European Journal of Pharmaceutical Sciences最新文献

{"title":"Safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of a novel anti-TSLP bispecific antibody (GR2002) in healthy Chinese adults: A randomized, placebo-controlled phase 1 trial","authors":"Rui Ding ,&nbsp;Fan Huang ,&nbsp;Ziyan Ding ,&nbsp;Yanting Li ,&nbsp;Qun Gu ,&nbsp;Fang Men ,&nbsp;Chongyou Lee ,&nbsp;Jiaojiao Zhang ,&nbsp;Wenyan Zhao ,&nbsp;Qian Wang ,&nbsp;Yian Liu ,&nbsp;Shuang Li ,&nbsp;Qingshan Zheng ,&nbsp;Haifeng Song ,&nbsp;Liming Chen ,&nbsp;Wei Wang ,&nbsp;Suping Niu ,&nbsp;Yi Fang","doi":"10.1016/j.ejps.2026.107432","DOIUrl":"10.1016/j.ejps.2026.107432","url":null,"abstract":"<div><h3>Background</h3><div>GR2002 is a novel bispecific antibody targeting dual epitopes on thymic stromal lymphopoietin (TSLP). We aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of GR2002 in healthy Chinese adults.</div></div><div><h3>Methods</h3><div>In this randomized, double-blind, placebo-controlled, dose-escalation, phase 1 trial of GR2002, healthy adults were enrolled and assigned to one of five dose cohorts. Within each cohort, participants were randomized (4:1) to receive a single subcutaneous dose of GR2002 (35, 70, 140, 280, or 420 mg) or placebo and were followed for 85 days. The primary endpoints included safety and tolerability. Secondary endpoints comprised PK, PD, and immunogenicity.</div></div><div><h3>Results</h3><div>Fifty eligible subjects were enrolled and randomized to receive either GR2002 (<em>n</em> = 40) or placebo (<em>n</em> = 10). A total of 92 treatment-emergent adverse events (TEAEs) were reported, with comparable incidence between the GR2002 and placebo groups. TEAEs were generally mild to moderate in severity and did not exhibit dose dependency. The most common treatment-related adverse event was upper respiratory tract infection, occurring in 7/40 (17.5%) participants in the GR2002 group and 2/10 (20%) in the placebo group. GR2002 displayed linear PK across the dose range tested, with a mean half-life ranging from 26.0 to 58.9 days. Dose-dependent reductions in serum TSLP levels from baseline were observed in the 140–420 mg dose groups. Anti-drug antibodies were detected in six subjects (15%) following GR2002 administration.</div></div><div><h3>Conclusions</h3><div>Single-dose subcutaneous administration of GR2002 demonstrated favorable safety and tolerability, linear PK, and low immunogenicity. These findings warrant the subsequent clinical development of GR2002.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107432"},"PeriodicalIF":4.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948433","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":"Assembled fixed-dose combination tablet for hypertension: A modular design inspired by LEGO® architecture","authors":"Tanikan Sangnim ,&nbsp;Kittipat Suwanpitak ,&nbsp;Pornsak Sriamornsak ,&nbsp;Kampanart Huanbutta","doi":"10.1016/j.ejps.2026.107430","DOIUrl":"10.1016/j.ejps.2026.107430","url":null,"abstract":"<div><div>Polypharmacy in chronic diseases like hypertension often compromises patient adherence and therapeutic success due to complex regimens. While conventional fixed-dose combination (FDC) tablets improve adherence, they lack the dose flexibility needed for personalized treatment. This study addresses this gap by developing and characterizing a novel, LEGO®-inspired assemblable FDC tablet system for customizable antihypertensive therapy. Using 3D-printed molds, individual, stackable modules containing either Amlodipine, Valsartan, or Hydrochlorothiazide (HCTZ) were created. The study evaluated two polymer matrices, revealing a critical dependence on the active pharmaceutical ingredient (API). Gelatin-based matrices were effective for Amlodipine and Valsartan, achieving rapid drug with USP dissolution standards; however, this matrix was incompatible release (&gt;90% within 30 min) compliant with HCTZ. Conversely, an HPMC-based matrix successfully formulated HCTZ with a controlled-release profile but was unsuitable for the other two drugs. This work validates the proof-of-concept for a modular FDC system as a promising platform for personalized polypharmacy. However, it also highlights that achieving desired drug release profiles requires careful, API-specific polymer selection, presenting a key formulation challenge for this innovative approach.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107430"},"PeriodicalIF":4.