European Journal of Pharmaceutical Sciences最新文献

{"title":"Combining chromatographic and spectroscopic fingerprinting with chemometrics and data fusion to characterize the phytochemical composition of anthocyanin-rich fruit extracts","authors":"Ance Bārzdiņa ,&nbsp;Daniela Paula Prudņikova ,&nbsp;Marta Žogota ,&nbsp;Baiba Mauriņa ,&nbsp;Dace Bandere ,&nbsp;Agnese Brangule","doi":"10.1016/j.ejps.2025.107177","DOIUrl":"10.1016/j.ejps.2025.107177","url":null,"abstract":"<div><div>Due to high visual similarity, rich anthocyanin content, drastically different availability, and wide use in the pharmaceutical and food industries, products that contain fruits of the genus <em>Vaccinium</em> can become targets of adulteration. This study aimed to obtain phytochemical fingerprints of two anthocyanin-rich fruit extracts (highbush blueberry and bilberry) using four different analytical techniques (HPLC-UV; HPLC-MS/MS; FTIR; UV/Vis) and explore the relationships and similarities of the chemical compositions by applying chemometric data analysis (PCA and PLS-DA) combined with low-level and mid-level data fusion approaches. Tentative identification with subsequent quantification of polyphenols found in these extracts was performed using HPLC-MS/MS analysis. To test the application of mid-level data fusion combined with chemometrics, mixed extracts containing highbush blueberry as well as bilberry extracts were prepared and analyzed. Highbush blueberry lyophilized extracts contained roughly 5 times more chlorogenic acid than bilberry extracts, while bilberry extract showed higher concentrations of anthocyanins and caffeic acid. Both extracts had highly similar spectroscopic fingerprints. After mid-level data fusion, an optimized PLS-DA model with 75 observations (65 pure extract samples, 10 mixed extract samples) and 7 key variables (first principal components of all analysis) was developed (R²X 0.950, R²Y 0.949, and Q² 0.941). This model allows to correctly classify pure extracts from mixed extracts, but cannot differentiate between different ratios of mixes. Combining fingerprinting information with mid-level data fusion can simplify the model while still accurately representing the key features of phytochemical fingerprints and is worth examining as a tool for the detection of anthocyanin-rich extract adulterations in the future.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107177"},"PeriodicalIF":4.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The thermodynamic pharma challenge: A cross-cutting perspective","authors":"Gabriele Sadowski ,&nbsp;Georgios M. Kontogeorgis ,&nbsp;Fiora Artusio ,&nbsp;Dimitrios I. Gerogiorgis ,&nbsp;Grazia De Angelis ,&nbsp;Antoon ten Kate ,&nbsp;Jean-Charles de Hemptinne","doi":"10.1016/j.ejps.2025.107178","DOIUrl":"10.1016/j.ejps.2025.107178","url":null,"abstract":"<div><div>The development of pharmaceutical products and processes is associated with inherent challenges related to the stability, safety and purity of products for therapeutic applications. Low solubility and bioavailability of newly developed active pharmaceutical ingredients are among the biggest challenges in pharmaceutical development today, as this affects &gt;90 % of newly developed drug molecules. Therefore, thermodynamic research could and should play a crucial role in the modelling and measurement of thermodynamic and kinetic data required for the understanding and design of safe and stable pharmaceutical products as well as their efficient and reliable production. The sixth edition of the IUT Symposium at the ECCE/ECAB 2023 meeting therefore focused on this “Thermodynamic Pharma Challenge”. The aim was to initiate an open discussion between stakeholders from industry and academia to share knowledge and identify bottlenecks that need to be addressed by the thermodynamic community. This manuscript addresses the topics discussed and presented in two sessions of the symposium: the panel discussion and the contributed talks. The symposium emphasized the need for advanced thermodynamic modeling to reduce the experimental effort required to estimate the solubility, stability and dissolution behavior of APIs. This is the most important prerequisite for the development of stable formulations and for increasing the efficiency of pharmaceutical production processes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107178"},"PeriodicalIF":4.