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PubMed1990

Sulfonamide resistance gene for plant transformation.

The sulfonamide resistance gene from plasmid R46 encodes for a mutated dihydropteroate synthase insensitive to inhibition by sulfonamides. Its coding sequence was fused to the pea ribulose bisphosphate carboxylase/oxygenase transit peptide sequence. Incubation of isolated chloroplasts with the fusion protein synthesised in vitro, showed that the bacterial enzyme was transported to the chloroplast stroma and processed into a mature form. Expression of the gene fusion in transgenic plants resulted in a high level of resistance to sulfonamides. Direct selection of transformed shoots on leaf explants was efficient using sulfonamides as sole selective agents. Transformed shoots rooted normally on sulfonamides at concentrations toxic for untransformed ones. Sulfonamide resistance was transmitted to the progeny of transformed plants as a single Mendelian dominant character. These results demonstrate that this chimeric gene can be used as an efficient and versatile selectable marker for plant transformation.

Amino Acid Sequence↗
PubMed1986

2-Substituted 1, 3, 4-thiadiazole-5-sulfonamides as carbonic anhydrase inhibitors: their effects on the transepithelial potential difference of the isolated rabbit ciliary body and on the intraocular pressure of the living rabbit eye.

In order to understand the pharmacology of carbonic anhydrase inhibitors in reduction of aqueous secretion, three sorts of studies were conducted using five 2-substituted 1, 3, 4-thiadiazole-5-sulfonamides: an inhibition study of carbonic anhydrase II, electrical measurements of the isolated ciliary body, and pharmacological study on intraocular pressure of living animals. The inhibitors of carbonic anhydrase employed here were 2-amino-1, 3, 4-thiadiazole-5-sulfonamide; 2-methylamino-1, 3, 4-thiadiazole-5-sulfonamide; 2-formylamino-1, 3, 4-thiadiazole-5-sulfonamide; 2-acetylamino-1, 3, 4-thiadiazole-5-sulfonamide (acetazolamide); and 2-propionylamino-1, 3, 4-thiadiazole-5-sulfonamide. All of these compounds showed significant inhibitory activity to carbonic anhydrase II which exists in the ciliary epithelium, but their potencies of inhibition varied relative to one another (I50S were 1.91 X 10(-7) to 3.3 X 10(-8) M). The effects of the five compounds on electrical phenomena were observed using isolated rabbit ciliary body mounted on an Ussing's chamber. Each compound decreased the negative electrical potential of the tissue (-0.70 mV as the average of the initial values) by 10- to 33%, and this effect was proportional to its inhibitory activity to carbonic anhydrase II. The effects of the five compounds on intraocular pressure were determined, and each compound decreased the intraocular pressure (18 mmHg as the average of the initial values) by 7- to 32%. This effect was also proportional to the inhibitory activity to the enzyme. Correlation between the two effects was studied, and good correlation was observed. This implies that both effects have a common basis which relates to the physiological role of carbonic anhydrase. The present study, therefore, shows the importance of the bicarbonate ion in the aqueous humor formation since it is both substrate and product of carbonic anhydrase II.

Acetazolamide↗
PubMed1991

Determination of sulfonamides by liquid chromatography, ultraviolet diode array detection and ion-spray tandem mass spectrometry with application to cultured salmon flesh.

Ion-spray mass spectrometry was investigated for the analysis of 21 antibacterial sulfonamide drugs. All of the sulfonamides analyzed gave positive ion mass spectra with abundant protonated molecules and no fragmentation. Tandem mass spectrometry (MS-MS) using collision-induced dissociation provided structural information, allowing the identification of common fragmentation pathways and the differentiation of isomeric and isobaric sulfonamides. A reversed-phase high-performance liquid chromatographic method was developed, using gradient elution and ultraviolet diode-array detection (DAD), enabling the separation of 16 of the sulfonamides. Combined liquid chromatography (LC)-MS was accomplished using the ion-spray interface. Analyses of a mixture of sulfonamide standards were performed with gradient elution and the mass spectrometer configured for full-scan acquisition, selected-ion monitoring, or selected-reaction monitoring. Procedures for the analysis of sulfadimethoxine (SDM), a representative sulfonamide used in the aquaculture industry, are described. The presence of SDM in cultured salmon flesh was confirmed at levels as low as 25 ng/g by a combination of LC-DAD and LC-MS-MS.

