Frontiers in Chemistry最新文献

{"title":"Comprehensive and robust stability-indicating reversed phase high performance liquid chromatography (RP-HPLC) method for Rivaroxaban: synergistic integration of infrared spectroscopy and clinical pharmacology insights.","authors":"Aktham Mestareehi","doi":"10.3389/fchem.2025.1551189","DOIUrl":"https://doi.org/10.3389/fchem.2025.1551189","url":null,"abstract":"<p><strong>Introduction: </strong>Rivaroxaban is an anticoagulant medication that targets a key stage in the blood clotting process, preventing the formation and growth of clots. It is commonly used to prevent thrombosis or inhibit the enlargement of existing clots. Rivaroxaban functions as a Factor Xa inhibitor and is indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treating deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as reducing the risk of recurrent DVT and PE, and prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.</p><p><strong>Methods: </strong>A robust, precise, and selective reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for analyzing Rivaroxaban in raw materials. Isocratic elution at a flow rate of 1 mL/min was performed using a Thermo ODS Hypersil C18 column (4.6 × 250 mm, 5 µm) at ambient temperature. The mobile phase consisted of monobasic potassium phosphate at pH 2.9 and acetonitrile in a 70:30 (v/v) ratio, with UV detection at 249 nm.</p><p><strong>Results: </strong>Linearity was established in the concentration range of 50-1,000 ppm (R² = 0.999), and the retention time for Rivaroxaban was approximately 12 min. The percentage relative standard deviation (RSD) for precision and accuracy was consistently below 2.0%, ensuring method reliability. Solution stability studies confirmed the stability of Rivaroxaban over the analysis period, as no peak loss, degradation, or additional peaks were observed between the first and last injections. Furthermore, forced degradation studies were conducted under various stress conditions, including acid and base hydrolysis, as well as hydrogen peroxide oxidation. The method successfully resolved Rivaroxaban from its degradation products, demonstrating its stability-indicating capability.</p><p><strong>Conclusion: </strong>Rivaroxaban is a novel oral anticoagulant that selectively and directly inhibits factor <i>Xa</i>. A method has been developed and validated for its analysis, adhering to guidelines from the International Conference on Harmonisation (ICH) and the U.S. Pharmacopeia (USP). The validation process assessed parameters such as specificity, robustness, linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ). The LOD for impurities and degradants was determined to be 0.3 ppm, while the LOQ was 1 ppm. This stability-indicating method is highly suitable for routine quality control and analytical applications in both raw materials and finished drug products, owing to its simplicity, efficiency, and robustness.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1551189"},"PeriodicalIF":3.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The quinoline framework and related scaffolds in natural products with anti-<i>Leishmania</i> properties.","authors":"Gloria Yaluff, Leídi Herrera, Miriam Soledad Rolón, Celeste Vega, Hugo Cerecetto","doi":"10.3389/fchem.2025.1571067","DOIUrl":"https://doi.org/10.3389/fchem.2025.1571067","url":null,"abstract":"<p><p>For almost one hundred years, the quinoline heterocycle has been recognized as a privileged pharmacophore in anti-<i>Leishmania</i> agents. Early on, the action of compounds with this scaffold, found in some natural alkaloids, was tested against different <i>Leishmania</i> stages and strains. Different structural arrangements containing the quinoline framework have been described in different <i>in vitro</i> and <i>in vivo</i> anti-<i>Leishmania</i> alkaloids, namely, quinoline proper, isoquinoline, and quinolone, among others. In recent years, new quinoline derivatives isolated from nature have been described, in addition to having carried out in-depth <i>in vitro</i> and <i>in vivo</i> biological studies, as well as chemical modifications to obtain new leaders. This review updates the state of the art on naturally occurring quinolines and some synthetic derivatives to provide therapeutic tools and strategies to explore new drugs based on this chemosystem for the treatment of leishmaniasis.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1571067"},"PeriodicalIF":3.