Medicinal Chemistry最新文献

{"title":"Design and Synthesis of Piperidine Hydroxamate Scaffolds as Novel HDAC Inhibitors with Apoptotic Potential in Human Cervical Cancer Cells.","authors":"Natarajan Kiruthiga, SureshKumar Krishnan, Stalin Arulsamy, Adhirajan Natarajan, Venkatesh Gunasekar, Sunil Kumar Bandral, Vaishnavi Vallinayagam","doi":"10.2174/0115734064378681251128061500","DOIUrl":"https://doi.org/10.2174/0115734064378681251128061500","url":null,"abstract":"<p><strong>Introduction: </strong>Histone deacetylase (HDAC) inhibitors are redefining cancer treatment paradigms by targeting epigenetic mechanisms, reactivating tumour suppressor genes, and promoting apoptosis in malignant cells. This study was designed to synthesize and evaluate novel piperidine hydroxamate scaffolds as potent HDAC inhibitors with specific apoptotic activity against cervical cancer cells.</p><p><strong>Methods: </strong>The structure-based design systematic approach was employed and anticipated druglikeness, physicochemical features, pharmacokinetic profiling, molecular docking, and molecular dynamics simulations to guide the synthesis of piperidine hydroxamate derivatives (3a-3m). These compounds were characterised using various spectroscopic analyses, and their anticancer efficacy was assessed through in-vitro evaluation using an HDAC-8 inhibitory assay and MTT assay on the HeLa cervical cancer cell line.</p><p><strong>Results: </strong>Computational analyses revealed robust binding interactions of the compounds with critical HDAC-8 residues, supported by favourable pharmacokinetic profiles. By specifically targeting HDAC-8 in cervical cancer cells, compound 3l (N-hydroxy-1-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] carbonothionyl] piperidine-4-carboxamide) was found to be the most significant one, with its IC50 value of 58.89 nM, revealing its anticancer effectiveness.</p><p><strong>Discussion: </strong>The synthesised scaffolds exhibited high specificity and significant apoptotic effects on selective inhibition of HDAC-8, which substantiates their potency in cervical cancer therapy. The effectiveness of compound 3l shows the importance of hydroxamate derivatives because they bind to zinc ions in HDAC-8. This interrupts key cancer-related processes and encourages apoptosis by increasing pro-apoptotic proteins.</p><p><strong>Conclusion: </strong>The findings of this research underscore the therapeutic potential of piperidine hydroxamate scaffolds, specifically compound 3l, as effective HDAC8-selective inhibitors with significant anticancer activity against cervical cancer, paving the way for future preclinical and clinical research.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Therapeutic Potential of Pyrazole-Based Scaffolds in Parkinson's Disease: Recent Progress and SAR Insights.","authors":"Saurabh Sharma, Deepika Paliwal, Aman Thakur, Ritam Mondal, Rakesh Sahu, Niranjan Kaushik","doi":"10.2174/0115734064402698251105025424","DOIUrl":"https://doi.org/10.2174/0115734064402698251105025424","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a chronic and degenerative neurological disease that affects millions of people worldwide. It is also characterized by motor symptoms, including trembling, muscle rigidity, and slow movement, along with non-motor symptoms that adversely affect the quality of life. Although much progress has been made in the field of medicine, there is no current cure for Parkinson's, and the available treatments are mainly comforting. This has, in turn, led to the development of new therapeutic approaches, including the application of small molecules with multiple pharmacological actions. Among them, pyrazole derivatives have been considered as potential drug candidates owing to their extensible structure and the ability to bind to different proteins and enzymes. These molecules have been found to positively influence oxidative stress, neuroinflammation, and other pathological processes that are associated with the pathogenesis of PD. Recent developments in the synthesis of pyrazole derivatives have shown that small changes in the pyrazole ring can lead to important improvements in the activity and selectivity of the molecules. This review aims to highlight the current state of the art in the application of pyrazole derivatives for the treatment of PD. It outlines their ability to offer neuroprotection, improve symptoms, and manage the multifaceted nature of the disease. To achieve this, this paper presents new findings and focuses on the structure-activity relationships of these compounds. The information provided in this review is expected to help stimulate more research and development of better treatment options for PD.