Animals↗
PubMed1995

Micellar liquid chromatographic separation of sulfonamides in physiological samples using direct on-column injection.

A mixture of twelve sulfonamides was separated by micellar liquid chromatography (MLC) using sodium dodecyl sulfate (SDS) micelles and a hydrophilic endcapped C18 column. Retention behavior and selectivity pattern of sulfonamides in MLC were examined with the change of SDS concentration and volume fraction of an organic modifier (1-propanol). The suitable condition was found to be 0.070 M SDS and 6.0% 1-propanol for the separation of these twelve sulfonamides. Under this condition, the isocratic separation of the sulfonamides was achieved within 15 min with a relatively high column efficiency for MLC (ca. 7000 plates/25 cm column). Retention times of these twelve sulfonamides were found to be very repeatable, which is due to the highly reproducible retention behavior in MLC. The same twelve sulfonamides were successfully separated in the spiked physiological fluids (human urine and cow milk) through direct on-column injection by MLC.

Animals↗
PubMed2006

Toxicity and biodegradability of sulfonamides and products of their photocatalytic degradation in aqueous solutions.

The photocatalytic degradation of sulfacetamide, sulfathiazole, sulfamethoxazole and sulfadiazine in water solutions during their illumination of UV radiation (lambda(max) 366 nm) with TiO2 catalyst was examined. The growth-inhibition effect of sulfonamides and intermediate products theirs photodegradation was investigated in aqueous solution with the green alga Chlorella vulgaris. The biodegradability of the investigated compounds was determined in the illuminated solutions and is expressed as Biochemical Oxygen Demand. It was found that all of the investigated sulfonamides in the initial solutions were resistant to biodegradation and were toxic relative to C. vulgaris. The toxicity (EC50 values) relative to C. vulgaris increased in the following order sulfacetamide, sulfathiazole, sulfamethoxazole, sulfadiazine. All of the investigated sulfonamides undergo photocatalytic degradation. The toxicity of intermediate products of the sulfonamides degradation was significantly lower than the toxicity of sulfonamides in the initial solutions and was dependent on illumination time and degradation rate. The intermediate products of photocatalysis in contrast to the initial sulfonamides, might be mineralized using biological methods.

Biodegradation, Environmental↗
PubMed2004

Sulfonamide hypersensitivity.

Sulfonamide antibiotics can result in a wide variety of hypersensitivity reactions. No validated diagnostic tests are available for sulfonamide reactions; therefore, clinicians must rely on the combination of a careful patient history, review of medical records, and a sound knowledge base regarding the common clinical manifestations of sulfonamide hypersensitivity reactions. Although HIV-infected individuals have a high risk for hypersensitivity reactions to sulfamethoxazole, readministering the drug can usually be performed safely by using a desensitization protocol. Sulfonamide-containing medications that are not antibiotics also have the capacity for causing hypersensitivity reactions. Whether the sulfa moiety confers a risk of cross-reaction is controversial. The preponderance of available evidence suggests that sulfonamide antibiotics probably do not cross-react with sulfonamide nonantibiotics.

Cross Reactions↗
PubMed2002

pH-induced solubility transition of sulfonamide-based polymers.

As an approach to designing new pH-sensitive polymers for bio-related application, we have modified selected sulfonamides, with various pK(a), to polymerizable monomers. The pK(a) of the monomers, homopolymers, and copolymers with N,N-dimethylacrylamide were examined, and pH-induced phase transition behavior, particularly in solubility, was investigated. The pK(a) of sulfonamide monomers and polymers at 25 degrees C was slightly higher than those of corresponding sulfonamides but the enthalpy of the ionization was influenced due to interfering resonance structures that are present in the mother compounds. The solubility transition of each homopolymer in aqueous solutions occurred at a degree of ionization of 85-90%. For the copolymers, the solubility transition observed by light transmittance completed in a narrow pH range (0.2-0.3 pH units) and this transition pH shifted to a higher pH region with the increasing sulfonamide unit in the copolymer, though the pK(a) was not considerably changed. This polymer precipitation occurs because of the relative balance of overall hydrophilicity/hydrophobicity along the polymer chain. Because the unionized form of sulfonamide units is considered to be hydrophobic, the copolymer with higher content of sulfonamide unit requires a higher degree of ionization for solubilization and thus solubility transition occurred at higher pH.