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of alkali metal cations on dehydrogenative coupling of formate anions to oxalate.","authors":"Atsushi Tahara, Aska Mori, Jun-Ichiro Hayashi, Shinji Kudo","doi":"10.3389/fchem.2025.1588773","DOIUrl":"https://doi.org/10.3389/fchem.2025.1588773","url":null,"abstract":"<p><strong>Introduction: </strong>With the growing global concern over CO₂ emissions, reducing CO₂ output has become an urgent requirement. The iron production industry is among those with the highest CO₂ emissions, primarily due to the use of coke as a reductant and the use of a heat source at approximately 2,000°C. To address this issue, various alternative reductants, including CO, H₂, and lignite, have been explored. Building on these efforts, we recently reported a novel ironmaking system using oxalic acid (HOOC-COOH) as the reductant. Formate salts, hydrogenated forms of CO₂, are promising precursors for oxalate salts; however, their behavior during dimerization remains poorly understood. Herein, we investigate the influence of group 1 and 2 metal cations on the base-promoted dehydrogenative coupling of formate to form oxalate.</p><p><strong>Methods: </strong>First, dehydrogenative coupling of sodium formate was executed by using various types of groups 1 and 2 metal carbonates. Second, the base was replaced from metal carbonates to metal hydroxides to check the reactivity. Finally, a countercation of sodium formate was replaced to various types of groups 1 and 2 metals. To elucidate the reaction mechanism, DFT calculation was executed.</p><p><strong>Results and discussion: </strong>Treatment of sodium formate with various bases (group 1 and 2 metal carbonates or hydroxides) revealed that group 1 metal hydroxides are more effective than metal carbonates for oxalate formation, with cesium hydroxide (CsOH) exhibiting high reactivity. Density functional theory (DFT) calculations suggest that this kinetic advantage arises not only from increased basicity but also from intermediate destabilization in the Na/Cs mixed-cation system. Additionally, both experimental and theoretical investigations reveal that oxalate yield is influenced by the thermodynamic stability of intermediates and products (oxalate salts), highlighting the crucial role of cations in the reaction.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1588773"},"PeriodicalIF":3.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12055785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LaF₃ doped with Ce/Gd/Eu: energy transfer and excitation dependence of photoluminescence rise-and-decay kinetics.","authors":"Andrii Shyichuk, Daria Szeremeta, Marcin Runowski, Eugeniusz Zych, Stefan Lis","doi":"10.3389/fchem.2025.1501039","DOIUrl":"https://doi.org/10.3389/fchem.2025.1501039","url":null,"abstract":"<p><p>In this paper, we analyze time-domain luminescence measurements using multiexponential rise-and-decay functions. The relationships between these functions and the physics behind the analyzed photoemission kinetics are shown using several basic arbitrary photoluminescence systems. The advantages and disadvantages of the different types of functions mentioned are discussed. The paper is focused on peculiarities of the fitting process, such as the role of initial guess, under- and overfitting problems, and estimating fit quality (using patterns in the fit residual). Systems of differential equations are used to analyze selected cases by adjusting certain parameters. Hydrothermally treated LaF₃:Ln³⁺ nanoparticles (where Ln³⁺ = Gd³⁺; Gd³⁺,Ce³⁺; Eu³⁺; Ce³⁺,Eu³⁺; Gd³⁺,Eu³⁺; or Ce³⁺,Gd³⁺,Eu³⁺) were used as a test case in which the role of interionic charge transfer was investigated by direct experimental measurements only, without the underlying theory. The methodological tips contained in this paper, although applied to the lanthanide (III) luminescence, should be interesting and useful for a much broader audience, for everyone working with smooth rise-and-decay curves.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1501039"},"PeriodicalIF":3.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicity mechanism analysis of cGAS-STING-TBK1 signaling pathway small molecule modulator based on network toxicology and molecular docking strategy: quinacrine acetate as an example.","authors":"Jinchao Zhu, Qingyuan Lin, Honglin Zhu, Siqi Xie, Shengdong Nie","doi":"10.3389/fchem.2025.1584588","DOIUrl":"https://doi.org/10.3389/fchem.2025.1584588","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to investigate the toxicity characteristics and mechanisms of quinacrine acetate, a small molecule modulator of the cGAS-STING-TBK1 signaling pathway, and to establish and validate the application value of network toxicology analysis strategy.</p><p><strong>Methods: </strong>ProTox and ADMETlab platforms were used to evaluate the toxic effects of quinacrine acetate on human tissues and organs. Potential targets associated with quinacrine acetate toxicity were identified through ChEMBL, STITCH, GeneCards, OMIM, and TD databases. GO and KEGG analyses were employed to elucidate related functions and molecular mechanisms. STRING and Cytoscape software were utilized to identify key hub genes, while molecular docking validation was performed using the CB-Dock2 database. Based on toxicity analysis results, COPD was selected as a disease model, and GEO database was used to analyze the expression characteristics, immune correlation, and drug target value of hub genes in COPD.