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the transformative power of near-infrared spectroscopy in biomedical and pharmaceutical analysis: Trends, advancements, and applications","authors":"Jiri Kos ,&nbsp;Denis Pavelek ,&nbsp;Massoud Kaykhaii ,&nbsp;Mark Olsen ,&nbsp;Josef Jampilek ,&nbsp;Radoslav Halko","doi":"10.1016/j.ejps.2025.107175","DOIUrl":"10.1016/j.ejps.2025.107175","url":null,"abstract":"<div><h3>Background</h3><div>Near-infrared spectroscopy has emerged as a revolutionary tool with transformative potential in the biomedical and pharmaceutical realms.</div></div><div><h3>Area covered</h3><div>This article explores the latest trends and advancements in near-infrared spectroscopy applications within these fields. The work begins with current trends and the development of novel miniaturized spectrometers and continues with the applications of near-infrared spectroscopy with other analytical techniques. Highlighted topics encompass the biomedical utilization of near-infrared spectroscopy, ranging from cancer diagnosis to detection of diseases and wounds. Special emphasis is placed on the role of near-infrared spectroscopy in ensuring medicinal quality and combating counterfeit medications, with insights into its advantages for low-cost systems in developing countries. Finally, the article explores near-infrared spectroscopy's role in analyzing natural medicines and presenting a holistic perspective on its diverse applications.</div></div><div><h3>Expert opinion</h3><div>This work demonstrates how the utilization of near-infrared spectroscopy is transforming both biomedical and pharmaceutical sciences landscapes, paving the way for improved patient safety, therapy effectiveness, and global healthcare initiatives.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107175"},"PeriodicalIF":4.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LPAR4-targeted dual-loaded liposome for synergistic lung cancer therapy","authors":"Simiao Wang ,&nbsp;Hao Jiang ,&nbsp;Jiayi Liu ,&nbsp;Jiayi Chen ,&nbsp;Siyuan Hu ,&nbsp;Yaxin Cui ,&nbsp;Xinhe Wang ,&nbsp;Shaohang Sun ,&nbsp;Jialin Li ,&nbsp;Lesheng Teng ,&nbsp;Jianan Shi ,&nbsp;Wei Liu ,&nbsp;Zhaogang Yang","doi":"10.1016/j.ejps.2025.107176","DOIUrl":"10.1016/j.ejps.2025.107176","url":null,"abstract":"<div><div>Lung cancer continues to be the primary contributor to global cancer deaths, with metastasis posing a major challenge to effective treatment. Although chemotherapy is a primary first-line intervention, its efficacy in preventing tumor dissemination is limited. This study explores a targeted therapeutic strategy by co-delivering doxorubicin (DOX), a potent chemotherapeutic, and ATN161, an integrin α5β1 antagonist, using a liposomal nanocarrier system. Integrin α5β1 is crucial in the advancement and invasion of tumors, leading its suppression a potential strategy for therapeutic approaches. Since lysophosphatidic acid receptor 4 (LPAR4) expression is minimal in normal cells, but transiently increases in tumor-initiating cells (TICs) under stress conditions, we designed LPAR4-targeted liposomes by conjugating anti-LPAR4 antibodies to their surface, enabling both active targeting of lung cancer cells and inhibition of LPAR4-induced tumor metastasis. This targeted delivery system enhances drug accumulation at tumor sites, potentiating cytotoxicity while reducing systemic toxicity. Additionally, ATN161 disrupts fibronectin-integrin interactions, thereby impairing tumor cell adhesion and metastatic progression. Collectively, our study demonstrates that LPAR4-targeted, DOX and ATN161 dual-loaded liposomes offer a promising therapeutic approach for suppressing lung cancer growth and metastasis, with potential clinical implications for improving treatment outcomes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107176"},"PeriodicalIF":4.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explainable artificial neural network as a soft sensor to predict the moisture content in a continuous granulation line","authors":"Petra Záhonyi,&nbsp;Dániel Fekete,&nbsp;Edina Szabó,&nbsp;Zsombor Kristóf Nagy,&nbsp;Brigitta Nagy","doi":"10.1016/j.ejps.2025.107173","DOIUrl":"10.1016/j.ejps.2025.107173","url":null,"abstract":"<div><div>The application of artificial neural networks (ANNs) has the potential to fundamentally change the pharmaceutical industry, making manufacturing more agile, robust, efficient and reliable. Although ANNs’ application as data-driven soft sensors has a particular potential, the black-box nature of most models creates mistrust and prevents their widespread application. Therefore, this study focuses on the development of an explainable ANN used as a soft sensor to monitor an integrated, continuous manufacturing process based on twin-screw granulation. Our goal was to estimate the moisture content, a