Anti-Infective Agents↗
PubMed2006

Broad-specificity immunoassays for sulfonamide detection: immunochemical strategy for generic antibodies and competitors.

Development of antibodies with broad specificity recognition for sulfonamide drugs was found to be surprisingly difficult when conventional immunochemical strategies were applied to hapten design. To improve the cross-reactivity pattern of antibodies for the family of sulfonamide drugs, a novel strategy based on the single-ring (fragment-derived) hapten moieties with different spacer substituent lengths was employed for the preparation of immunogens, coating conjugates, and enzyme competitors. The rabbit antibodies raised against a common (one-ring) p-aminobenzenesulfonamide hapten moiety (attached to a carrier protein through the N-1 position) in combination with a homologous hapten-peroxidase tracer allowed the detection of 15 sulfonamide species at the maximum residue limit level using direct ELISA. The two-ring 6-(4-aminobenzensulfonylamino)hexanoic hapten mimics, previously reported in the literature as a weak generic antigen, generated surprisingly superior immune responses in rabbits. The antibodies raised against this two-ring hapten were capable of detecting at least 19 and 17 sulfonamides in a direct ELISA system at the regulatory level with sensitivities corresponding to 20 and 50% binding inhibition, respectively. A negligible cross-reaction with N4 metabolites makes it possible to measure responses of parent sulfonamides in the presence of their metabolized forms. In skimmed milk, the highest limit of detection (LOD) for sulfacetamide defined as 20% inhibition was 65.2 microg x L(-1) (IC20 value), whereas the additional 18 sulfonamides tested exhibited LODs in the range of 0.2-36.8 microg x L(-1). This sensitivity allows simple multisulfonamide tests to be established for use in the laboratory or on site.

Animals↗
PubMed1981

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.

Binding Sites↗
PubMed2005

Adsorption of sulfonamide antimicrobial agents to clay minerals.

Adsorption of three sulfonamide antimicrobials to clay minerals was investigated as a function of pH, ionic strength, and type of exchangeable cation. Sulfonamide antimicrobial adsorption exhibited pronounced pH dependence consistent with sorbate speciation and clay properties. Sulfonamide antimicrobials did not intercalate into montmorillonite, and surface charge density influenced sorption by determining adsorption domain size. Adsorption edge data were best fit to a model including terms for the cationic and uncharged species. Adsorption of uncharged sulfamethazine to montmorillonite was relatively insensitive to pH, ionic strength, and type of exchangeable cation, while that to kaolinite was highly sensitive to ionic strength. Adsorption of cationic sulfamethazine to montmorillonite exceeded that of the neutral species by 1-2 orders of magnitude, but was unimportant for kaolinite atthe pH values examined. Cation exchange appeared to contribute to sorption of cationic sulfonamide species to montmorillonite. Anionic sulfamethazine adsorption was negligible. The nature of the sulfonamide R group influenced the degree of adsorption of cationic and neutral species. Our results highlight the importance of considering sulfonamide speciation and clay surface charge density in predicting the transport of these antimicrobials.

Adsorption↗
PubMed2004

Engineering of a broad specificity antibody for simultaneous detection of 13 sulfonamides at the maximum residue level.

Sulfa antibiotics (sulfonamides) are a group of molecules sharing the p-aminobenzenesulfonamide moiety. Sulfonamides are used in veterinary and human medicine. Sometimes, the meat or milk of medicated animals is contaminated with residual sulfonamides. Current analytical methods for sulfonamides are unfit for screening of food, because they are either too laborious, insensitive, or specific for a few sulfa compounds only. A rapid immunoassay for detection of all sulfas in a single reaction would thus be useful. Previously, we used protein engineering to improve the broad specificity of sulfa antibody 27G3. In this study, we improved the best mutant of the previous studies with site-directed mutagenesis. The new mutants recognized different sulfonamides with affinities sufficient for detection of all 13 tested sulfonamides below the MRL level. We furthermore demonstrated the functionality of one mutant in some real sample matrices.

Antibodies↗
PubMed2006

Hapten synthesis and development of polyclonal antibody-based multi-sulfonamide immunoassays.