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941418","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":"Corrigendum to “Physiologically-based pharmacokinetic modeling of natalizumab for multiple sclerosis patients to predict the withdrawal time in pregnancy and vaccine time in infants” [European Journal of Pharmaceutical Sciences, 215 (2025), 107301]","authors":"Peilin Zhou ,&nbsp;Chenming Zhong ,&nbsp;Wanhong Wu ,&nbsp;Meng Ke ,&nbsp;Jianwen Xu ,&nbsp;Rongfang Lin ,&nbsp;Pinfang Huang ,&nbsp;Cuihong Lin","doi":"10.1016/j.ejps.2025.107420","DOIUrl":"10.1016/j.ejps.2025.107420","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107420"},"PeriodicalIF":4.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921395","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":"Novel porphyrin photosensitizer LD4-PDT alleviates asthma airway remodeling by inhibiting EGR1-dependent TGF-β1/Smad signaling","authors":"Zhuo Tao ,&nbsp;Hongzhi Yu ,&nbsp;Bin Xu ,&nbsp;Xueming Wang ,&nbsp;Junping Wu ,&nbsp;Ying Wen ,&nbsp;Tianjun Liu","doi":"10.1016/j.ejps.2026.107431","DOIUrl":"10.1016/j.ejps.2026.107431","url":null,"abstract":"<div><div>Asthma, a common chronic inflammatory airway disease, affects 300 million people globally. Pathologically, it features Th2/Th17-driven airway inflammation and remodeling, which worsens disease and impairs lung function. Current therapies alleviate symptoms but cannot prevent irreversible airway structural changes, highlighting the need for targeted treatments. The TGF-β1/Smad axis is pivotal for epithelial‒mesenchymal transition (EMT) and airway fibrosis‒key features of asthmatic remodeling. This study aimed to explore the interaction between the TGF-β1/Smad pathway and EGR1 and evaluate the effect of LD4-based photodynamic therapy (LD4-PDT) as a potential anti-inflammatory agent on asthma by evaluating inflammatory cell infiltration, nitrosative and oxidative stress markers, and EMT-related substances in a rat model of asthma. Primarily, we evaluated the efficacy of LD4-PDT in ovalbumin (OVA)-induced asthmatic rats. Assessments included pulmonary function (FVC, MMF), airway histopathology, oxidative stress markers, and EMT-related proteins (TGF-β1, Smad, MMP-9). Transcriptomics identified key targets, molecular docking verified binding, and TGF-β1-stimulated BEAS-2B/16HBE cells validated mechanisms in vitro. LD4-PDT exerted dose-dependent effects: improved lung function (increased FVC/MMF), reduced inflammation (lower IgE/TNF-α), and attenuated remodeling (decreased collagen deposition and PAS+ cells). Mechanistically, it suppressed EMT by inhibiting EGR1-dependent TGF-β1/Smad signaling and modulating arachidonic acid metabolism. Transcriptomics confirmed EGR1 as a critical mediator, and molecular docking showed strong LD4-EGR1 binding—providing a molecular basis for LD4-PDT’s effects. LD4-PDT effectively targets EGR1-driven EMT, inflammation, and metabolic dysregulation, emerging as a novel therapeutic strategy for asthma.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107431"},"PeriodicalIF":4.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941419","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":"Development and in vitro/in vivo evaluation of polymeric dissolving microneedle formulation for psoriasis treatment","authors":"Meryem Kaplan ,&nbsp;Fatma Betül Arslan ,&nbsp;Süleyman Can Öztürk ,&nbsp;Sıla Ulutürk ,&nbsp;Çisel Aydın Meriçöz ,&nbsp;Güneş Esendağlı ,&nbsp;Sema Çalış ,&nbsp;Kıvılcım Öztürk","doi":"10.1016/j.ejps.2026.107429","DOIUrl":"10.1016/j.ejps.2026.107429","url":null,"abstract":"<div><div>Psoriasis is an inflammatory autoimmune skin disease that significantly impacts quality of life. The chronic and recurrent nature of the disease can last a lifetime. Current conventional treatment options have several drawbacks, including inadequate or short-lived efficacy, issues with tolerability and adherence, practical limitations associated with topical applications and phototherapy, and significant safety and cost concerns related to systemic treatments. Generally, symptomatic treatments are applied, but complete recovery is rarely achieved. Researchers are exploring alternative treatment approaches, such as biologically based therapies. These therapies specifically target the immune mechanisms involved in psoriasis and offer advantages such as more reliable disease control, noticeable improvements in patients’ quality of life, and a more favorable safety profile compared to conventional treatments. One innovative approach being investigated for the treatment of psoriasis is the use of microneedles as a transdermal drug delivery strategy, which has shown promising results in research. In this study, a