Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

An LC-MS/MS method for the simultaneous quantitation of sulfasalazine and sulfapyridine in human placenta.

Sulfasalazine has been identified as a candidate molecule to be investigated as an intervention to treat preterm pre-eclampsia during pregnancy. However, placental exposure of sulfasalazine and its systemically absorbed metabolite, sulfapyridine, is unknown. A robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously quantitate these analytes in human placenta with an application to a pilot clinical trial. The placental tissue was homogenised using a water:methanol (1:1, v/v) mixture, followed by sample extraction using both protein precipitation and solid phase extraction. Sulfasalazine-d4 and sulfapyridine-d4 were used as internal standards. An Agilent Poroshell EC-C18 (3.0 ×100 mm, 2.7 µm) column was used for chromatographic separation, with gradient elution employed at a flow rate of 0.450 mL/min over a total run time of seven minutes. The mobile phases consisted of water with 0.1% formic acid (mobile phase A) and acetonitrile:methanol (90:10, v/v) with 0.1% formic acid (mobile phase B). A Shimadzu-8040 mass spectrometer was operated in multiple reaction monitoring (MRM) mode using positive electrospray ionisation (ESI). For both analytes, the assay was validated over the range 30-30,000 ng/mL, or 150-150,000 ng/g. During inter-day validations (n = 18), the average accuracies of quality controls ranged from 101.6% to 112.7% with corresponding precisions of 4.4-6.7% for sulfasalazine, and from 97.4% to 108.4%, with corresponding precisions of 3.7-10.0% for sulfapyridine. No significant matrix effects were observed, and the method proved to be sensitive and specific for both analytes. This study presents the first validated analytical method for quantifying sulfasalazine and sulfapyridine in human placenta as part of a pilot clinical trial to generate preliminary data on its pharmacokinetics and efficacy as in intervention for preterm pre-eclampsia.

Successful Treatment of Linear IgA Disease and Ulcerative Colitis With Sulfasalazine.

Linear IgA disease (LAD) is an uncommon autoimmune blistering disease that has been associated with medications, malignancy, and other autoimmune diseases, such as ulcerative colitis (UC). In this case report, a patient with a history of UC developed characteristic LAD lesions. While dapsone is considered first-line therapy for LAD, the treatment team opted for an underutilized, plausibly less toxic, and more simplified treatment regimen with sulfasalazine, successfully utilizing the two distinct actions of sulfasalazine's components - sulfapyridine and 5-aminosalicylate (5-ASA) - to concurrently treat both the LAD and UC symptoms. The authors discuss the pathophysiology of LAD and UC and expound on the mechanistic theory of their association. Additionally, the pharmacodynamics of sulfasalazine and considerations of its side effect profile are examined.

Indirect photodegradation of sulfadimidine and sulfapyridine: Influence of CDOM components and main seawater factors.

This study investigated the indirect photodegradation of sulfadimidine (SM2) and sulfapyridine (SP) in the presence of chromophoric dissolved organic matter (CDOM), and studied the influences of main marine factors (salinity, pH, NO3- and HCO3-). Reactive intermediate (RI) trapping experiments demonstrated that triplet CDOM (3CDOM*) played a major role in the photodegradation of SM2 with a 58% photolysis contribution, and the contributions to the photolysis of SP were 32%, 34% and 34% for 3CDOM*, hydroxyl radical (HO·) and singlet oxygen (1O2), respectively. Among the four CDOMs, JKHA, with the highest fluorescence efficiency, exhibited the fastest rate of SM2 and SP photolysis. The CDOMs were composed of one autochthonous humus (C1) and two allochthonous humus (C2 and C3). C3, with the strongest fluorescence intensity, had the strongest capacity to generate RIs and accounted for approximately 22%, 11%, 9% and 38% of the total fluorescence intensity of SRHA, SRFA, SRNOM and JKHA, respectively, indicating the predominance of CDOM fluorescent components in the indirect photodegradation of SM2 and SP. These results demonstrated the photolysis mechanism: The photosensitization of CDOM occurred after its fluorescence intensity decreased, and a large number of RIs (3CDOM*, HO· and 1O2, etc.) were generated by energy and electron transfer, then these RIs reacted with SM2 and SP to cause photolysis. The increase in salinity stimulated the photolysis of SM2 and SP consecutively. The photodegradation rate of SM2 first increased and then decreased with increasing pH, whereas the photolysis of SP was remarkably promoted by high pH but remained stable at low pH. NO3- and HCO3- had little effect on the indirect photodegradation of SM2 and SP. This research may contribute to a better understanding of the fate of SM2 and SP in the ocean and provide new insights into the transformation of other sulfonamides (SAs) in marine ecological environments.