This paper reports the synthesis of five sulfonamide derivatives, the production of broad-specificity polyclonal antibodies for immunoassay of sulfonamides, and the analysis of milk samples by developed assay. The three-step synthesis procedure reported in most of the literature was adopted and modified in this study. In the procedure, the purification of the intermediate was avoided and the time of synthesis was shortened from >20 to 6-9 h with improved yields. This method is generally applicable to the synthesis of haptens containing the common structure of sulfonamides. Three haptens were coupled to keyhole limpet hemocyanin, and polyclonal antibodies were obtained from rabbits immunized with these conjugates. Using the antibodies obtained, from one of these was developed an enzyme-linked immunosorbent assay (ELISA) based on the competition between free sulfonamides and the hapten-horseradish peroxidase (HRP) conjugates. The hapten-HRP conjugate giving the best competitive results and 11 structurally different sulfonamides showed 50% inhibition at concentrations of <100 ng mL(-1). After removal of the protein with acetone, milk samples were analyzed by ELISA directly; a matrix effect could be avoided when a 1:20 dilution with phosphate-buffered saline was used, and 104-131% recoveries of spiked samples were obtained. The developed immunoassay is suitable to determine sulfisozole, sulfathiazole, sulfameter, sulfamethoxypyridazine, sulfapyridine, and sulfamethizole below the maximum residue limit in milk (100 ng mL(-1) of total sulfonamides) rapidly and reliably.

Animals↗
PubMed1980

Studies on anticoccidial agents. 13. Synthesis and anticoccidial activity of nitropyridine-2- and -3-sulfonamides and derivatives.

Eight nitropyridinesulfonamides and pyridinesulfonamide N-oxides as their bioisosteres were prepared and evaluated for anticoccidial activity. Of these compounds, 2-, 4- and 5-nitropyridine-3-sulfonamides and pyridine-2- and -3-sulfonamide N-oxides were found to be active against Eimeria tenella. Thus, the relative positions, ortho or meta, of the substituents in nitropyridine-3-sulfonamides and pyridinesulfonamide N-oxides are important for anticoccidial activity. N-Substituted analogues of 5-nitropyridine-3-sulfonamide were also prepared and optimal anticoccidial activity was attained with the sulfonamide and its lower N-alkyl derivatives. The mode of action of 5-nitropyridine-3-sulfonamide was examined and found to be active in the sporozoite and the first schizogony stages.

Animals↗
PubMed2003

A new strategy for solid phase synthesis of a secondary amide library using sulfonamide linker via radical traceless cleavage.

A new strategy for solid phase synthesis of a secondary amide library using sulfonamide linker via radical traceless cleavage is reported. Polystyrylsulfonyl chloride (1) reacted with primary amines to afford polystyryl-supported N-alkyl sulfonamides (2), which were acylated with acid chlorides and followed by radical cleavage with TiCl4/Zn to afford secondary amides. It was interestingly found that the products released from acyl alkanesulfonamide resins are closely dependent on the substituents of benzene rings of alkyl or acyl groups on the resins. When the substituent on benzene ring of N-benzyl group of sulfonamides is an electron rich MeO-group, the products released from sulfonamide resins are dependent on the substitution position on benzene ring: para-MeO- to yield 1,2-bis (p-methoxylphenyl)ethane and N--p-methoxylbenzyl benzamide (30:1); ortho-MeO- to give 1,2-bis (o-methoxylphenyl)ethane and N--o-methoxylbenzyl benzamide (1:15); and meta-MeO- only to release N--m-methoxylbenzyl benzamide. Neither N-benzoyl sulfonamide resins on benzene ring with electron-drawing para-O2N-, nor the one with electron-donating para-H2N- could release any amide product, while the N-benzoyl sulfonamide resins on benzene ring with para-acetamido group released para-acetamidobenzamides. The conjugation effect to stabilize the radical groups in the radical cleaving process was observed.

Amides↗
PubMed1991

Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions.

Delayed hypersensitivity reactions are among the most severe adverse effects of the sulfonamides in current clinical use. These reactions appear to occur because of differences in the metabolism and detoxification of reactive metabolites of the sulfonamides. N-Acetylation is a major metabolic pathway for the sulfonamides. Slow acetylation phenotype might be a risk factor for the development of these reactions. We determined the acetylation phenotype of 21 patients who had suffered hypersensitivity reactions to the sulfonamides. There were 11 females and 10 males in the group, with a mean age of 15 years (age range, 1.8 to 50 years). Their acetylator phenotype was determined by determining the ratio of urinary caffeine metabolites (1-methylxanthine to 5-amino-6-formylmethyluracil after an oral dose of 50 mg caffeine). Nineteen (90%) of the patients were slow acetylators compared to a 55% incidence of slow acetylators in a race-matched control population (p less than 0.008). This suggests that a slow acetylator phenotype is a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.

