Archiv der Pharmazie最新文献

{"title":"AI/ML-Driven DPP-4 Inhibitor Predictor (d4p_v1) for Enhanced Type 2 Diabetes Mellitus Management: Insights Into Chemical Space, Fingerprints, and Electrostatic Potential Maps","authors":"Anu Manhas,&nbsp;Ritam Dutta,&nbsp;Stefano Piotto,&nbsp;Sk. Abdul Amin","doi":"10.1002/ardp.70106","DOIUrl":"https://doi.org/10.1002/ardp.70106","url":null,"abstract":"<p>Dipeptidyl peptidase-4 inhibitors (DPP-4i) represent a relatively new class of oral antidiabetic drugs. This study focuses on: (a) identifying favourable and unfavourable fingerprints governing DPP-4 inhibition using fragment-based analysis, (b) validating key fingerprints through HOMO–LUMO gap analysis and electrostatic potential (ESP) maps, and (c) developing AI/ML-driven DPP-4 predictor, an online cheminformatics tool for efficient DPP-4i screening using a trained, validated AI/ML model. The fragment-based QSAR model finds key substructures linked to potent DPP-4 inhibition, including 2-cyanopyrrolidine, 3-amino tetrahydropyran, and difluoro phenyl groups. D0010 (3-aminotetrahydropyran fingerprint G10) is the most reactive, while D0094 (difluorophenyl fingerprint G14) is the most stable, with D0012 and D0013 (2-cyanopyrrolidine fingerprints G1, G5) offering a balance between stability and reactivity. In addition, the d4p_v1 tool (https://github.com/Amincheminfom/d4p_v1) reliably distinguishes active and inactive DPP-4i using molecular descriptors derived from input SMILES strings. Therefore, this study not only revealed the chemical space of DPP-4i but also opened up a horizon in developing novel potent DPP-4i for the management of type 2 diabetes mellitus (T2DM) in the future.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validated Stability-Indicating RP-HPLC Method for Nirmatrelvir in Self-Emulsifying Drug Delivery Systems: Formulation Characterization and Permeability Enhancement","authors":"Ravi Patel,&nbsp;Ritu Sharma,&nbsp;Dignesh Khunt,&nbsp;Binit Patel","doi":"10.1002/ardp.70100","DOIUrl":"https://doi.org/10.1002/ardp.70100","url":null,"abstract":"<div>\u0000 \u0000 <p>This study presents a novel analytical and formulation strategy to enhance the oral delivery and quality assessment of Nirmatrelvir, a poorly water-soluble antiviral agent. A self-emulsifying drug delivery system (SEDDS) was developed using Labrafac MC 60, ethanol, and Transcutol HP (55:25:20), resulting in a nanoemulsion with a droplet size of 145.23 ± 3.23 nm, low polydispersity index (0.189 ± 0.023), and high transmittance (98.97 ± 0.25%). The formulation exhibited rapid emulsification (&lt; 90 s) and significantly improved permeability, achieving a fivefold increase (Papp: 4.20 × 10⁻⁶ cm/s) across Caco-2 cell monolayers compared to the tablet formulation. A stability-indicating reverse-phase HPLC method was developed using a mobile phase of 5 mM potassium dihydrogen phosphate buffer (pH 4.0) and acetonitrile (40:60, v/v), and validated per ICH Q2(R1) guidelines. The method showed excellent linearity (<i>R</i>² = 0.9999), accuracy (98.6%–100.2%), precision (%RSD &lt; 0.3%), and robustness. An optimized sample preparation protocol ensured efficient extraction of Nirmatrelvir from the SEDDS matrix with minimal interference. Forced degradation studies under ICH Q1A(R2) demonstrated that Nirmatrelvir remained stable under oxidative (98.44%), thermal (98.45%), and photolytic (98.50%) conditions. Maximum degradation was observed under alkaline stress (20.56% at 0.5 N NaOH), followed by acidic stress (13.53% at 5 N HCl). The major alkaline degradant (Rt 2.7 min) was characterized by LC-TQ/MS (<i>m/z</i> 518.2 [M+H]⁺). The method's sustainability was supported by an AGREE score of 0.64 and a Whiteness score of 85.4, offering a validated platform for routine analysis of Nirmatrelvir in lipid-based formulations.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111339","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":"Exploring Micellar Systems for Intra-Articular Delivery of Vanillic Acid in Management of Osteoarthritis","authors":"Shaimaa S. Ibrahim,&nbsp;Hend Abd-allah","doi":"10.1002/ardp.70099","DOIUrl":"10.1002/ardp.70099","url":null,"abstract":"<div>\u0000 \u0000 <p>The current research investigates a new therapeutic strategy for the management of knee osteoarthritis (KOA). For this purpose, we developed mixed polymeric micelles (MPM) encapsulating a natural phytotherapeutic drug, vanillic acid (VA), for intra-articular (IA) delivery. The developed systems were characterized by their particle size profile, zeta potential, morphology, physical stability, and in vitro drug release. Cremophor was found to be an essential component for the production of MPM with optimum particle size profile, as well as maintaining an F127/Cremophor/TPGS weight ratio of 3:2:1. Coating the optimized formulation with hyaluronic acid (HA) provided a dual benefit of sustaining VA release and providing synergistic anti-osteoarthritic activity in an monosodiumiodoacetate-induced KOA model in rats. The proposed HA-coated MPM system encapsulating VA provides a promising strategy for the inhibition of KOA progression.