Predicting combined antibacterial activity of sulfapyridine and its transformation products during sulfapyridine degradation.

Antibiotics have strong antibacterial activity, even trace antibiotics can greatly inhibit the pollutant degradation efficiency. In order to effectively improve the pollutant degradation efficiency, it was hence of great significance to explore sulfapyridine (SPY) degradation and the mechanism of antibacterial activity. This study selected SPY as the research object, of which the trend of SPY concentration through hydrogen peroxide (H2O2), potassium peroxydisulfate (PDS) and sodium percarbonate (SPC) and resultant antibacterial activity at pre-oxidation was examined. The combined antibacterial activity (CAA) of SPY and its transformation products (TPs) was further analyzed. The SPY degradation efficiency reached more than 90 %. However, the degradation efficiency of antibacterial activity was between 40-60 %, and the mixture's antibacterial activity was difficult to be removed. The antibacterial activity of TP3, TP6 and TP7 was higher than that of SPY. TP1, and TP8 and TP10 were more prone to synergistic reaction with other TPs. The antibacterial activity of binary mixture gradually changed from synergism to antagonism as binary mixture concentration increased. The results provided a theoretical basis for the efficient degradation of antibacterial activity of the SPY mixture solution.

Dissemination of antibiotics through the wastewater-soil-plant-earthworm continuum.

Under the ongoing climate change scenario, treated municipal wastewater (TMW) is a potential candidate for irrigated agriculture but may result in the exposure of agricultural environments to antibiotics. We studied the transfers of trimethoprim, sulfamethoxazole, and sulfapyridine in the TMW-soil-plant-earthworm continuum under greenhouse/laboratory conditions. Irrigation of potted spinach and radish with as-collected TMW resulted in no transfers of antibiotics into soil or plants owing to their low concentrations in the tertiary-treated TMW. However, TMW spiked with higher antibiotic concentrations led to transfers through this continuum. High initial inputs, slow soil degradation, and chemical speciation of the antibiotics, coupled with an extensive plant-root distribution, were important factors enhancing the plant uptake of antibiotics. In microcosm studies, transfers from vegetable materials into earthworms were low but showed potential for bioaccumulation. Such food chain transfers of antibiotics may be a driver for antibiotic resistance in agricultural systems, which is an area worthy of future study. These issues can perhaps be mitigated through high levels of TMW purification to effectively remove antibiotic compounds.

Removal Efficiency of Sulfapyridine from Contaminated Surface Water by Carboxylated Graphene Oxide Blended PVDF Composite Ultrafiltration Membrane with Activated Carbon.