Acetylation↗
PubMed2000

Carbonic anhydrase inhibitors. metal complexes of 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide with topical intraocular pressure lowering properties: the influence of metal ions upon the pharmacological activity.

Metal complexes of a sulfonamide possessing strong carbonic anhydrase (CA) inhibitory properties, 5-(2-chlorophenyl)-1,3,4-thiadiazole-2-sulfonamide (chlorazolamide) have been obtained from the sodium salt of the sulfonamide 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 and its complexes were assayed for the 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) behaved as powerful inhibitors against the three investigated isozymes. The parent sulfonamide possessed an extremely weak topical pressure lowering effect when administered as a 1-2% suspension into the rabbit 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 very well. Ex vivo data showed a 99.5-99.9% CA II inhibition in ocular fluids and tissues of rabbits treated with these agents, proving that the observed IOP lowering is due to CA inhibition. The influence of the different metal ions upon the efficiency of the obtained complexes as pressure lowering drugs are discussed, leading to the possibility of designing more selective/potent pharmacological agents from this class.

Animals↗
PubMed2003

The in vitro and in vivo inhibitory effects of some sulfonamide derivatives on rainbow trout (Oncorhynchus mykiss) erythrocyte carbonic anhydrase activity.

The in vitro and in vivo inhibitory effects of 5-(3alpha, 12alpha-dihydroxy-5-beta-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (1), 5-(3alpha, 7alpha, 12alpha-trihydroxy-5-beta-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (2), 5-(3alpha, 7alpha, 12alpha-triacetoxy-5-beta-cholanamido)-1,3,4-thiadiazole-2-sulfonamide (3) and acetazolamide on rainbow trout (Oncorhynchus mykiss) (RT) erythrocyte carbonic anhydrase (CA) were investigated. The RT erythrocyte CA was obtained by affinity chromatography with a yield of 20.9%, a specific activity of 422.5EU/mg protein and a purification of 222.4-fold. The purity of the enzyme was confirmed by SDS-PAGE. Inhibitory effects of the sulfonamides and acetazolamide on the RT erythrocyte CA were determined using the CO2-Hydratase method in vitro and in vivo studies. From in vitro studies, it was found that all the compounds inhibited CA. The obtained I50 value for the sulfonamides (1), (2) and (3) and acetazolamide were 0.83, 0.049, 0.82 and 0.052 microM, respectively. From in vivo studies, it was observed that CA was inhibited by the sulfonamides (1), (2) and (3) and acetazolamide.

Animals↗
PubMed2004

Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing.

We studied 28 patients with fixed drug eruption (FDE) caused by sulfonamide antibiotics to investigate cross-reactivity between sulfonamide derivatives and p-amino compounds and to explore the usefulness of patch testing, as an alternative to controlled oral challenge testing (COCT), in diagnosis within this clinical area. COCT with sulfamethoxazole (SMX), sulfadiazine (SDZ), sulfamethizole (SMZ), furosemide (FU), procaine (PRO) and glipizide (GPZ) was performed. Patch testing (PT) with SMX and SDZ was carried out. In all patients, the diagnosis of FDE was confirmed by positive COCT and allergy to trimethoprim ruled out by COCT. 42.8 and 31.8% of the SMX-induced FDE patients reacted to SMZ and SDZ, respectively. All patients (n = 28) tolerated FU, PRO and GPZ. COCT performed with the 3 sulfonamide antibiotics in 12 patients was positive in 2 subjects with the 3 drugs, in 2 patients only with SMX and SMZ and in the remaining 8, SMX was the only causative drug. PT was positive in 5 of 25 patients positive on COCT. The probability of obtaining a positive PT was higher among patients who had a residual lesion than that among those who lacked this. Cross-reactivity between different sulfonamide antibiotics is thus variable, being most likely between SMX and SMZ. We have found no cross-reactivity between sulfonamide antibiotics and other sulfonamide derivatives or p-amino drugs in FDE. PT is a useful tool in the diagnosis of FDE, especially if there are residual lesions, because it avoided the need for COCT in 20% of patients.

Administration, Oral↗