Solubility advantage of sulfanilamide and sulfacetamide in natural deep eutectic systems: experimental and theoretical investigations

Objective: The aim of this study was to explore the possibility of using natural deep eutectic solvents (NADES) as solvation media for enhancement of solubility of sulfonamides, as well as gaining some thermodynamic characteristics of the analyzed systems.

Significance: Low solubility of many active pharmaceutical ingredients is a well-recognized difficulty in pharmaceutical industry, hence the need for different strategies addressing this problem. Among such strategies, those that are environmentally and economically beneficial are of particular interest.

Methods: The solubility of sulfanilamide and sulfacetamide in 21 different NADES compositions comprising choline chloride with sugars or sugar alcohols was measured spectrophotometrically. Thermodynamic parameters describing the studied systems were determined using the COSMO-RS computational protocol.

Results: All of the considered NADES compositions gave an increase in solubility of the studied sulfonamides, with the highest solubilities obtained for the system comprising choline chloride and glycerol in unimolar proportions, which gave a solubility advantage of 83.7 and 73.8 for sulfanilamide and sulfacetamide, respectively. Theoretical studies indicated that the dissolution of both considered sulfonamides has a low endothermic character, with the lowest enthalpy values obtained for the most optimal, i.e. unimolar, proportions. The non-monotonous trend of enthalpy of dissolution was also discussed in terms of intermolecular interactions.

Conclusions: The obtained results show the feasibility of using NADES as solubility enhancers for sulfonamides and encourage for further exploration in this field.     

Investigation of Antigen-Antibody Interactions of Sulfonamides with a Monoclonal Antibody in a Fluorescence Polarization Immunoassay Using 3D-QSAR Models

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAb(SMR)) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAb(SMR), expressed as Log(10)IC(50), for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAb(SMR) binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q(2) (cv) values of 0.600 and 0.523, and r(2) values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens.     

采用超高效液相色谱串联质谱法检测饲料中3种磺胺类药物

用超高效液相色谱串联质谱法测定饲料中磺胺嘧啶、磺胺甲基嘧啶和磺胺二甲基嘧啶含量.结果显示:磺胺药物浓度与仪器响应值的相关系数0.996 7～0.999 2,方法的检出限为10μg/kg,加标回收率87.67％～100％,相对标准差1.3％～4.3％,精密度相对标准差3.50％～4.40％.表明回收率、相对标准差和精密度符合相关要求,此方法可快速、高效、准确检测饲料中磺胺类药物,同时该方法还可以扩充到其他磺胺类药物的检测.     

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC₅₀ = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.     

Multi‐residue analysis of sulfonamides in animal tissues by capillary zone electrophoresis with electrochemical detection

BACKGROUND: The objective of this study was to adapt and improve previously published analysis methods aimed at the simultaneous determination of sulfonamide residues in edible animal tissues by capillary zone electrophoresis with electrochemical detection. RESULTS: The effects of several factors such as the acidity and concentration of running buffer, the separation voltage, the applied potential and the injection time on CZE‐ED were investigated. Complete separation of six sulfonamides was achieved within 17 min by using 40 mmol L^?1 Na₂B₄O₇/25 mmol L^?1 KH₂PO₄ (pH 6.2) at an applied voltage of 18 kV. Excellent linearity was obtained over two orders of magnitude with the improved detection limits (S/N = 3) ranged from 1.7 × 10^?7 to 4.4 × 10^?9 g mL^?1 for all six sulfonamides in comparison with previous reports. A solvent extraction/centrifuge/evaporation procedure was used to extract sulfonamides from animal tissues, sample clean‐up and pre‐concentration of sulfonamides prior to CZE‐ED analysis. Good recoveries from 81% to 92% were achieved. CONCLUSION: Results obtained in this work indicated that the proposed CZE‐ED method was sensitive, rapid and simple for the simultaneous determination of sulfonamides in edible animal tissues. Therefore, the new faster and easy handling procedure provides an additional powerful tool that can be employed for the analysis of sulfonamide residues in foodstuff. Copyright © 2009 Society of Chemical Industry     

Smartphone-based colorimetric determination of sulfadiazine and sulfasalazine in pharmaceutical and veterinary formulations

A novel, simple, accurate, and low-cost colorimetric device based on an Android smartphone was developed for sulfonamide determination. A software program was developed to be used for analyzing the samples. Various parameters for digital colorimetric detection were investigated and optimized, such as the volume of the sample drop, the type of sample holder, the distance from the mobile phone camera to the sample holder, and the effect of ambient light. From the optimized conditions, a calibration curve was created by the intensity of blue channel for sulfonamides for the concentration range of 0.5–2.5?µg?mL^?1 with good linearity and a regression coefficient (R²) of 0.996. The results obtained by the smartphone method were compared with a spectrophotometric procedure at the 95% confidence level (n?=?3). Both methods correlated well with a regression coefficient (R²) of 0.997. The limit of detection of both methods was equal to 0.11?µg?mL^?1. The developed smartphone system was successfully used for the determination of sulfonamides in pharmaceutical and veterinary formulations with recoveries of 102 and 98.7%, respectively. The developed method provides good accuracy (relative error <5%) and precision (relative standard deviation <7%) and offers simple, convenient, rapid, and inexpensive determination of sulfonamides.     