</p><p><strong>Results: </strong>ProTox and ADMETlab analyses revealed that quinacrine acetate exhibited significant toxicity to the respiratory system (toxicity level 4, risk coefficient 0.959). Through integrated multi-database analysis, 14 potential targets related to quinacrine acetate-induced respiratory system toxicity were identified. GO and KEGG pathway analyses indicated that quinacrine acetate-induced respiratory toxicity was primarily mediated through metabolic pathways. Network analysis via STRING and Cytoscape identified AKT1, PLA2G4A, and ALOX5 as three core targets. Molecular docking results confirmed strong binding affinity between quinacrine acetate and these core targets. In COPD patients, PLA2G4A and ALOX5 showed significantly upregulated expression, with hub gene ROC curve AUC value reaching 0.829, demonstrating good diagnostic value. Further immune correlation analysis revealed that ALOX5 and PLA2G4A were closely associated with various immune cell expressions and served as targets for multiple drugs including histamine, melittin, and formic acid.</p><p><strong>Conclusion: </strong>This study demonstrates that quinacrine acetate may influence the progression and risk of respiratory system diseases by regulating metabolic pathways. The findings provide not only a theoretical foundation for understanding the molecular mechanisms of quinacrine acetate-induced respiratory toxicity but also new perspectives and methodological references for evaluating the toxic effects of small molecule compounds in respiratory diseases. Therefore, we demonstrates the practical application value of network toxicology as an efficient predictive tool for identifying potential toxicity targets and pathways, which can guide subsequent experimental validation and provide mechanistic insights that traditional toxicology approaches might miss.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1584588"},"PeriodicalIF":3.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In situ</i> monitoring of ligand-to-metal energy transfer in combination with synchrotron-based X-ray diffraction methods to elucidate the synthesis mechanism and structural evolution of lanthanide complexes.","authors":"Ban H Al-Tayyem, Philipp Müscher-Polzin, Kanupriya Pande, Oleksandr Yefanov, Valerio Mariani, Anja Burkhardt, Henry N Chapman, Christian Näther, Michael Braun, Marvin Radke, Steve Waitschat, Kenneth R Beyerlein, Huayna Terraschke","doi":"10.3389/fchem.2025.1536383","DOIUrl":"https://doi.org/10.3389/fchem.2025.1536383","url":null,"abstract":"<p><p>Despite wide application of lanthanide complexes in solar cells, light-emitting diodes and sensors, their crystallization mechanisms have not been studied in detail. Further investigations of this kind can lead to the development of targeted synthesis protocols and tailoring of their structure-related physical properties. In this work, the structural evolution during the synthesis of the luminescent [Tb (bipy)₂(NO₃)₃] (bipy = 2,2'-bipyridine) complex is studied by monitoring the ligand-to-metal energy transfer through <i>in situ</i> luminescence measurements combined with synchrotron-based X-ray diffraction (XRD) analysis. These experiments reveal an interesting crystallization pathway involving the formation of a reaction intermediate that is dependent on parameters such as ligand-to-metal molar ratios. In addition, the structure of [Tb (bipy)₂(NO₃)₃] is solved from serial crystallography data collected at a microfocused synchrotron X-ray beamline. This is an emerging technique that can be used to interrogate individual crystallites and overcome beam damage effects. The resulting structure is found to correspond to that determined by classical single crystal XRD, and a perspective on realizing future <i>in situ</i> measurements of this type is given. This work therefore describes multiple advancements combining crystallite-specific diffraction probes and <i>in situ</i> techniques to track the synthesis kinetics of luminescent materials.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1536383"},"PeriodicalIF":3.