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079127","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":"Sustainable Strategies for Carbazole Synthesis: A Green Chemistry Perspective","authors":"Drashti Shah,&nbsp;Maitri Patel,&nbsp;Abha Vyas,&nbsp;Ashish Patel","doi":"10.1002/ardp.70096","DOIUrl":"10.1002/ardp.70096","url":null,"abstract":"<div>\u0000 \u0000 <p>Carbazoles are an important class of aromatic compounds having numerous applications in pharmaceuticals, including anticancer, anti-inflammatory, and antibacterial activity. Traditional synthesis methods, while successful, frequently use toxic chemicals, hazardous solvents, and energy-intensive procedures, raising serious environmental problems. This study discusses current advances in green carbazole synthetic approaches, with a focus on environmentally friendly strategies such as microwave-assisted reactions, photoredox catalysis, and the use of recyclable metal catalysts such as gold and palladium. Sustainable techniques, such as solvent-free processes, aqueous systems, and renewable resources, are explored alongside mechanistic insights into improving atom economy and reducing waste. These changes, which incorporate green chemistry concepts, not only increase the sustainability of carbazole synthesis but also expand its therapeutic potential, paving the way for environmentally friendly advances in medicinal chemistry.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079061","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":"Discovery of Novel Autotaxin Inhibitors Bearing the 4,5,6,7-Tetrahydro-7H-Pyrazolo[3,4-c]Pyridine-7-One Core for Pulmonary Fibrosis Therapy","authors":"Jiahe Zhang,&nbsp;Jiachen Zhang,&nbsp;Jiandong Li,&nbsp;Deyi Ma,&nbsp;Zehui Tan,&nbsp;Xin Zhai","doi":"10.1002/ardp.70095","DOIUrl":"https://doi.org/10.1002/ardp.70095","url":null,"abstract":"<div>\u0000 \u0000 <p>Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7<i>H</i>-pyrazolo[3,4-<i>c</i>]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound <b>19</b> exhibited potent ATX inhibition (IC₅₀ = 4.2 nM) and significantly reduced lipophilicity (cLogP = 2.992) compared with PAT-409 (IC₅₀ = 4.9 nM, cLogP = 7.647). Molecular dynamics simulations indicated that <b>19</b> bound to the ATX protein in a highly stable manner. Furthermore, predictive analyses of drug-like properties and toxicity uncovered that <b>19</b> demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062614","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":"Cell-Type-Dependent Differential Cytotoxic and Genotoxic Effects: Comprehensive Mechanistic Insights of L-Ascorbic Acid on Healthy Lymphocytes and HL-60 Cancer Cells","authors":"Mehmet Tahir Hüsunet,&nbsp;Mehmet Bertan Yilmaz,&nbsp;Hasan Basri İla","doi":"10.1002/ardp.70093","DOIUrl":"10.1002/ardp.70093","url":null,"abstract":"<div>\u0000 \u0000 <p><span>l</span>-Ascorbic acid exhibits paradoxical behavior as both antioxidant and pro-oxidant in cancer treatment, with mechanisms and optimal dosing remaining unclear. This in vitro study investigated <span>l</span>-ascorbic acid's effects on healthy lymphocytes and HL-60 leukemia cells using concentrations of 0.5–2 mg/mL for 6 and 24 h. Analyses included cell viability, gene expression, DNA damage, mutagenicity, and oxidative stress markers. The results demonstrated a dose-dependent increase in the metabolic activity of HL-60 cells, with a ~ sixfold increase observed at 2 mg/mL (<i>p</i> ≤ 0.001), and opposing modulation of FAS/catalase gene expression between the two cell types. In healthy lymphocytes, both genes were suppressed with increasing exposure, while HL-60 cells exhibited significant early induction (29-fold for FAS and 47-fold for catalase, <i>p</i> ≤ 0.001). <span>l</span>-Ascorbic acid concentrations (0.5–2 mg/mL) exhibited no significant genotoxicity in healthy cells, increased antioxidant status in healthy lymphocytes, and elevated oxidative stress (a 1.4-fold increase in the oxidative stress index at 24 h, <i>p</i> ≤ 0.001) in HL-60 cells. Ames testing confirmed non-mutagenicity, while plasmid analysis revealed bimodal effects, being pro-oxidant at an intermediate dose and protective at a high dose. These findings suggest that <span>l</span>-ascorbic acid requires cell-type-specific application in hematological malignancies and may offer a therapeutic window in leukemia treatment protocols, providing a foundation for optimizing combination strategies with conventional chemotherapeutics.