Bio-oriented synthesis of new sulphadiazine derivatives for urease inhibition and their pharmacokinetic analysis.

Current research is based on biology-oriented synthesis of sulphadiazine derivatives and determination of their urease inhibitory activity. In this regard, a series of (E)-4-(benzylideneamino)-N-(pyrimidin-2-yl)benzenesulfonamide was synthesized from sulphadiazine and substituted aromatic aldehydes. The structures of synthesized compounds were ascertained by spectroscopic techniques, such as, FTIR, NMR and HRMS analysis, and in-vitro and in-silico investigation were carried out for the inhibition of urease. Ureases are harmful for humans by producing by-products of urea (ammonia and carbon dioxide). The most active compound (3l) against urease exhibited IC50 value of 2.21 ± 0.45 µM which is 10 times more potent than the standard thiourea (20.03 ± 2.06 µM). It is noteworthy that most of our synthesized compounds showed significant to excellent activities against urease enzyme and most of them substituted by halogen or hydroxy groups at ortho and para positions in their structures. Inhibition of enzyme by the synthesized analogues was in descending order as 3l > 3a > 3b > 3q > 3e > 3o > 3s > 3t > 3g > 3k > 3r > 3f > 3m > 3p > 3n > 3j > 3i > 3h. Moreover, molecular docking studies were performed to rationalize the binding interactions of the synthesized motifs with the active pocket of the urease enzyme. The synthesized sulphadiazine derivatives (3a-u) were found to be non-toxic, and presented passive gastrointestinal absorption.

Synthesis of sulpha drug based hydroxytriazene derivatives: Anti-diabetic, antioxidant, anti-inflammatory activity and their molecular docking studies.

Herein, we report synthesis, characterization, anti-diabetic, anti-inflammatory and anti-oxidant activities of hydroxytriazenes derived from sulpha drugs, namely sulphanilamide, sulphadiazine, sulphapyridine and sulphamethazine. Before biological screening of the compounds, theoretical prediction using PASS was done which indicates probable activities ranging from Pa (probable activity) values 65-98% for anti-inflammatory activity. As per the predication, experimental validation of some of the predicted activities particularly anti-diabetic, anti-inflammatory and anti-oxidant was done. Anti-diabetic activities have been screened using two methods namely α-amylase and α-glucosidase inhibition method and IC50 values were ranging from 66 to 260 and 148 to 401 µg/mL, while for standard drug acarbose the values were 12 µg/mL and 70 µg/mL, respectively. Docking studies have also been done for antidiabetic target pancreatic alpha amylase. The molecular docking studies in α-amylase enzyme reveal that the middle phenyl ring of all the compounds mainly occupies in the small hydrophobic pocket formed by the Ala198, Trp58, Leu162, Leu165 and Ile235 residues and sulphonamide moiety establish H-bond interaction by two water molecules. Further, anti-inflammatory activity has been evaluated using carrageenan induced paw-edema method and results indicate excellent anti-inflammatory activity by hydroxytriazenes (71 to 97%) and standard drug diclofenac 94% after 4 h of treatment. Moreover, antioxidant effect of the compounds was tested using DPPH and ABTS methods. All the compounds displayed good results (24-488 µg/mL) against ABTS radical and many compounds are more active than ascorbic acid (69 µg/mL) while all other compounds showed moderate activity against DPPH radical (292-774 µg/mL) and ascorbic acid (29 µg/mL). Thus, the studies reveal potential of sulfa drug based hydroxytriazenes as candidates for antidiabetic, anti-inflammatory and antioxidant activities which have been experimentally validated.

Some Studies in Sulfadiazine Incorporating Pyridine, Pyrimidine, Oxadiazole, and Azo Moieties Endowed with Pharmaceutical Potency.

A set of substituted sulfadiazine compounds was prepared as cytotoxic and antitumor agents by using 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide (1) as the starting material. Compound 1 was reacted with different reagents to give the corresponding sulfadiazines 2-18 and hydrozaones 19a-h which were evaluated for their in vitro cytotoxicity versus four cancer cell lines. Compounds 3, 5, 19d and 19h were active against the tested cancer cells.

Sulfadiazine Salicylaldehyde-Based Schiff Bases: Synthesis, Antimicrobial Activity and Cytotoxicity.

The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development.

Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking.

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC50 = 0.081 ± 0.003 µM), 6a (IC50 = 0.0022 ± 0.0002 µM), 9e (IC50 = 0.0250 ± 0.0007 µM) and 12d (IC50 = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC50 = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.