In this study, sulfapyridine (SPY), an antibiotic that is less commonly treated by membrane filtration techniques but is frequently detected in the aqueous environment and at higher concentrations than other detected antibiotics, was selected for investigation. A composite ultrafiltration membrane for the removal of sulfapyridine (SPY) antibiotics from water was fabricated using polyvinylidene fluoride (PVDF), polyvinylpyrrolidone (PVP), and carboxyl-functionalized graphene oxide (CFGO) as additives. The changes in retention rate and pure water flux of sulfapyridine by the composite ultrafiltration membrane were investigated by changing the ratios of the prepared ultrafiltration membrane materials under the conditions of low-pressure operation to explore the optimal experimental conditions. The results showed that the addition of PVP and CFGO significantly increased the number of membrane pores and their pore size. The addition of CFGO in the membrane significantly improved the hydrophilicity of the membrane. The contact angle decreased from 83.7 to 31.6°. Compared to ordinary PVDF ultrafiltration membranes, the membrane's pure water flux increased nearly three times to 2612.95 L/(m2·h). The removal rate of SPY was 56.26% under the optimal conditions. When the composite ultrafiltration membrane was combined with activated carbon, the removal rate of SPY was 92.67%, which was nine times higher than that of activated carbon alone. At this time, the flux of the composite membrane was 2610.23 L/(m2·h). This study proposes a simple, efficient, and low production cost solution for the removal of sulfapyridine from water.

Peroxymonosulfate activation using heterogeneous catalyst Sr2FeO4 coated on SBA-15 for efficient degradation of antibiotic sulfapyridine.

It is significant to explore the advanced oxidation process (AOP) for antibiotic degradation. Herein, a peroxymonosulfate (PMS) activator, Sr2FeO4/SBA-15 (SFS) heterogeneous catalyst, was synthesized by in situ growth of Sr2FeO4 on the surface of SBA-15. In SFS/PMS catalytic system, Sr atom provided electrons to Fe(II) ↔Fe(III) ↔Fe(II) redox cycle through Sr-O-Fe bonds for PMS activation. The SFS catalyst could activate PMS to generate a free radical coexistence system, including sulfate radical (SO4∙-) and hydroxyl radicals (∙OH). The catalyst possessed high catalytic activity and high stability. The degradation efficiency of sulfapyridine (SAD) over the SFS/PMS catalytic system could reach 99.0% after 90 min reaction. After the 5th reuse, the degradation efficiency of SAD was still more than 94.0%, and the phase structure of the catalyst did not alter. The low ion leaching concentration would be more conducive to reuse and avoiding secondary pollution, in comparison to homogeneous catalysts. This catalyst can be widely applied to organic wastewater treatment.-->.

The influence of the gut microbiota on the bioavailability of oral drugs.

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

Enhanced peroxymonosulfate activation over heterogeneous catalyst Cu0.76Co2.24O4/SBA-15 for efficient degradation of sulfapyridine antibiotic.

The largest source of resistant bacteria or viruses is the overuse and misuse of antibiotics in humans and animals. These resistant bacteria or viruses may evolve into superbacteria or superviruses, which causes global plague. Therefore, it is significant to find a highly efficiency and low-cost method to eliminate antibiotics in water environment from inappropriate discharge. Here, a highly active and highly stable heterogeneous catalyst, Cu0.76Co2.24O4/SBA-15 (CCS) was prepared for peroxymonosulfate (PMS) activation in aim of decomposing persistent sulfapyridine (SPD). The reaction mechanism was thoroughly investigated via in situ quenching test and in situ electron paramagnetic resonance. Four reactive species, SO4·-, O2·-, 1O2 and ·OH were generated in Cu0.76Co2.24O4/SBA-15/PMS (CCSP) system. The SO4·- and O2·- were dominant active species responsible for SPD degradation. Co(Ⅱ)↔Co(Ⅲ)↔Co(Ⅱ) redox reaction cycle was constructed due to the different redox potential of Co(Ⅱ)/Co(Ⅲ), HSO5-/SO4∙-, and HSO5-/SO5∙-. Interestingly, Cu(Ⅰ) could urge the redox reaction cycle for PMS activation to be more thermodynamically feasible. Therefore, CCS possessed a highly catalytic activity and excellent stability. Meanwhile, the anions interference test indicated Cl-, NO3-, HCO3-, and H2PO4- had almost no inhibitory effect on SPD degradation over this catalytic system. We sincerely expected that this catalyst system would be applied extensively into antibiotics degradation in real water bodies.