biocompatible polymeric dissolving microneedle formulation composed of hyaluronic acid and sucrose was prepared using micro-molding. Microneedles were loaded with secukinumab (a human monoclonal antibody specific to IL-17A) and Stattic (a STAT3 inhibitor) for a combined treatment approach. It was expected that applying the microneedles directly to the psoriasis plaques would increase the localized drug concentration. Following <em>in vitro</em> characterization and cell culture studies, a psoriasis model was established in adult mice. The therapeutic effects of the microneedles containing secukinumab and Stattic (both individually and simultaneously loaded) were compared to control groups. Lesion progression was visually monitored and histologically examined following treatment. The results indicated that the secukinumab-loaded microneedles provided a more effective treatment at lower doses.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107429"},"PeriodicalIF":4.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932971","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":"Design and evaluation of dual-functional aptamer-peptide conjugates as a platform for targeted cancer therapy","authors":"Simona Marzano ,&nbsp;Maria Grazia Ferraro ,&nbsp;Nicola Grasso ,&nbsp;Rossella Buono ,&nbsp;Valentina Arciuolo ,&nbsp;Federica Iazzetti ,&nbsp;Marialuisa Piccolo ,&nbsp;Assunta Passarelli ,&nbsp;Federica D’Aria ,&nbsp;Francesco Merlino ,&nbsp;Paolo Grieco ,&nbsp;Antonio Randazzo ,&nbsp;Bruno Pagano ,&nbsp;Carlo Irace ,&nbsp;Jussara Amato","doi":"10.1016/j.ejps.2026.107428","DOIUrl":"10.1016/j.ejps.2026.107428","url":null,"abstract":"<div><div>AS1411 is a G-rich DNA aptamer that exhibits intrinsic antitumor activity through selective binding to nucleolin, a protein overexpressed in many cancers. Beyond its cytotoxic effects, AS1411 can also serve as an effective targeting ligand for the delivery of therapeutics with poor cellular uptake, including peptide-based drugs. One such candidate is the pro-apoptotic peptide KLA, which selectively disrupts mitochondrial membranes and induces apoptosis upon internalization. In this study, AS1411-KLA conjugates were designed and synthesized using strain-promoted azide-alkyne cycloaddition chemistry, incorporating protease-cleavable peptide linkers to enable intracellular release of both the aptamer and peptide as independent active units. Circular dichroism analysis showed that, in all constructs, the AS1411 domain preserved the characteristic G-quadruplex structural features, while surface plasmon resonance experiments revealed that all conjugates retained nucleolin binding. The biological activity of the conjugates was evaluated in MCF-7 breast cancer cells and in non-tumorigenic MCF-10A cells, and compared with that of the individual aptamer and peptide. One conjugate displayed an enhanced antiproliferative effect compared to the unconjugated components, underscoring the therapeutic potential of this modular design. Overall, this work demonstrates the potential of aptamer-peptide conjugates as a promising strategy for next-generation targeted cancer therapeutics, combining targeted delivery with synergistic therapeutic effects.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107428"},"PeriodicalIF":4.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932985","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":"Deconvoluting the in vitro to in vivo drug clearance gap: Questioning the predictive performance of traditional hepatic clearance models","authors":"Sofie Heylen ,&nbsp;Johan Nicolaï ,&nbsp;Stijn Van Asten ,&nbsp;Katie De Wagter ,&nbsp;Andrea Treyer ,&nbsp;Jan Snoeys ,&nbsp;Raymond Evers ,&nbsp;Stephanie Kourula ,&nbsp;Pieter Annaert","doi":"10.1016/j.ejps.2026.107427","DOIUrl":"10.1016/j.ejps.2026.107427","url":null,"abstract":"<div><div><em>In vitro</em> to <em>in vivo</em> extrapolation (IVIVE) methods for hepatic clearance (CL_H) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM). The <em>ex vivo</em> isolated perfused rat liver (IPRL) model bridges <em>in vitro</em> and <em>in vivo</em> data, providing mechanistic insights into the predictive accuracy of IVIVE models. This study evaluates the IPRL model across a diverse selection of 16 compounds, and benchmarks results against <em>in vitro</em> and <em>in vivo</em> data to verify the predictive performance of the WSM and PTM. Results demonstrate that both the IPRL and <em>in vivo</em> clearance conflict with assumptions of the WSM (AAFE = 2.85) or PTM (AAFE = 1.74), which consider the liver outlet