Determination of sulfadiazine, trimethoprim, and N(4) -acetyl-sulfadiazine in fish muscle plus skin by Liquid Chromatography-Mass Spectrometry. Withdrawal-time calculation after in-feed administration in gilthead sea bream (Sparus aurata L.) fed two different diets.

This study presents a depletion study for sulfadiazine and trimethoprim in muscle plus skin of gilthead sea bream (Sparus aurata L.). N(4) -acetyl-sulfadiazine, the main metabolite of sulfadiazine (SDZ), was also examined. The fish were held in seawater at a temperature of 24-26 °C. SDZ and trimethoprim (TMP) were administered orally with medicated feed for five consecutive days at daily doses of 25 mg SDZ and 5 mg TMP per kg of fish body weight per day. Two different diets, fish oil- and plant oil-based diets, were investigated. Ten fish were sampled at each of the days 1, 3, 5, 6, 8, 9, 10, and 12 after the start of veterinary medicine administration. However for the calculation of the withdrawal periods, sampling day 1 was set as 24 h after the last dose of the treatment. Fish samples were analyzed for SDZ, TMP, and acetyl-sulfadiazine (AcSDZ) residues by liquid chromatography-mass spectrometry. SDZ and TMP concentrations declined rapidly from muscle plus skin. Considering a maximum residue limit of 100 µg/kg for the total of sulfonamides and 50 µg/kg for TMP residues in fish muscle plus skin, the withdrawal periods of the premix trimethoprim-sulfadiazine 50% were calculated as 5 and 6 days, at 24-26 °C, in fish oil (FO) and plant oil (PO) groups, respectively. The investigation of this work is important to protect consumers by controlling the undesirable residues in fish.

Synthesis, characterization and antibacterial activity of a tridentate Schiff base derived from cephalothin and sulfadiazine, and its transition metal complexes.

Metal(II) coordination compounds of a cephalothin Schiff base (H2L) derived from the condensation of cephalothin antibiotic with sulfadiazine were synthesized. The Schiff base ligand, mononuclear [ML(H2O)3] (M(II)=Mn,Co,Ni,Zn) complexes and magnetically diluted dinuclear copper(II) complex [CuL(H2O)3]2 were characterized by several techniques, including elemental and thermal analysis, molar conductance and magnetic susceptibility measurements, electronic, FT-IR, EPR and (1)H NMR spectral studies. The cephalothin Schiff base ligand H2L behaves as a dianionic tridentate NOO chelating agent. The biological applications of complexes have been studied on two bacteria strains (Escherichia coli and Staphylococcus aureus) by agar diffusion disc method.

Sulfa drugs as inhibitors of carbonic anhydrase: new targets for the old drugs.

Sulfa drugs are well-known antibacterial agents containing N-substituted sulfonamide group on para position of aniline ring (NH2RSO2NHR'). In this study 2,4-dichloro-1,3,5-triazine derivatives of sulfa drugs, sulfamerazine (1b), sulfaquinoxaline (2b), sulfadiazine (3b), sulfadimidine (4b), and sulfachloropyrazine (5b) (1a-5a) were synthesized and characterized. Their carbonic anhydrase inhibition activity was evaluated against bovine cytosolic carbonic anhydrase isozyme II (bCA II). For the sake of comparison the CA inhibition activity of the parent sulfa drugs (1b-5b) was also evaluated. A significant increase in CA inhibition activity of sulfa drugs was observed upon substitution with 2,4-dichloro-1,3,5-triazine moiety. Molecular docking studies were carried out to highlight binding site interactions. ADME properties were calculated to evaluate drug likeness of the compounds.

Dissipation and sequestration of the veterinary antibiotic sulfadiazine and its metabolites under field conditions.

Veterinary antibiotics introduced into the environment may change the composition and functioning of soil microbial communities and promote the spreading of antibiotic resistance. Actual risks depend on the antibiotic's persistence and (bio)accessibility, which may differ between laboratory and field conditions. We examined the dissipation and sequestration of sulfadiazine (SDZ) and its main metabolites in soil under field conditions and how it was influenced by temperature, soil moisture, plant roots, and soil aggregation compared to controlled laboratory experiments. A sequential extraction accounted for easily extractable (CaCl2-extractable) and sequestered (microwave-extractable, residual) SDZ fractions. Dissipation from both fractions was largely temperature-dependent and could be well predicted from laboratory data recorded at different temperatures. Soil moisture additionally seemed to control sequestration, being accelerated in dry soil. Sequestration, as indicated by increasing apparent distribution coefficients and decreasing rates of kinetic release into CaCl2, governed the antibiotic's long-term fate in soil. Besides, we observed spatial gradients of antibiotic concentrations across soil aggregates and in the vicinity of roots. The former were short-lived and equilibrated due to aggregate reorganization, while dissipation of the easily extractable fraction was accelerated near roots throughout the growth period. There was little if any impact of the plants on residual SDZ concentrations.