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green biosynthesis of titanium dioxide nanoparticles incorporated gellan gum hydrogel for biomedical application as wound dressing.","authors":"Yongtao Su, Xianwei Zhu, Guangqi Xu, Zhongzheng Guan, Wei Jiao, Zhixin Zhang, Yifei Sun, Chunlei Wang, Rong Zhang, Qianqian Luo, Ying Sui, Mahani Yusoff, Mohd Hasmizam Razali","doi":"10.3389/fchem.2025.1560213","DOIUrl":"https://doi.org/10.3389/fchem.2025.1560213","url":null,"abstract":"<p><p>Titanium dioxide nanoparticles (TiO₂NPs) are widely synthesized chemically for industrial applications. However, these methods often have negative environmental impacts, rendering them unsuitable for biomedical applications. Green synthesis approaches offer a promising alternative due to their simplicity, environmental friendliness, and cost-effectiveness. In this study, we report the biosynthesis of TiO₂NPs using Morus alba leaf extract and their subsequent incorporation into a gellan gum (GG) biopolymer to create a hydrogel. The physicochemical properties of the biosynthesized TiO₂NPs and the TiO₂NP@GG hydrogel were characterized using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). Furthermore, the bioactivity of the materials was investigated through antibacterial assays against <i>Staphylococcus aureus</i> and <i>Escherichia coli</i>, as well as <i>in vitro</i> wound healing studies using a 3T3 fibroblast scratch assay. XRD analysis confirmed the successful formation of anatase phase TiO₂. SEM images revealed the presence of irregular and rod-shaped TiO₂ nanoparticles, with EDS analysis confirming their composition of oxygen and titanium. The particle size was determined to be 80-90 nm, and the nanoparticles exhibited homogeneous distribution throughout the gellan gum biopolymer network. The TiO₂NP@GG hydrogel displayed significant antibacterial activity against both <i>S. aureus</i> and <i>E. coli</i>. <i>In vitro</i> wound healing studies using a scratch assay on 3T3 fibroblast cells seeded onto the hydrogel demonstrated a high cell survival rate and enhanced cell migration, suggesting potential for biomedical applications as a wound dressing material.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1560213"},"PeriodicalIF":3.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective and realistic sequestration of Sr²⁺ and B³⁺ ions from the aqueous environments using coral reefs based Ca-MCM-41: Gulf of Suez as case study.","authors":"Alshaima Sayed, Ahmed M El-Sherbeeny, Gouda Ismail Abdel-Gawad, Essam A Mohamed, Wail Al Zoubi, Mostafa R Abukhadra","doi":"10.3389/fchem.2025.1550726","DOIUrl":"https://doi.org/10.3389/fchem.2025.1550726","url":null,"abstract":"<p><p>A mesoporous calcium-bearing siliceous framework (Ca-MCM-41) was synthesized using natural coral reef carbonate rocks as precursors. The structural characterization, confirmed through XRD, SEM, FT-IR, and BET analyses, validated the formation of the MCM-41 framework with well-defined mesoporous properties and a high surface area of 159.6 m²/g. The developed Ca-MCM-41 was evaluated as a potential adsorbent for the removal of Sr²⁺ and B³⁺ ions from both aqueous solutions and real seawater samples collected from the Gulf of Suez, Egypt. The adsorption capacity at saturation reached 285.9 mg/g for Sr²⁺ and 86.1 mg/g for B³⁺, demonstrating the framework's high affinity for these contaminants. The adsorption mechanisms were elucidated using steric and energetic parameters, as derived from statistical physics-based isotherm models. The Ca-MCM-41 framework exhibited a higher active site density (148.9 mg/g) for Sr²⁺ compared to B³⁺ (54.8 mg/g), explaining its superior sequestration performance for strontium ions. Each receptor site was capable of accommodating up to three Sr²⁺ ions and 2 B³⁺ ions, indicating a multi-ionic interaction process and preferential vertical alignment during adsorption. Energetic analysis revealed that the sequestration process occurred via physical adsorption with interaction energies below 7 kJ/mol, alongside exothermic and spontaneous behavior, as evidenced by calculated internal energy, entropy, and enthalpy values. The developed Ca-MCM-41 structure demonstrated notable efficiency in real seawater applications, achieving sequestration percentages of 80% for Sr²⁺ and 64% for B³⁺, considering their average concentrations (24.2 mg/L for Sr²⁺ and 12.85 mg/L for B³⁺) in a 1-L volume. These findings highlight the high potential of Ca-MCM-41 as an effective and sustainable adsorbent for Sr²⁺ and B³⁺ removal in environmental water treatment applications.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1550726"},"PeriodicalIF":3.