critical quality attribute of granules only based on the applied process parameters without any direct measurements. Two separate ANNs – a multilayer perceptron (MLP) and a Nonlinear Autoregressive with Exogenous Inputs (NARX) – were built and compared with a near-infrared (NIR) spectra-based method. The validation of the methods – carried out by performing off-line loss-on-drying measurements – revealed that the accuracy of the ANNs and the NIR models was comparable, and the moisture content could be determined with a root mean square error of prediction below 1 % in all cases. Additionally, the explainability of an MLP was also investigated by SHAP analysis, revealing which parameters impacted the prediction and strength of their impact, making the technology transparent and providing valuable insight into the model. This study highlights the potential of ANNs applied as data-driven soft sensors, offering a viable, orthogonal alternative to traditional analytical methods that is cost-efficient and enhances process understanding.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107173"},"PeriodicalIF":4.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving solubility by crystallographic disorder: Enabling Peposertib first-in-human trials","authors":"Michael Lange,&nbsp;Clemens Kühn,&nbsp;Anita Nair,&nbsp;Thomas Fuchß,&nbsp;Christoph Saal","doi":"10.1016/j.ejps.2025.107174","DOIUrl":"10.1016/j.ejps.2025.107174","url":null,"abstract":"<div><div>Peposertib is a small molecule inhibitor of the DNA-dependent protein kinase, currently being evaluated in clinical trials in patients with advanced solid tumours. The active pharmaceutical ingredient (API) exhibits low solubility as a result of the required multi-parameter optimization drug design that in turn necessitated an innovative approach to enable a fast-track first-in -human clinical trial. Peposertib belongs to class II according to the biopharmaceutical classification system (BCS) and class IIb according to the developability classification system (DCS). During polymorphic screening a crystallographically disordered solid-state form (A2D) was discovered which showed significantly increased in vitro performance compared to the thermodynamically stable solid-state form (A2). Disorder occurs along one crystallographic axis and leads to reduced lattice energy and consequently higher solubility. Despite being a metastable morphic form, the solid material of desired form A2D showed very high chemical and physical stability as well as favorable physical properties. These attributes are frequently considerable drawbacks in the case of amorphous materials. A significant challenge when compared to amorphous or highly crystalline phases, which are usually better defined, is the variability in the degree of disorder. This issue was addressed through the development of a process that demonstrated robustness at the manufacturing scale. By employing microstrain analysis, we established a reliable method for material characterization, while thermal analysis further aids in identifying higher crystalline fractions within the disordered bulk material. It allowed fast entry into first-in-human clinical trials with the objective of transitioning to a bio-enabling formulation, which necessitates a more time-consuming development process. To the best of our knowledge, this is the first time a crystallographically disordered phase has not only been discovered but also thoroughly investigated, and consequently utilized to accelerate entry into clinical development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107174"},"PeriodicalIF":4.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence-driven discovery of novel scaffolds for selective TLR7 antagonists and their application in enhancing mRNA translation efficiency","authors":"Soyeon Yoo ,&nbsp;Kounghwa Youn ,&nbsp;Nawoon Kim ,&nbsp;Gyochang Keum ,&nbsp;Hahnbeom Park ,&nbsp;Eun-Kyoung Bang","doi":"10.1016/j.ejps.2025.107172","DOIUrl":"10.1016/j.ejps.2025.107172","url":null,"abstract":"<div><div>Toll-like receptor 7 (TLR7) is crucial in the innate immune response, responsible for recognizing single-stranded RNA from external pathogens and initiating the production of inflammatory cytokines and type I interferons. Despite the potential therapeutic benefits of modulating TLR7 activity, particularly in autoimmune diseases and viral infections, the development of TLR7 antagonists remains limited compared to that of TLR7 agonists. Therefore, this study aims to utilize artificial intelligence to identify novel scaffolds for TLR7 antagonists. Using MotifGen, thousands