A conceptual model describing the fate of sulfadiazine and its metabolites observed in manure-amended soils.

Sulfadiazine (SDZ) belongs to the chemical class of sulfonamides, one of the most important groups of antibiotics applied in animal husbandry in Europe. These antibiotics end up in the soil after manure from treated animals is applied as fertilizer. They can inhibit soil microbial functions and enhance the spread of resistance genes among soil microorganisms. In order to assess the exposure of soil microorganisms to SDZ, a conceptual kinetic model for the prediction of temporally resolved antibiotic concentrations in soil was developed. The model includes transformation reactions, reversible sequestration and the formation of non-extractable residues (NER) from SDZ and its main metabolites N(4)-acetyl-sulfadiazine (N-ac-SDZ) and 4-hydroxy-sulfadiazine (OH-SDZ). The optimum model structure and rate constants of SDZ kinetics and its metabolites were determined by fitting different model alternatives to sequential extraction data of a manure-amended Cambisol soil. N-ac-SDZ is degraded to SDZ with a half-life of 4d, whereas OH-SDZ is not. Though, based on the available data, the hydroxylation of SDZ seems to be negligible, it is still included in the model structure since this process has been observed in recent studies. Sequestration into a residual fraction has similar kinetics for SDZ, N-ac-SDZ and OH-SDZ and is one order of magnitude faster than the reverse translocation. The irreversible formation of NER is restricted to SDZ and OH-SDZ. The model shows good agreement when applied to extraction data measured independently for a Luvisol soil. The combination of sequential extraction data and the conceptual kinetic model enables us to gain further insight into the long-term fate and exposure of sulfonamides in soil.

New simple liquid chromatographic method for the determination of trimethoprim, sulfadiazine and N4-acetylsulfadiazine in plasma of broilers.

A new method for simultaneous quantification of trimethoprim, sulfadiazine and N4-acetylsulfadiazine in plasma of broilers at levels down to 13-16 ng/ml has been developed. Samples were deproteinized with acetonitrile, defatted with hexane, and extracted with dichloromethane. Chromatographic analysis was carried out on a C18 column in the presence of tetrabutylammonium hydrogen sulfate, a competing base, while detection was performed at 240 nm for trimethoprim, and 270 nm for both sulfadiazine and N4-acetylsulfadiazine. Accuracy and precision data showed recoveries and relative standard deviation values better than 87.3% and 3.1%, respectively, for all three analytes. The good analytical characteristics of the method could allow limits of detection in the low ng/ml range to be realised. The method was successfully applied to determine drug concentrations in plasma samples from broilers administered a combination of sulfadiazine and trimethoprim.

Solucion tecnológica al proceso de precipitación del producto sulfadiazina sodica al 10 por ciento inyectable / Technological solution of the precipitation injectable sodium-sulphadiazine product

Se realizó un estudio tecnológico integral del proceso de elaboración del inyectables sulfadiazina sódica 10 por ciento en ampolletas de 10 mL, para resolver, definitivamente, el problema de carbonización, opalescencia y precipitación del producto. Se aborda el diseño de la formulación vigente y, colateralmente, se realizan sugerencias durante la fase industrial de llenado y cerrado, por la incidencia de la carbonización, la que produce elevadas pérdidas que se reportan en los registros históricos fabriles. Se exponen los resultados obtenidos al considerar dos variantes de reformulación (I y II) y el estudio de estabilidad de la variante escogida para reemplazar la fórmula oficial. El método analítico empleado (nitritrométrico) se acopló a un ensayo cromatográfico en capa delgada, para lograr la especificidad requerida. Los resultados estadísticos obtenidos en la aplicación del método analítico determinaron la validez del trabajo(AU)

Antifungal activity of silver and zinc complexes of sulfadrug derivatives incorporating arylsulfonylureido moieties.

Two well known antimicrobial sulfonamides, sulfadiazine and sulfamerazine were reacted with arylsulfonyl isocyanates, affording several new arylsulfonylureido derivatives. These compounds were subsequently used as ligands (in the form of conjugate bases, as sulfonamide anions) for the preparation of metal complexes containing silver and zinc. The newly synthesized complexes, unlike the free ligands, proved to act as effective antifungal agents against several Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 1.5-5 microg/ml. The mechanism of antifungal action of these complexes seems to be different from that of the azole antifungals acting as lanosterol-14-alpha-demethylase inhibitors. Levels of sterols assayed in the fungi cultures treated with these new antifungals were equal in the absence or in the presence of the tested compounds. This is in strong contrast with similar experiments in which ketoconazole has been used as antifungal, when drastically reduced ergosterol amounts could be detected. Thus, it is probable that the inhibition of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls, imparts antifungal activity to the new metal complexes reported here.