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032414","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 Synthesis of New Multi-Target Coumarin Analogues Acting as Carbonic Anhydrases IX/XII and Topoisomerase II Inhibitors With Apoptotic Potential","authors":"Ahmed A. Al-Karmalawy,&nbsp;Tarek A. Yousef,&nbsp;Ali Khalil Ali,&nbsp;Mohamed A. Zeidan,&nbsp;Marwa Sharaky,&nbsp;Arwa Omar Al Khatib,&nbsp;Hela Ferjani,&nbsp;Eslam M. Abbass","doi":"10.1002/ardp.70094","DOIUrl":"10.1002/ardp.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>Through applying the hybridization technique, new coumarin derivatives (<b>2–17</b>) were prepared with substitution at coumarin C-3 utilizing various heterocyclic derivatives, aiming to afford multi-target carbonic anhydrases (CAs) IX/XII and topoisomerase II (Topo II) inhibitors with potent antiproliferative activity. Eight different cell lines were used to evaluate the growth inhibition percentages (GI%) of cancer cells determined by coumarin analogues <b>1–17</b>. Analogues <b>16</b> and <b>17</b> had the most substantial cytotoxic effects, achieving mean GI% of 86.59% and 85.74%, respectively, exceeding doxorubicin (Dox), which demonstrated a mean GI% of 69.15. Furthermore, the CAs IX/XII and Topo II inhibitory potentials for compound <b>17</b> were evaluated according to the protein expression analysis in the MG-63 cancer cells. Analogue <b>17</b> downregulated the expression of CA IX, CA XII, and Topo II proteins by 0.43-, 0.51-, and 0.56-fold change, respectively, indicating frontier inhibitory potentials. Additionally, analogue <b>17</b> achieved upregulation of apoptotic proteins (Caspases 3, 7, and 9, and BAX by 1.52-, 3.10-, 1.67-, and 1.90-fold change, respectively). On the contrary, compound <b>17</b> induced downregulation of the antiapoptotic proteins BCL-2, MMP2, and MMP9 by 0.44-, 0.38-, and 0.45-fold change, respectively. Besides, compound <b>17</b> achieved an arrest at the G0–G1 phase of the cell cycle and elevated the cellular levels from 65.75% of the control cells to 92.54%. Finally, three molecular docking processes of the superior analogue <b>17</b> toward CA IX, CA XII, and Topo II targets were performed to investigate its molecular interactions.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032419","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, Synthesis, Biological Evaluation, and In Silico Studies of New Nitazoxanide Derivatives: Toward Broad-Spectrum Antimicrobial Agents","authors":"Mahmoud Saleh,&nbsp;Momen M. Thabet,&nbsp;Jyothi Kumari,&nbsp;Yaser A. Mostafa,&nbsp;Dharmarajan Sriram,&nbsp;Keisuke Suganuma,&nbsp;Mahmoud Kandeel,&nbsp;Hajjaj H. M. Abdu-Allah","doi":"10.1002/ardp.70091","DOIUrl":"https://doi.org/10.1002/ardp.70091","url":null,"abstract":"<div>\u0000 \u0000 <p>Nitazoxanide (NTZ), an FDA-approved drug, served as the framework for synthesizing 22 new broad-spectrum antimicrobial agents from 4-aminosalicylic acid via protection–deprotection, Staudinger reduction, Clauson–Kaas pyrrole synthesis, and nucleophilic substitution. These compounds were evaluated for antibacterial, antimycobacterial, and antitrypanosomal activities. Several compounds, particularly <b>10</b>, <b>11</b>, <b>13</b>, and <b>22</b>, surpassed the antibacterial activity of NTZ and its active metabolite tizoxanide (TIZ) against all tested pathogens, with MICs ranging from 1.025 to 9.81 μM. Compounds <b>10</b> and <b>13</b> were twice as potent as ciprofloxacin against <i>Klebsiella pneumoniae</i>, while <b>11</b> and <b>17</b> were equipotent against <i>Pseudomonas aeruginosa</i> (MIC 5.34 μM). Compounds <b>11</b> and <b>14</b> matched ciprofloxacin against <i>Staphylococcus aureus</i> (MIC 3.20 and 2.98 µM), whereas <b>13</b> and <b>21</b> were 1.5- and 2.5-fold more potent against <i>Enterococcus faecalis</i>, respectively. Compound <b>10</b> outperformed ciprofloxacin against <i>Helicobacter pylori</i> (MIC 1.025 μM). Compounds <b>6</b> (MIC 9.46 μM) and <b>7</b> (MIC 