of potential TLR7-binding compounds were screened, followed by ligand-docking simulations to narrow down the selection to 50 candidates. Of these, 10 compounds with high docking scores for TLR7 and distinct structures were selected. Among them, two promising TLR7 antagonists were identified: 8-Methoxy-<em>N</em>-[(2,4,5,6-tetrahydro-2-methyl-3-cyclopentapyrazol)methyl]-5-quinoline and <em>N</em>-ethyl-2-[(5-fluoro-2,6-dimethyl-4-pyrimidinyl)amino]-<em>N</em>-(phenylmethyl)acetamide. Both compounds exhibited low IC₅₀ values, high selectivity for TLR7 over TLR8 and TLR9, and low cytotoxicity. Additionally, these antagonists showed potential for enhancing mRNA translation efficiency, suggesting their utility in mRNA-based therapeutics. These findings highlight the potential of these novel TLR7 antagonists in treating autoimmune diseases and advancing mRNA therapeutic applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107172"},"PeriodicalIF":4.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144368722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing hepatic clearance prediction across in vitro, ex situ, and in vivo systems to facilitate in vitro-to-in vivo extrapolation","authors":"Hsin-Chung Cheng ,&nbsp;Hsueh-Tien Chen ,&nbsp;Hsin-Ying Chen ,&nbsp;Nai-Hsin Chou ,&nbsp;Hong-Jaan Wang ,&nbsp;Li-Heng Pao ,&nbsp;Sung-Ling Tang","doi":"10.1016/j.ejps.2025.107171","DOIUrl":"10.1016/j.ejps.2025.107171","url":null,"abstract":"<div><h3>Background</h3><div>With rapid pharmaceutical development, hepatic clearance has become crucial for assessing drug metabolism. Rapid and effective estimation of hepatic clearance can be achieved through <em>in vitro</em>-to-<em>in vivo</em> extrapolation (IVIVE) without complicated animal experiments. However, this well-established method frequently leads to significant underestimation, limiting its clinical applicability.</div></div><div><h3>Methods</h3><div>We propose a series of optimizations to address these limitations. Metoprolol was selected as the target drug. <em>In vitro</em> microsomal assays, <em>ex situ</em> isolated perfused rat liver (IPRL) experiments, and <em>in vivo</em> pharmacokinetic studies in rats were performed to systematically investigate the factors that contribute to IVIVE deviation.</div></div><div><h3>Results</h3><div>To rectify the previously overlooked errors in IVIVE, we incorporated the apparent volume of distribution to refine the estimation of the intrinsic hepatic clearance derived from the Michaelis–Menten equation. Additionally, a more cytosolic-like environment was provided for microsome experiments to better simulate <em>in vivo</em> reactions. By integrating the findings from the IPRL experiments and pharmacokinetic studies, we identified the optimal hepatic clearance model from the perspective of liver drug metabolism-driving concentrations. Ultimately, our results indicate that the IVIVE-predicted hepatic clearance increased from the previously underestimated value of 28.1 to <span><math><mo>∼</mo></math></span>70 mL/min/kg, which is closer to the <em>in vivo</em> value of 73.9 mL/min/kg. Moreover, the HEPES-KOH buffer system exhibits superior performance under these conditions.</div></div><div><h3>Conclusions</h3><div>We anticipate that the improved IVIVE method will provide a more comprehensive and accurate framework for predicting hepatic clearance, paving the way for its application in clinical drug dosage adjustments and new drug development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107171"},"PeriodicalIF":4.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rheological and physicochemical optimization of hydrogels as potential vitreous body substitutes for in vitro release testing","authors":"Felix Reichel ,&nbsp;Tobias Auel ,&nbsp;Michael C. Hacker ,&nbsp;Anne Seidlitz","doi":"10.1016/j.ejps.2025.107156","DOIUrl":"10.1016/j.ejps.2025.107156","url":null,"abstract":"<div><div>Due to an aging society and the associated increase in age-related eye diseases of the posterior segment of the eye, an optimized in vitro vitreous model would be beneficial to assess drug release and distribution in preclinical dosage form development. A key component in such a test system is a compartment simulating the vitreous body. Several hydrogels have been proposed for this purpose. In this work the rheological properties of several vitreous body substitutes based on hyaluronic acid, hypromellose, polyacrylamide, gellan gum in combination with hyaluronic acid, and hyaluronic acid in combination with agar were investigated. By systematically comparing these potential in vitro