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational identification of potential natural terpenoid inhibitors of MDM2 for breast cancer therapy: molecular docking, molecular dynamics simulation, and ADMET analysis.","authors":"Eva Azme, Md Mahmudul Hasan, Md Liakot Ali, Rashedul Alam, Neamul Hoque, Fabiha Noushin, Mohammed Fazlul Kabir, Ashraful Islam, Tanzina Sharmin Nipun, S M Moazzem Hossen, Hea-Jong Chung","doi":"10.3389/fchem.2025.1527008","DOIUrl":"https://doi.org/10.3389/fchem.2025.1527008","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) remains a leading cause of cancer-related mortality in women. The oncoprotein MDM2 negatively regulates the tumor suppressor p53, and its overexpression in BC promotes tumor progression and resistance to therapy. Targeting the MDM2-p53 interaction represents a promising therapeutic approach. However, many existing MDM2 inhibitors suffer from poor pharmacokinetics and off-target toxicity, necessitating the discovery of novel, more selective alternatives. This study aims to identify natural terpenoid compounds with potent MDM2 inhibitory potential through computational approaches.</p><p><strong>Methods: </strong>A library of 398 natural terpenoids was sourced from the NPACT database and filtered based on Lipinski's Rule of Five. A two-stage docking strategy was applied: 1) rigid protein-flexible ligand docking to screen for high-affinity binders, followed by 2) ensemble docking using multiple MDM2 conformations derived from molecular dynamics (MD) simulations. The top candidates were further evaluated for their pharmacokinetic and toxicity profiles using ADMET analysis. Finally, 150 ns MD simulations and binding free energy (MM-PBSA) calculations were performed to assess the stability and strength of protein-ligand interactions.</p><p><strong>Results: </strong>Three terpenoid compounds, olean-12-en-3-beta-ol, cabralealactone, and 27-deoxyactein demonstrated strong binding affinities toward MDM2 in ensemble docking studies. ADMET analysis confirmed their favorable pharmacokinetic properties. Further MD simulations indicated that these compounds formed highly stable complexes with MDM2. Notably, 27-deoxyactein exhibited the lowest binding free energy (-154.514 kJ/mol), outperforming the reference inhibitor Nutlin-3a (-133.531 kJ/mol), suggesting superior binding stability and interaction strength.</p><p><strong>Conclusion: </strong>Our findings highlight 27-deoxyactein as a promising MDM2 inhibitor with strong binding affinity, stability, and a favorable pharmacokinetic profile. This study provides a computational foundation for further experimental validation, supporting the potential of terpenoid-based MDM2 inhibitors in BC therapy.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1527008"},"PeriodicalIF":3.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, <i>in silico</i> studies, and apoptotic antiproliferative activity of novel thiazole-2-acetamide derivatives as tubulin polymerization inhibitors.","authors":"Lamya H Al-Wahaibi, Ali M Elshamsy, Taha F S Ali, Bahaa G M Youssif, Stefan Bräse, Mohamed Abdel-Aziz, Nawal A El-Koussi","doi":"10.3389/fchem.2025.1565699","DOIUrl":"https://doi.org/10.3389/fchem.2025.1565699","url":null,"abstract":"<p><strong>Introduction: </strong>Tubulin polymerization inhibitors have emerged as interesting anticancer therapies. We present the design, synthesis, and structural elucidation of novel thiazole-based derivatives to identify novel tubulin inhibitors with potent antiproliferative efficacy and strong inhibition of tubulin polymerization.</p><p><strong>Methods: </strong>The novel compounds consist of two scaffolds. Scaffold A compounds <b>10a-e</b> and scaffold B compounds <b>13a-e</b>. the structures of the newly synthesized compounds <b>10a-e</b> and <b>13a-e</b> were validated using ¹H NMR, ¹³C NMR, and elemental analysis.</p><p><strong>Results and discussion: </strong>The most effective antitubulin derivative was <b>10a</b>, exhibiting an IC₅₀ value of 2.69 μM. Subsequently, <b>10o</b> and <b>13d</b> exhibited IC₅₀ values of 3.62 μM and 3.68 μM, respectively. These compounds exhibited more potency than the reference combretastatin A-4, which displayed an IC₅₀ value of 8.33 μM. These compounds had no cytotoxic effects on normal cells, preserving over 85% cell viability at 50 μM. The antiproliferative experiment demonstrated that compounds <b>10a</b>, <b>10o</b>, and <b>13d</b> displayed significant activity against four cancer cell lines, with average GI₅₀ values of 6, 7, and 8 μM, equivalent to the reference's doxorubicin and sorafenib. Compounds 10a, 10o, and 13d were demonstrated to activate caspases 3, 9, and Bax, while down-regulating the anti-apoptotic protein Bcl2. Molecular docking studies demonstrated superior binding affinities for <b>10a</b> (-7.3 kcal/mol) at the colchicine binding site of tubulin, forming key hydrophobic and hydrogen bonding interactions that enhance its activity. ADMET analysis confirmed favorable drug-like properties, establishing these compounds as promising candidates for further development as anticancer agents targeting tubulin polymerization.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1565699"},"PeriodicalIF":3.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}