High-temperature and freeze-thaw aged biochar impacts on sulfonamide sorption and mobility in soil.

Biomass-derived biochar is a carbon-rich product for soil amendment and sulfapyridine (SPY) is a typical sulfonamide of antibiotics in the soil. Amendment with biochar for soil could control SPY sorption or mobility. However, the pristine biochar inevitably goes through the long-term ageing in the environment and the information on such ageing impact on SPY sorption is not fully recognized. The simulated ageing process methods were employed for high-temperature and freeze-thraw climate to treat the biochar for two months in the present study. The batch adsorption of SPY and leaching column experiments were conducted for comparison of the fresh/aged biochar-soil system. The results showed that biochar addition could increase soil pH and saturated moisture, aged biochars own more O-containing functional groups and exhibit higher hydrophilicity and polarity. The sorption mechanism of unamended soil with SPY primarily resulted from the weak hydrophobic distribution. All fresh and aged biochar amended soil increased SPY sorption due to improvement of H-bonding interaction between SPY and biochar surface functional groups, indicating such initiative adsorption was stronger than passive partitioning. It is of importance for us to reconsider that aged biochar-amended soil, especially two-month high-temperature aged biochar-amended soil showed the highest adsorption performance and the lowest desorption capacity towards SPY. Both SPY leaching column experiments and the acid rain leaching tests suggested that the application of biochar in tropical or high-temperature climate regions for organics polluted soil remediation is favorable, but we should be aware of the uncertainty of soil amendment with biochar in cold regions.

Enhanced adsorption of sulfonamides by a novel carboxymethyl cellulose and chitosan-based composite with sulfonated graphene oxide.

A novel multiple active sites sponge was fabricated from carboxymethyl cellulose (CMC) and genipin crosslinked carboxyalkyl-chitosan (GCC) combined with sulfonated graphene oxide (CMC/SGO-GCC) and used as a material for adsorbing sulfonamide antibiotics. The GO contains a variety of carboxyl and hydroxyl groups, which can interact with the hydroxyl groups of chitosan and CMC to form strong hydrogen bonds. This adsorption process is spontaneous and pH dependent, and shows high sulfamethoxazole (SMX) and sulfapyridine (SPD). Removal efficiency from aqueous solutions. Equilibrium adsorption studies showed that the maximum adsorption capacities of SMX and SPD decreased from 312.28 to 272.83 mg/g and 161.89 to 146.56 mg/g, respectively, as the temperature increased from 298 to 318 K. Reusability experiments indicated that CMC/SGO-GCC maintained a high adsorption capacity for SMX and SPD upon its reuse. This study shows that CMC/SGO-GCC is an ideal material for adsorbing SMX and SPD.

Fail-safe nano-formulation of prodrug of sulfapyridine: Preparation and evaluation for treatment of rheumatoid arthritis.

Aim of the present study was to give a second life to the long-abandoned drug, sulfapyridine (SP) for its anti-arthritic potential by design of nano-vesicular delivery system. For this, intra-articular delivery of its liposomal formulation was tried. As the prepared formulation exhibited rapid drug leakage, an arthritis responsive prodrug of SP showing lability towards synovial enzymes was synthesized to exploit the over-expression of arthritis specific enzymes. Prodrug (SP-PD) exhibited better retention in liposomes as compared to the drug, preventing its escape from synovium. Hydrolysis of SP-PD in human plasma and synovial fluid indicated its high susceptibility to enzymes. The liposomes of SP-PD exhibited larger mean size, less PDI and higher zeta potential as compared to those for SP liposomes. In arthritic rats, prodrug liposomes were found to reverse the symptoms of inflammation, including the levels of biochemical markers. Liposomes of bio-responsive prodrug, therefore, offer a revolutionary approach in the treatment of rheumatoid arthritis.