concentration as a driver for the hepatic elimination rate. However, except for terfenadine, IPRL clearance predictions were within two-fold (AAFE = 1.59) of <em>in vivo</em> clearance when the liver inlet concentration was utilized to calculate the CL_H. When employing the WSM or PTM for <em>in vitro</em> to <em>ex vivo</em> extrapolation, underpredictions were observed for compounds with high plasma protein binding and subject to sinusoidal hepatic uptake, reflecting model oversimplification compared to <em>in vivo</em> dynamics. Our findings experimentally challenge the theoretical assumptions underlying the use of the WSM and PTM in IVIVE methods. Unique insights from the IPRL model point to the next steps needed to advance IVIVE: refining current liver disposition models through enhanced and next-generation <em>in vitro</em> assays, capturing dynamic <em>in vivo</em> disposition mechanisms, and exploring complementary models.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107427"},"PeriodicalIF":4.7,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899620","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":"Impact of cocrystal dissolution-supersaturation-precipitation (DSP) behaviour on drug permeation across the PermeaPad® biomimetic barrier","authors":"Lucy May Newman ,&nbsp;Matteo Guidetti ,&nbsp;Annette Bauer-Brandl ,&nbsp;Naír Rodríguez-Hornedo ,&nbsp;Tatiane Cogo Machado","doi":"10.1016/j.ejps.2025.107426","DOIUrl":"10.1016/j.ejps.2025.107426","url":null,"abstract":"<div><div>The purpose of this study was to evaluate how the dissolution-supersaturation-precipitation (DSP) behaviour of cocrystals translates into drug permeation<strong>,</strong> employing the biomimetic PermeaPad® barrier in a side-by-side cell set-up. Building on our previous work, which demonstrated that reducing an unnecessarily high cocrystal solubility advantage (SA = S_cocrystal/S_drug) through the generation of non-stoichiometric solution conditions can significantly extend the drug supersaturation, we now investigate this approach in the presence of an absorptive environment. Our findings with the 1:1 ketoconazole (KTZ) -<em>p</em>-aminobenzoic acid (PABA) cocrystal indicate the existence of an optimal SA value (7), where KTZ-PABA dissolution performance resulted in 8-fold AUC increase, translating to a 7-fold increase in cumulative KTZ permeation after 6 h. This enhancement was achieved by dissolving cocrystal (based on the drug therapeutic dose) with an additional coformer solid phase, rationally designed using a graphical approach grounded in the cocrystal thermodynamic (K_sp, S_cocrystal, S_drug) and kinetic parameters (σ_crit). The strategy presented in this work can be readily applied during the pre-formulation stage of cocrystal development, enabling targeted selection of coformer concentrations for formulation development. Overall cocrystals offer unique flexibility as a formulation strategy for poorly water-soluble drugs, allowing for tailored DSP behaviour and drug transport over biological barriers based on mechanistic understanding<strong>,</strong> as demonstrated in this study.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107426"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896350","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":"Structurally Similar, Functionally Different: Impact of Coformer Positional Isomerism on Co-Amorphous Enzalutamide.","authors":"Venkata Krishna Rao Balaga, Argyro Chatziadi, Luděk Ridvan, Miroslav Šoóš","doi":"10.1016/j.ejps.2025.107425","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107425","url":null,"abstract":"<p><p>Coamorphization is an attractive approach to modifying the physicochemical properties of drug molecules, especially the solubility, dissolution, and associated bioavailability. Although these formulations may be advantageous, they exhibit poor physical stability and undergo recrystallisation. To address this limitation, this study investigates the effect of positional isomerism on the coamorphous formation and associated physicochemical properties, to select an optimum solid form with improved stability. Enzalutamide (ENZ), a BCS class II drug, was used as a model compound. Four positional isomers including 2,3-, 2,4-, 2,5- and 2,6-dihydroxybenzoic acid (DHB) were used as coamorphous coformers. Coamorphous formulations were prepared by ball mill in a 2:1 molecular ratio (API:coformer). The solid-state properties of the prepared coamorphous forms were characterised using X-ray powder diffractometer (XRPD), modulated differential scanning