vitreous body substitutes with porcine vitreous bodies within one study employing a series of rheological characterizations, a direct comparison was achieved, allowing opportunities for optimization to be identified. The main characterization focused on the viscosity and loss factor in the linear viscoelastic region and, for the most promising gels, also on the behavior in frequency sweeps. Additionally, the recovery times, pH values, and osmolalities of the gels were determined. Initially, phosphate-buffered saline, which served as the basis for the hydrogels, was successfully adjusted to match the pH and osmolality of porcine and human vitreous bodies. Gels made from gellan gum-hyaluronic acid and hyaluronic acid-agar proved most promising. These could be adjusted in concentrations of 0.034 % gellan gum &amp; 0.264 % hyaluronic acid or 0.22 % hyaluronic acid &amp; 0.09 % agar to match both the viscosity of the vitreous body and the loss factor in the linear viscoelastic region. Additionally, the pH values, osmolalities, and behavior in frequency sweeps of the gels were also comparable to the vitreous body, as these exhibit physicochemical gel formation mechanisms and reversibly linked frameworks probably similar to those of the vitreous body. Under the measurement conditions used here, the gels can therefore be considered as good in vitro vitreous body substitutes. Further diffusion studies, which will likely be influenced by the adjusted rheological properties, should be conducted in the future to further investigate the suitability of the optimized gels presented here.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107156"},"PeriodicalIF":4.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and biological activity of isoperrottetin A and its phosphonium salts derivatives","authors":"Mário Markuliak ,&nbsp;Dominika Kos ,&nbsp;Veronika Vojáčková ,&nbsp;Branislav Horváth ,&nbsp;Emil Švajdlenka ,&nbsp;Janka Leskovská ,&nbsp;Martin Pisárčik ,&nbsp;Vladimír Kryštof ,&nbsp;Alois Čížek ,&nbsp;Josef Jampílek ,&nbsp;Miloš Lukáč","doi":"10.1016/j.ejps.2025.107167","DOIUrl":"10.1016/j.ejps.2025.107167","url":null,"abstract":"<div><div>Bacterial resistance to antibiotics in use represents a critical threat to public health. The treatment of nosocomial, often life-threatening infections is often challenging and requires the search for new antibacterial compounds. In this study a series of phosphonium salts derived from bis(bibenzyl) isoperrottetin A were studied. Bis(bibenzyls) are compounds unique for liverworts. Phosphonium salts were prepared by an eight-step synthesis. The key steps in its preparation were the Ullmann reaction and the Wittig reaction. Ten phosphonium salts were prepared. Isoperrottetin A and its phosphonium salts were tested for antibacterial activity. Some of the compounds exhibit significant biological activity. Most of the prepared derivatives are more potent than the original isoperrottetin A. Compounds were evaluated for the antibacterial activity against selected Gram-positive bacteria such as <em>Staphylococcus aureus</em>, methicillin sensitive and resistant, <em>Enterococcus faecalis</em> and vancomycin sensitive and resistant and Gram-negative bacteria such as <em>Escherichia coli, Pseudomonas aeruginosa</em>, and <em>Klebsiella pneumoniae. Mycobacterium smegmatis</em> and <em>Mycobacterium marinum</em> belonging to the genus <em>Mycobacterium</em> were also tested. Besides antibacterial activity, the compounds inhibit cell breathing and show cytotoxic activity against melanoma cells, retinal and epithelial cells. The results of antibacterial tests showed that the most effective compound is 5,5′,5′',5′''-[1,7(1),4,5(1,3)-tetrabenzenaoctaphane-1³,4⁴,5⁶,8³-tetrayltetrakis(oxy)]tetrakis(5-oxo-<em>P,P,P</em>-triphenylpentane-1-phosphonium) tetrabromide (<strong>4P</strong>). The values of minimum bactericidal concentration (MBC) against <em>S. aureus</em> methicillin sensitive and resistant and <em>E. faecalis</em> vancomycin sensitive and resistant were &lt; 1 µM. At the same time, the compound does not involve damaging the cell wall, as is known for cationic amphiphilic compounds, and showed favorable safety profiles at MBC values. These findings highlight the potential of compounds found in liverworts as active agents against sensitive and resistant bacterial strains. Chemical modification of bis(bibenzyls) with a phosphonium cation is promising in preparation of potent microbicidal compounds.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107167"},"PeriodicalIF":4.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}