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanocarrier-Mediated Pharmacokinetic Optimization of Piperine: Expanding the Therapeutic Spectrum of a Multifaceted Bioactive Compound.","authors":"Devika Tripathi, Vivek Kumar Gupta, Awani Kumar Rai","doi":"10.2174/0115734064406697251205105311","DOIUrl":"https://doi.org/10.2174/0115734064406697251205105311","url":null,"abstract":"<p><p>Piperine, the principal bioactive alkaloid of Piper nigrum, has emerged as a potent phytoconstituent with a diverse pharmacological portfolio spanning anticancer, antiinflammatory, antimicrobial, anti-diabetic, and neuroprotective domains. Despite its therapeutic versatility, Piperine's clinical translation is significantly hindered by physicochemical constraints, including low aqueous solubility, poor oral bioavailability, and crystallization-induced instability. Central to overcoming these barriers is the advent of nanostructured drug delivery systems. Nanocarriers such as liposomes, solid lipid nanoparticles, polymeric micelles, and electrospun nanofibers not only enhance solubility and protect against degradation but also enable controlled, site-specific delivery. This review examines three core aspects driving the development of Piperine- based therapies: inherent molecular limitations, innovations in formulation techniques, and the potential for clinical translation. Detailed discussions encompass design strategies, synthesis techniques, and characterization protocols, supported by in-vitro/in-vivo efficacy studies. By critically synthesizing recent advances, the article highlights the transformative role of nano-enabled formulations in extending the therapeutic reach of phytoconstituent-based interventions, paving the way for future clinical integration.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Screening, ADME Study, and Evaluation of Benzothiazole Derivatives as Potential Anticancer Agents.","authors":"Sahil Banwala, Anuradha Kush, Sunaina Aggarwal, Shivkant Sharma, Rakesh K Sindhu","doi":"10.2174/0115734064407493251127111054","DOIUrl":"https://doi.org/10.2174/0115734064407493251127111054","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Benzothiazole derivatives have garnered considerable interest in medicinal chemistry due to their diverse biological activities, including anticancer potential. The synthesis of 2-substituted benzothiazoles is traditionally achieved via two main approaches: (1) condensation of 2-aminothiophenols with aldehydes or carboxylic acid derivatives under highly acidic conditions, and (2) cyclization of thiobenzanilides. In this study, approximately 65 benzothiazole analogs were evaluated for anticancer potential using in silico tools and ADME profiling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Materials and methods: &lt;/strong&gt;ADME properties were predicted using SwissADME, while molecular docking studies were performed using Molegro Virtual Docker 6.0. Gefitinib and Erlotinib were used as reference drugs for both pharmacokinetic and in silico comparisons. Biological activity predictions were conducted using the PASS online web server.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Docking scores for the analogs ranged from -134.60 to -114.36, with several compounds outperforming standard drugs Gefitinib (-122.87) and Erlotinib (-119.22). Compounds 12, 17, 27, 43, and 49 exhibited five hydrogen bond interactions, whereas compound 45 showed a maximum of six, exceeding the interactions observed for the standard drugs. Most compounds had molecular weights below 500 and favorable Log P values (e.g., compounds 4: 2.34, 5: 2.85, 7: 2.56, 10: 2.76, 17: 2.78, 19: 2.51, 26: 2.09, 30: 1.20, 40: 1.78, 45: 1.76, 56: 1.75), lower than the reference drugs (3.92, 3.20). Selected compounds also displayed improved topological polar surface area (TPSA) values (e.g., 5: 80.05 Ų, 11: 79.46 Ų, 13: 71.83 Ų, 15: 87.74 Ų, 23: 68.82 Ų, 32: 61.36 Ų, 36: 45.53 Ų, 52: 41.13 Ų) compared to standard drugs (68.74 Ų, 74.73 Ų). Targeting EGFR using PASS predictions, compounds 32, 33, 35, 39, 46, and 48 exhibited activities similar to Gefitinib and Erlotinib.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Docking and ADME analyses indicated that several benzothiazole analogs outperformed standard drugs in binding affinity and pharmacokinetic profiles. EGFR, a transmembrane receptor tyrosine kinase, plays a central role in cell proliferation, survival, angiogenesis, and migration. Most compounds demonstrated good gastrointestinal absorption, suggesting favorable oral bioavailability according to Lipinski, Ghose, Veber, Egan, and Muegge rules. PASS predictions indicated potential anticancer activities, including inhibition of transcription factor STAT3, DNAdirected RNA polymerase, Mcl-1, proto-oncogene tyrosine-protein kinase Fgr, and EGFR, with potential antineoplastic effects across multiple cancer types, including solid tumors, lung, gastric, lymphoma, sarcoma, breast, and pancreatic cancers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Compounds 12, 17, 27, 43, 45, and 49 demonstrated strong binding affinities and superior pharmacokinetic profiles compared to Gefitinib and Erlotinib. Overall, benzothiazole ","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzimidazole and Benzimidazole Derivatives as Anticancer Scaffolds: A Review of Synthetic Approaches.","authors":"Pushkar Kumar Ray, Shubham Verma, Md Sarfaraz Alam, Satyendra Kumar Mishra, Vikas Chauhan","doi":"10.2174/0115734064392414251117064748","DOIUrl":"https://doi.org/10.2174/0115734064392414251117064748","url":null,"abstract":"<p><strong>Introduction: </strong>The objective of exploiting benzimidazole, a chemical compound with the molecular formula C7H6N2, varies depending on its application. In this review, articles published between 2001 and 2025 were analyzed. Its adaptability and multiple chemical properties make it valuable in fields such as pharmaceuticals, materials science, and chemical research. The structural characteristics of benzimidazole allow for a wide range of modifications and applications.