Tissue residues of some sulphonamides in normal and Eimeria stiedai infected rabbits.

Tissue residues of sulphadiazine (SDZ), sulphadimidine (SDD) and sulphquinoxaline (SQ) were studied in healthy and E. stiedai infected rabbits following oral administration of 0.5 g/l drinking water for 5 days. The solid-phase extraction and HPLC was used to determine the concentration of the three sulphonamides in a single tissue sample. SDZ was detected in the liver and kidney in concentrations below the tolerance levels at day 5 and no residues could be detected at day 7 after drug withdrawal. SDD and SQ were detected in all of the tested organs of healthy rabbits up to day 5, where the highest concentration was reported in the liver (0.08 +/- 0.02 and 0.09 +/- 0.02 g/g respectively). In infected rabbits, the three sulphonamides were detected up to day 7 in concentrations higher than the tolerance limits (> 0.1 g/g) in the liver and kidney and lower levels in other tissues. A withdrawal period of 4 days for SDZ and 5 days for SDD and SQ in healthy rabbits and 7 days for SDZ and 8 days for SDD and SQ in E. stiedai infected rabbits is suggested.

Características clínicas y correlación endoscópico-histológica en pacientes con colitis ulcerosa crónica inespecífica / Colitis ulcerative patients: endoscopy, clinical and histopathological correlations

El objetivo del presente trabajo fue evaluar en forma prospectiva, objetiva y sistematizada las manifestaciones de pacientes con Colitis Ulcerativa y Crónica Inespecífica (CUCI) con actividad moderada. Se estudiaron 14 pacientes de la consulta externa del hospital, como parte de un protocolo de tratamiento experimental de CUCI. La actividad de la enfermedad se estableció con bases clínicas, endoscópicas e histológicas. El análisis estadístico se realizó mediante el índice de Kappa (K). En cuanto a los resultados, el promedio de evacuaciones fue de 4/día. En el 100 por ciento se refirió rectorragia y urgencia, 78 por ciento diarrea y 64 por ciento dolor abdominal. La severidad de la rectorragia y urgencia fue grado II o III (92 por ciento y 78 por ciento, respectivamente). Hubo concordancia moderada entre endoscopia y biopsias (K=0.55), así como entre parámetros clínicos y endoscópicos (K=0.45). No hubo correlación clínico-histopatológica. Concluimos que la subjetividad de los síntomas hace poco útil a la evaluación clínica como la única forma de decisiones terapéuticas. Se requiere, además, correlación endoscópico-histológica.

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows.

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.

Pharmacokinetics of co-trimazine (sulphadiazine plus trimethoprim) in geriatric patients.

The study was aimed at analyzing the pharmacokinetics of sulphadiazine (SDZ) and trimethoprim (TMP) in geriatric patients and was carried out in two stages. The first stage compared 11 geriatric patients (68-89 years old) and 9 healthy volunteers (21-34 years old). Serum concentration and urine elimination were determined on day 4 after 12-hourly administration of 1 tablet of co-trimazine containing 410 mg sulphadiazine (SDZ) plus 90 mg trimethoprim (TMP). The mean serum concentrations of SDZ were significantly higher in the older subjects than in the volunteers after 1, 8 and 12 h (p less than 0.05, 0.01, 0.01), but were not differentiable after 2 or 4 h. For TMP, the serum levels were higher (p less than 0.05) in the patients only after 8 h. The amounts collected in urine were higher in the normal volunteers for SDZ during the intervals 0-2 h (p less than 0.05), 2-4 h (p less than 0.01), and 4-8 h (p less than 0.01), but not for 8-12 h. The 12-hour recovery was 69% SDZ + acetyl-SDZ recovered in the patients compared to 66.0% in the volunteers. Indistinguishable amounts of TMP were recovered during each interval in the two groups of subjects, 59.2% in the patients compared to 70.0% in the volunteers. The second stage of the study comprised 9 geriatric patients of mean age 83.6 years and creatinine clearance 59.2 ml/min who were followed for 11 days. A steady increase in serum levels was observed. The mean peak serum concentration for SDZ was 16.7 +/- 4.2 mg/l after the first dose and 44.7 +/- 11.3 mg/l on day 10. For acetyl-SDZ, the respective concentrations were 2.1 +/- 0.9 and 7.1 +/- 3.1 mg/l.(ABSTRACT TRUNCATED AT 250 WORDS)