calorimetry (mDSC), and Fourier transformed infrared spectrometry (FTIR). Additionally, intra isomer variability in the amorphization kinetics and dissolution enhancement of ENZ, along with physical stability, were evaluated. All coformers formed coamorphous systems, as confirmed by XRPD. mDSC data showed that the glass transition temperature (Tg) varied among the prepared coamorphous forms and was lower than that of pure ENZ. Although there was no significant difference in the dissolution behaviour, the physical stability data reveal a contrast trend. Among the prepared coamorphous forms, ENZ-24DHB^CAM exhibited superior stability, while ENZ-26DHB^CAM exhibited poor stability. This article summarises the similarities and differences between the physicochemical properties of coamorphous forms of Enz because of the change in coformer positional isomerism. Stability studies under different humidity conditions revealed significant differences: at 40% RH, all coamorphous forms remained stable for up to 8 weeks, with minor deviations for ENZ-23DHB^CAM and ENZ-25DHB^CAM. Under 75% RH, the stability varied markedly; ENZ-24DHB^CAM maintained stability for at least 8 weeks, while ENZ-26DHB^CAM became unstable within 1-2 weeks, and ENZ-AMP and ENZ-23DHB^CAM lost stability by week 6. These results demonstrate the careful selection of coformer positional isomer can quantitatively enhance the stability of coamorphous forms, highlighting the importance of positional isomerism associated chemical design space in optimizing solid-state properties.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107425"},"PeriodicalIF":4.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892224","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":"Febuxostat analogs as anti-quorum sensing and antibacterial agents","authors":"Praveen Kumar Singh ,&nbsp;Matej Zore ,&nbsp;Paola San-Martin-Galindo ,&nbsp;Moritz M. Kornmayer ,&nbsp;Inés Reigada ,&nbsp;Leena Hanski ,&nbsp;Kirsi Savijoki ,&nbsp;Jari Yli-Kauhaluoma ,&nbsp;Jayendra Z. Patel","doi":"10.1016/j.ejps.2025.107424","DOIUrl":"10.1016/j.ejps.2025.107424","url":null,"abstract":"<div><div>Febuxostat, a marketed anti-gout drug, has been reported to inhibit quorum sensing (QS), biofilm formation, and virulence in Gram-negative bacteria <em>Pseudomonas aeruginos</em>a PAO1 and <em>Chromobacterium violaceum</em> CV026. However, no structure-activity relationship (SAR) studies have been reported to date. To address this gap, we synthesized 27 novel febuxostat analogs and evaluated their QS inhibitory activity using wild-type <em>C. violaceum</em> and the mutant strain CV026. This dual-strain assay enabled differentiation between quorum sensing inhibition and quorum quenching mechanisms, allowing determination of whether QS interference occurred at the level of signal synthesis or signal reception.</div><div>Here, we demonstrated that febuxostat acts as a quorum quencher at concentrations lower than previously reported, strongly inhibiting violacein production in CV026 without affecting bacterial viability. At 400 µM, several analogs showed comparable or stronger activity than febuxostat in one or both strains. At 40 µM, trifluoromethoxyphenyl analog <strong>49</strong> emerged as the most effective QS inhibitor in the wild-type strain, whereas cyclopentyl analog <strong>24</strong> was most active in CV026, with a few other derivatives also retaining notable activity. We also assessed whether febuxostat and its analogs exhibit antibacterial activity. While febuxostat showed no antibacterial activity, seven analogs (<strong>26</strong>–<strong>30, 33</strong>, and <strong>49</strong>) exhibited minimum inhibitory concentrations (MICs) ranging from 2.5 to 40 µM against Gram-positive bacteria <em>Staphylococcus aureus, S. epidermidis, Enterococcus faecalis</em>, and <em>E. faecium</em>. On the other hand, no activity was observed against Gram-negative bacteria. In follow-up studies, the two most potent antibacterial compounds <strong>29</strong> (MIC = 5 µM) and <strong>30</strong> (MIC = 10 µM), showed no cytotoxicity against the mammalian cell line A549, while they were less tolerated by THP-1 cells. In summary, our results provide SAR insights into febuxostat analogs and highlight their potential as novel anti-QS and antibacterial agents against multidrug-resistant bacteria.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107424"},"PeriodicalIF":4.7,"publicationDate":"2025-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862528","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}