</p><p><strong>Methods: </strong>The benzimidazole derivatives were synthesized and analyzed. An extensive literature search was conducted using databases such as Google Scholar, PubMed, ScienceDirect, SpringerLink, Wiley Online Library, RSC Publishing, and Eureka Select. Key synthetic methods, including Philip's reaction, oxidative/reductive cyclization, multicomponent reactions, and microwave-assisted synthesis, were illustrated using ChemDraw Ultra.</p><p><strong>Results: </strong>This review outlines synthetic strategies for developing potent benzimidazole-based anticancer agents, highlighting their therapeutic potential through a summary of in vitro efficacy in inducing apoptosis and cell cycle arrest across various cancer cell lines.</p><p><strong>Discussion: </strong>Benzimidazole derivatives exhibit strong in vitro anticancer activity through apoptosis and cell cycle arrest, yet face challenges such as low bioavailability and limited clinical translation. The review highlights gaps in resistance mechanisms and delivery strategies, urging the use of in vivo studies, SAR-based optimization, and clinical advancement to realize their therapeutic potential.</p><p><strong>Conclusion: </strong>The study highlights the chemical versatility of benzimidazole scaffolds and their structure-activity relationships in the design of anticancer drugs. Key findings emphasize efficient synthetic methodologies and functional modifications that enhance bioactivity. These insights contribute to the rational development of novel, potent anticancer agents, reinforcing the value of benzimidazoles in medicinal chemistry.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146064606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel and Selective Cyclooxygenase 2 (COX-2) Inhibitors: Comprehensive <i>In-Silico</i> Investigations.","authors":"Alexandria Xavier, M V Komali, Avani Sawant, Serena Botelho, Sonam Chokey, Kevin Tochukwu Dibia, Raghuvir R S Pissurlenkar","doi":"10.2174/0115734064406120251030094222","DOIUrl":"https://doi.org/10.2174/0115734064406120251030094222","url":null,"abstract":"<p><strong>Introduction: </strong>Cyclooxygenase-2 (COX-2) is a key enzyme in the inflammatory cascade and is implicated in chronic conditions, including arthritis, cancer, and cardiovascular diseases. Selective inhibition of COX-2, while sparing COX-1, is crucial to minimize gastrointestinal and renal side effects associated with non-selective NSAIDs. Computational drug discovery offers a strategic advantage for efficiently identifying novel, selective COX-2 inhibitors.</p><p><strong>Methods: </strong>Comprehensive in-silico studies were performed, which included ligand and structurebased screening, ML-based QSAR model, ADME/toxicity profiling, and molecular dynamics simulation. Five potent COX-2 inhibitors were used as query compounds to identify a dataset of 9213 similar molecules using the SwissSimilarity Server, which employed fingerprint-based screening of the ZINC database. Subsequently, these molecules were docked into the active sites of the COX-1 and COX-2 targets using AutoDock Vina to discover selective COX-2 inhibitors.</p><p><strong>Results: </strong>A pool of 236 compounds was selected based on docking scores (≤ -8.0 kcal/mol for COX-2 and ≥ -6.0 kcal/mol for COX-1), indicating potential selectivity. ADME/toxicity filtering narrowed the pool to 23 candidates. QSAR predictions identified 13 biologically active molecules, which were further evaluated for toxicity. Molecular dynamics simulations confirmed ten compounds with stable binding and favorable interaction profiles.</p><p><strong>Discussion: </strong>The integrated computational workflow enabled the identification of ten highly selective COX-2 inhibitors with promising pharmacokinetic and safety profiles. These candidates demonstrated strong potential for experimental validation and development into anti-inflammatory therapeutics.</p><p><strong>Conclusion: </strong>The in-silico studies offer valuable insights into discovering selective COX-2 inhibitors for potential therapeutic and pharmacological applications. The findings provide a strong foundation for future experimental validation and the development of anti-inflammatory medicine.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing Purines: Anticancer Activity and Target-Specific Approaches.","authors":"Gourav Arora, Sourav Kalra, Rajwant Kaur, Rajiv Sharma","doi":"10.2174/0115734064390291251128060307","DOIUrl":"https://doi.org/10.2174/0115734064390291251128060307","url":null,"abstract":"<p><strong>Introduction: </strong>In the discovery of anticancer drugs, Purine analogues demonstrated crucial attention due to their structural similarity to natural purines, which are essential for DNA and RNA synthesis. Cytotoxic effects are exerted by these compounds by interfering with nucleic acid metabolism, enzymatic activity and signal transduction, which is necessary for cancer cell proliferation.