QuEChERS-高效液相色谱-串联质谱法联用测定鸡肉中磺胺类药物残留

目的建立QuEChERS-高效液相色谱-串联质谱法测定鸡肉中磺胺类药物残留量的分析方法。方法以乙腈为提取溶剂,氯化钠盐析分层,离心后上清液经C18填料萃取净化,用乙腈和0.1%(V:V)甲酸水溶液作为流动相进行梯度洗脱,EndeavorsilC18柱色谱柱进行色谱分离,在高效液相色谱-串联质谱仪上采用电喷雾正离子扫描模式(electrospray ionization, ESI+)检测,外标法定量。结果该方法在5～200μg/L范围内有良好的线性关系, 8种磺胺类药物残留的相关系数均大于0.99,方法检出限在3～6μg/kg范围,定量限在10～20μg/kg范围。分别在3个浓度水平20、100、300μg/kg加标,平均回收率在75.6%～115.2%范围,相对标准偏差在1.9%～12.4%范围。结论本方法操作简便,准确度和精密度好,可快速检测鸡肉中磺胺类药物的残留量。     

动物源性食品磺胺类抗生素残留快速前处理与检测方法研究进展

磺胺类抗生素具有抗菌谱广、使用简单和价廉等优点,被广泛应用于动物抗菌治疗,但抗生素的滥用易导致动物源性食品抗生素超标等食品安全问题。食品中磺胺类抗生素残留检测方法主要为高效液相色谱法,而动物源性食品样品复杂、基质干扰大,色谱分析方法通常耗时较长,费用昂贵,因此开发高效的快速样品前处理技术和快检方法对磺胺类抗生素残留检测尤为重要。本文综述了近十年来动物源性食品磺胺类抗生素残留快速样品前处理技术的研究进展,包括场辅助加速样品前处理技术和基于材料加速的相分离样品前处理技术,介绍了磺胺类抗生素的多种快检方法如荧光光谱法、化学发光法、表面增强拉曼光谱法、电化学法、免疫分析法和微生物抑制法等的研究进展,并对动物源性食品磺胺类抗生素残留快速样品前处理和检测方法存在的问题和未来发展趋势进行了分析和展望。     

Incorporation of Sulfonamide Moiety into Biguanide Scaffold Results in Apoptosis Induction and Cell Cycle Arrest in MCF-7 Breast Cancer Cells

Metformin, apart from its glucose-lowering properties, has also been found to demonstrate anti-cancer properties. Anti-cancer efficacy of metformin depends on its uptake in cancer cells, which is mediated by plasma membrane monoamine transporters (PMAT) and organic cation transporters (OCTs). This study presents an analysis of transporter mediated cellular uptake of ten sulfonamide-based derivatives of metformin in two breast cancer cell lines (MCF-7 and MDA-MB-231). Effects of these compounds on cancer cell growth inhibition were also determined. All examined sulfonamide-based analogues of metformin were characterized by greater cellular uptake in both MCF-7 and MDA-MB-231 cells, and stronger cytotoxic properties than those of metformin. Effective intracellular transport of the examined compounds in MCF-7 cells was accompanied by high cytotoxic activity. For instance, compound 2 with meta-methyl group in the benzene ring inhibited MCF-7 growth at micromolar range (IC₅₀ = 87.7 ± 1.18 µmol/L). Further studies showed that cytotoxicity of sulfonamide-based derivatives of metformin partially results from their ability to induce apoptosis in MCF-7 and MDA-MB-231 cells and arrest cell cycle in the G0/G1 phase. In addition, these compounds were found to inhibit cellular migration in wound healing assay. Importantly, the tested biguanides are more effective in MCF-7 cells at relatively lower concentrations than in MDA-MB-231 cells, which proves that the effectiveness of transporter-mediated accumulation in MCF-7 cells is related to biological effects, including MCF-7 cell growth inhibition, apoptosis induction and cell cycle arrest. In summary, this study supports the hypothesis that effective transporter-mediated cellular uptake of a chemical molecule determines its cytotoxic properties. These results warrant a further investigation of biguanides as putative anti-cancer agents.     

磺胺类药物水溶解度的测定与关联

采用平衡法测定了(298.15～333.15)K温度范围内磺胺嘧啶、磺胺二甲基嘧啶、磺胺二甲氧嘧啶、磺胺对甲氧嘧啶、磺胺间甲氧嘧啶和磺胺甲恶唑6种常见磺胺类药物在水中的溶解度数据,并运用λh方程进行了关联,确定了方程参数,总均方根偏差为0.26×10~(-6)。结果表明,实验范围内磺胺嘧啶、磺胺二甲基嘧啶、磺胺二甲氧嘧啶、磺胺对甲氧嘧啶、磺胺间甲氧嘧啶和磺胺甲恶唑6种常见磺胺类药物的水溶解度均较小,且分别随温度的升高而略有增加,计算值与实验值吻合较好。根据溶解过程热力学,由溶解度实验数据计算出6组磺胺类药物水溶液的超额焓H~E>0,表明其溶解为吸热过程。