCV2 = 0.8246). Identification of molecules in validation set with high estimated value of inhibitory activity of CA IX is correct enough to have practical value, even if the calibration/validation set contains aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties derivatives with very different chemical structures.

Polymorphism of Aromatic Sulfonamides with Fluorine Groups

N-(2-Phenoxyphenyl)benzenesulfonamide (1) and fluorine-substituted N-(2-phenoxyphenyl)benzene sulfonamides (2–5) were designed to examine the effect of a fluorine group in the polymorphism of aromatic sulfonamides. Single-crystal X-ray analysis revealed that those with a fluorine (2–5) afforded polymorphs or pseudopolymorphs while the sulfonamide without fluorine (1) did not. From the differential scanning calorimetry measurements, stable (2a–5a) and metastable (2b–5b) crystalline forms were identified. The sulfonamide 1 formed a dimer through hydrogen bonds (H-bonds), which were aligned into two-dimensional (2D) layers via π/π and CH/π interactions. In 2b, 3b, and 4a, the sulfonamide constructed a dimer through H-bonds, which formed 2D layers via CH/F interactions. The sulfonamides 4 formed a one-dimensional (1D) straight chain via H-bonds, which were arranged into 2D layers via CH/F, CH/O, and CH/π interactions in 4b. The sulfonamide 5 either formed a dimer through H-bonds, which formed 2D layers via CH/O and π/π interactions in 5a, or formed a 1D straight chain via CH/O and π/π interactions, which were arranged into 2D layers via F/F and CH/F interactions in 5b. In the pseudopolymorph 5c, the sulfonamide 5 formed a 1D zigzag chain via CH/F interactions and was assembled into 2D layers via π/π interactions.

3D-QSAR Study of Some Heterocyclic Sulfonamide Analogs as hCAII Inhibitors

Three-dimensional quantitative structure-activity relationship (3-D QSAR) was performed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques in order to understand the carbonic anhydrase inhibition activity. A large number of 25 structurally and functionally diverse series of aromatic heterocyclic sulfonamides carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA II were chosen for the study. Based on the alignment generated by docking conformations, a highly predictive comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed with q2 value of 0.532 and 0.486 & r2 value of 0.978 and 0.952, respectively. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to respective contours. This integrated molecular docking based alignment followed by 3D-QSAR studies should provide further insights to support structure based design of human carbonic anhydrase II inhibitors with improved activity profile.

Targeting Carbonic Anhydrases with Fluorescent BODIPY‐Labelled Sulfonamides

AbstractIn the pursuit of dual‐mode imaging agents of the tumour hypoxia markers carbonic anhydrases (CA) IX and XII, sulfonamides 4‐(2‐aminoethyl)benzenesulfonamide and 1,3,4‐thiadiazole were functionalised with a 4,4‐difluoro‐4‐borata‐3a‐azonia‐4a‐aza‐s‐indacene (BODIPY) dye to afford fluorescent aromatic sulfonamide conjugates as potential agents for simultaneous positron emission tomography and fluorescence imaging. Both compounds exhibited nanomolar potency as inhibitors of four CA isoforms: the cytosolic CA I and II, and the transmembrane CA IX and XII. Cell uptake experiments with a CA IX positive and null cell line showed no uptake with the 1,3,4‐thiadiazole species in either cell line, whilst the benzenesulfonamide species showed uniform internalisation in both cell lines that limited these compounds as selective imaging agents.

Mechanism of SO2 elimination from the aromatic sulfonamide anions: A theoretical study

Based on the density functional theory (DFT), the mechanism of SO2 elimination from the aromatic sulfonamide anions has been analyzed in this paper. Three reaction pathways have been proposed. Calculations indicate that the most favorable reaction pathway is Pathway I, namely the nucleophilic attack of the nitrogen anion followed by a three-membered ring rearrangement to lose SO2. It is found there exists good linear relationship between the activation enthalpies and the reaction enthalpies in Pathway I. The corresponding correlation coefficient is as high as 0.931. The Marcus theory analyses suggest that the major driving force for the acceleration effect of the substituent is the intrinsic factor. Moreover, as for the N-phenyl-benzenesulfonamide anion series, the effect of the substituent in the p-position of the benzene ring has also been studied and moderate linear relationship between the activation enthalpies and the substituent constants can be obtained. Meanwhile, the electron-withdrawing group in the N-substituted benzene ring can hold back the three-membered ring rearrangement to lose SO2, while the similar group in the S-substituted benzene ring has the opposite effect.