Effects of Esomeprazole on Pharmacokinetic Behavior of Sulfasalazine in Rats / 中国药房

OBJECTIVE：To develop a metho d for determining the plasma concentration of sulfasalazine （SSZ）metabolite sulfapyridine（SP）in rats ，and to investigate the effects of esomeprazole （ESOM）on the pharmacokinetic behavior of SSZ in rats. METHODS：Male SD rats were randomly divided into SSZ group and SSZ+ESOM group ，with 6 rats in each group. SSZ+ESOM group were given Esomeprazole enteric-coated tablets [ 90 mg/（kg·d）] intragastrically for 14 days. On the 15th day ，the rats in 2 groups were given Sulfasalazine enteric coated tablets （90 mg/kg）intragastrically，and blood sample was collected from the inner canthus at 0.5，1，1.5，2，3，4，6，8，10，12，24，36，48，72 h after administration. After protein precipitation with methanol ， using diazepam as internal standard ，Agilent XDR-C 18 column was adopted with methanol- 0.1％ formic acid solution （gradient elution）as mobile phase. The concentration of SSZ metabolite SP in plasma was determined by LC-MS/MS. The pharmacokinetic parameters were calculated by using DAS 3.0.1 software and compared between 2 groups. RESULTS ：The linear range of SP were 2-1 000 ng/mL. The methodology met the requirements of Chinese Pharmacopeia . There was no statistical significance in pharmacokinetic parameters of SP between 2 groups，such as AUC 0－t，tmax，t1/2z，cmax，MRT0－t（P＞0.05）. CONCLUSIONS ：The established method is simple ，rapid and sensitive ；it can be used for the concentration determination of SSZ metabolite SP in plasma. ESOM has no significant effect on the pharmacokinetic behavior of SSZ in rats.

Development of Novel Magneto-Biosensor for Sulfapyridine Detection.

In this work, we report the development of a highly sensitive biosensor for sulfapyridine detection based on an integrated bio micro-electromechanical system (Bio-MEMS) containing four gold working electrodes (WEs), a platinum counter electrode (CE), and a reference electrode (RE). Firstly, the cleaned WEs were modified with 4-aminophenylacetic acid (CMA). Then, (5-[4-(amino)phenylsulfonamide]-5-oxopentanoic acid (SA2BSA) was immobilized onto the transducers surface by carbodiimide chemistry. The analyte was quantified by competitive detection with SA2BSA immobilized on the WE toward a mixture of Ab155 antibody (with fixed concentration) and sulfapyridine. In order to obtain a highly sensitive biosensor, Ab155 was immobilized onto magnetic latex nanoparticles surface to create a 3D architecture (Ab-MLNp). Using electrochemical impedance spectroscopy (EIS), we investigated the influence of the Ab-MLNp on the sensitivity of our approach. The optimized system was analyzed, as competitive assay, with different concentrations of sulfapyridine (40 µM, 4 µM, and 2 nM) and with phosphate buffer solution. From data fitting calculations and graphs, it was observed that the EIS showed more linearity when Ab-MLNp was used. This result indicates that the magnetic latex nanoparticles increased the sensitivity of the biosensor.

High-Performance Liquid Chromatography and Liquid Chromatography/Mass Spectrometry Studies on Stress Degradation Behavior of Sulfapyridine and Development of a Validated, Specific, Stability-Indicating HPLC Assay Method.