16.78 μM) outperformed NTZ against <i>Mycobacterium</i> t<i>uberculosis</i>, and compound <b>3</b> emerged as a promising antitrypanosomal agent (MICs 2.59–4.73 μg/mL) against six <i>Trypanosoma</i> species. Cytotoxicity and pharmacokinetic studies confirmed the compounds’ favorable drug-like properties and high selectivity. Docking results showed strong binding to key targets like pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS), dihydrofolate reductase (DHFR), and ornithine decarboxylase (ODC). Overall, several NTZ derivatives, particularly compounds <b>3</b>, <b>6</b>, <b>10</b>, <b>11</b>, <b>13</b>, and <b>22</b>, showed potent broad-spectrum antimicrobial activity and offer convenient leads for further optimization.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012191","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":"Synthesis and Evaluation of Thiosemicarbazone Inhibitors for SARS-CoV-2 Mpro by Spectroscopy and Microscale Thermophoresis","authors":"Leyao Chen,&nbsp;Xinluan Lv,&nbsp;Xiaoyu Chang,&nbsp;Ruiyong Wang","doi":"10.1002/ardp.70089","DOIUrl":"https://doi.org/10.1002/ardp.70089","url":null,"abstract":"<div>\u0000 \u0000 <p>The SARS-CoV-2 pandemic has spurred global efforts to develop therapeutic approaches. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and a key target for therapeutic development. In this study, 22 thiosemicarbazone derivatives were synthesized. Enzyme activity assays showed compound <b>3c</b> exhibited obvious inhibition of Mpro, with an IC₅₀ value of 3.89 μM. The interaction mechanisms between thiosemicarbazone derivatives and Mpro were investigated using synchronous fluorescence, three-dimensional fluorescence, and circular dichroism spectroscopy. The fluorescence results indicate that static quenching is predominant. The equilibrium dissociation constant (<i>K</i>_d) of 2.3 μM between <b>3c</b> and Mpro was obtained by microscale thermophoresis. This <i>K</i>_d value demonstrates the binding affinity of <b>3c</b> for Mpro, consistent with the spectral results. Meanwhile, the binding modes and stability of thiosemicarbazone derivatives with Mpro were evaluated through molecular docking and molecular dynamics simulations, which also confirmed the stable binding between compound <b>3c</b> and Mpro. This study provides valuable insights into the interaction mechanism between thiosemicarbazone derivatives and Mpro and provides clues for the design of Mpro inhibitors.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012192","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":"Discovery of Furopyrimidine-Pyrazole Hybrid Compounds Targeting p53-MDM2 Interaction as Anticancer Agents","authors":"Mai A. Mansour,&nbsp;Ghaneya S. Hassan,&nbsp;Maiy Y. Jaballah,&nbsp;Rabah A. T. Serya,&nbsp;Necmi Dege,&nbsp;Onur Şahin,&nbsp;Marwa Sharaky,&nbsp;Xiaoliang Zhang,&nbsp;Ruixin Su,&nbsp;Dexin Kong,&nbsp;Khaled A. M. Abouzid","doi":"10.1002/ardp.70085","DOIUrl":"https://doi.org/10.1002/ardp.70085","url":null,"abstract":"<div>\u0000 \u0000 <p>Inhibiting the p53-MDM2 interaction restores the function of the tumour suppressor protein, p53, and offers a promising avenue for anticancer therapies. Herein, a novel series of pyrazoline-derived compounds was developed and synthesised to serve as potential inhibitors of the p53-MDM2 interaction. Scaffold hopping was adopted via replacing the <i>cis</i>-imidazoline core of Nutlin-2 with a pyrazoline core, and molecular docking confirmed the binding orientation of the designed compounds at the p53-MDM2 interaction site. The antiproliferative activities of these compounds were evaluated against the NCI60 cell lines, where compounds <b>6c</b>, <b>6d</b> and <b>9d</b> displayed the highest inhibitory activities. Subsequently, compound <b>6d</b> was selected for the five-doses NCI60 cell panel assay to afford a mean GI₅₀ value of 8.39 μM. Moreover, <b>6d</b> significantly reduced MDM2 expression and elevated the expression of p53 in an ELISA-based assay, yielding a biochemical IC₅₀ value of 13.8 μM against MDM2, which was confirmed by Western blot as well. Cytotoxicity study confirmed the selectivity of <b>6d</b> towards cancerous cell lines over normal cell lines. Additionally, X-ray crystallography was used to check the stereochemistry of compound <b>6d</b>. These newly identified MDM2 inhibitors represent promising candidates for the development of novel targeted anticancer agents.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929981","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}