The objective of the current investigation was to develop a simple, rapid, and stability-indicating high-performance liquid chromatography method and to study the degradation behavior of sulfapyridine (SP) under different International Conference on Harmonization (ICH)-recommended conditions. The chromatographic method was developed using C18 (250 × 4.6 mm, 5 µ) column, and mobile phase consisting of acetonitrile-0.1% formic acid (30:70 v/v) at ambient temperature, at a flow rate of 1 mL/min. The elution was monitored at 265 nm using a photodiode array detector. The developed method was subsequently validated as per ICH Q2 (R1) guidelines. The retention time of SP was observed as 4.56 min with the linearity range between 2 to 10 µg/mL. Limit of detection and limit of quantitation for SP were 0.115 and 0.35 µg/mL, respectively. Forced degradation studies were carried out on bulk samples of SP using prescribed acidic, basic, oxidative, thermal, and photolytic conditions. Extent of degradation in 0.1 M hydrochloric acid and under photolytic conditions was found to be 21.56% and 28.57%, respectively. The degradation products formed in stress conditions were identified by liquid chromatography-mass spectrometry (LC-MS). The utility of the method was verified by quantification of SP in different laboratory-made pharmaceutical preparations. The proposed method could be successfully used to quantify SP in different pharmaceutical dosage forms.

Synergistic Enhancement Effect for Boosting Raman Detection Sensitivity of Antibiotics.

In this paper, a two-step method is used to prepare a regenerative three-dimensional (3D) ZnO/Ag@Au substrate for developing a superior sensitive surface enhanced Raman scattering (SERS) method for detecting antibiotics. A great electromagnetic enhancement is observed from the as-prepared composite substrate, which is triggered by tuning the electron distribution of metals and semiconductor metal oxide. The strong interaction between target sample and the huge surface area of ZnO/Ag@Au composite promotes the charge transfer to produce promising chemical enhancement. The synergistic physical and chemical enhancement mechanisms are validated by density functional theory and finite difference time domain simulation. Additionally, the presence of light "echo effect" in the 3D structure of ZnO support could also amplify the efficiency of light excitation for Raman scattering. The above-stated merits benefit to boost the Raman scattering detection sensitivity for real samples. The ZnO/Ag@Au-based SERS substrate could detect rhodamine 6G molecules with an enhancement factor of up to 1.48 × 109 and the lowest detectable concentration of 10-10 M. As a real application, antibiotics sulfapyridine in milk is determined by using the proposed SERS protocol, and the limit of detection at 1 × 10-9 M could be reached. As a prospective, the ZnO/Ag@Au-based SERS method would be extended for food safety and biomedicine analysis.

Nanostructured hybrid surface enhancement Raman scattering substrate for the rapid determination of sulfapyridine in milk samples.

The fabrication of surface-enhanced Raman spectroscopy (SERS) substrates, which can offer the advantages of strong Raman signal enhancement with good reproducibility, is still a challenge for practical applications. In this work, a simple and reproducible SERS substrate combining the properties of multi-walled carbon nanotubes (MWCNTs) and gold nanoparticles (AuNPs), is proposed for the determination and quantification of sulfapyridine in milk samples with a concentration range of 10-100 ng mL-1. The Raman signals of sulfapyridine is enhanced at factor of 4394. The procedure presented is capable of detecting and quantifying small quantities of sulfapyridine without implying any preconcentration step, just using an affordable and portable Raman spectrometer. The precision, in terms of repeatability and inter and intermediate precision, was lower than 8% in all cases.

Removal of sulfapyridine by ferrate(VI): efficiency, influencing factors and oxidation pathway.

The removal of sulfapyridine (SPY) by ferrate(VI) in aqueous solutions under a broad range of reaction conditions, including ferrate(VI) dosage, solution pH, natural organic matter and coexisting inorganic ions, was systematically investigated and the oxidation pathway of SPY by ferrate(VI) was deeply explored. Results showed that 500 µg/L of SPY was efficiently decomposed (86%) within 1 min by 5 mg/L ferrate(VI) at pH 5.6. The increment in ferrate(VI) dosage was surely favorable for SPY removal. The best SPY degradation was achieved at pH 5.6, under or above which the removal decreased. The introduction of inorganic ions in solutions retarded SPY removal. Ten oxidation intermediates were identified and the cleavages of C-S and S-N bonds might be the primary ways of SPY oxidation by ferrate(VI).