</p><p><strong>Methods: </strong>This study was carried out to investigate the potential anticancer effects of purine-based hybrid compounds by evaluating their impact on cell cycle regulation, proinflammatory cytokine inhibition, and induction of apoptotic gene expression in cancer cells. The studies involve peerreviewed articles on purine analogues used in cancer therapy, which focus on molecular targets, preclinical or clinical efficacy data and structure-activity relationships (SAR).</p><p><strong>Results: </strong>Classic purine analogues such as 6-mercaptopurine, thioguanine, and cladribine have proven effective against hematologic cancers. Recent innovations have broadened their use to solid tumours by targeting kinases (e.g., CDKs, PI3K), epigenetic regulators (e.g., DNMTs), and immune checkpoints. Improved molecular modelling and SAR studies have enhanced drug specificity and pharmacokinetics. Additionally, combining purine analogues with other chemotherapeutics or targeted agents has shown synergistic effects and potential for overcoming resistance.</p><p><strong>Discussion: </strong>The current outlook of the purine-based anticancer agents is aimed at this review by concentrating on their mechanisms of action, the development of target-specific strategies and therapeutic targets for the enhancement of anticancer efficacy and decreasing target toxicity.</p><p><strong>Conclusion: </strong>For the anti-cancer drugs, Purine-based compounds remain a versatile and evolving class. Their targeted design offers promising avenues for personalized cancer therapy, warranting further clinical exploration.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In-silico</i> Identification of Novel Inhibitors Targeting Dengue Virus Serotype 3 RNA-Dependent RNA Polymerase.","authors":"Shailaja Mallya, Raghuvir R S Pissurlenkar","doi":"10.2174/0115734064401324251014093219","DOIUrl":"https://doi.org/10.2174/0115734064401324251014093219","url":null,"abstract":"<p><strong>Introduction: </strong>Dengue infection, caused by four serotypes of the dengue virus (DENV), poses a significant global health threat, with millions of cases reported annually. RNAdependent RNA polymerase (RdRp) is an essential viral enzyme involved in the replication cycle and is a promising target for antiviral drug development. In the present study, computational methods were employed to identify novel compounds with potential inhibitory activity against DENV serotype 3 RdRp.</p><p><strong>Methods: </strong>Molecular docking-based virtual screening approaches were used to screen a diverse library of small molecules against the three-dimensional structure of DENV-3 RdRp. Furthermore, pharmacokinetic and toxicity predictions were utilized to prioritize compounds with favorable drug-like properties. Subsequently, molecular dynamics simulation studies were performed to assess the stability and binding affinity of the predicted inhibitors.</p><p><strong>Results: </strong>The computational studies yielded three promising DENV serotype 3 RNA-dependent RNA polymerase inhibitors, with docking scores ranging from -8.89 to -8.19 kcal/mol. MD simulations over 100 ns demonstrated stable protein-ligand complexes, with backbone RMSDs varying from 0.77 to 1.87 Å.</p><p><strong>Discussions: </strong>Comprehensive interaction analysis revealed that Z248 and Z982 engaged key catalytic residues Arg729 and Arg737 within the palm domain, while Z389 exhibited hydrophobic stabilization through interaction with Trp795. These residues are critical for enzymatic activity, and their engagement highlights the mechanistic relevance of the identified compounds. The dynamic stability of the RdRp-ligand complexes was further validated through 100 ns molecular dynamics simulations, with both protein backbone and ligand RMSDs remaining within acceptable limits.</p><p><strong>Conclusions: </strong>The identified inhibitors, obtained from exhaustive computational studies, represent promising candidates for further experimental validation and optimization as potential antiviral agents for the treatment of DENV-3 infections.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diaryl Ether Derivatives as Dual Inhibitors of Selective COX-2 and EGFR: Synthesis, <i>In silico</i>, and <i>In Vitro</i> Analysis.","authors":"Vivekananda Saha, Aynal Hoque, Abbas Ali, Souvik Sarkar, Prasun Kanti Pradhan, Soma Das Pradhan, Goutam Biswas","doi":"10.2174/0115734064421626251114091432","DOIUrl":"https://doi.org/10.2174/0115734064421626251114091432","url":null,"abstract":"<p><strong>Introduction: </strong>The rising prevalence of cancers with chronic inflammation is a leading global health concern. Modern anticancer treatments require dual inhibitors of cyclooxygenase- 2 (COX-2) and Epidermal Growth Factor Receptor (EGFR) with minimal adverse effects.</p><p><strong>Methods: </strong>The emergence of diaryl ether derivatives has encouraged the development of new therapeutic strategies for inflammation-linked conditions. A series of nine diaryl ether derivatives was designed, and in silico studies were performed to predict their interactions with COX- 1, COX-2, and EGFR proteins. Drug likeness and toxicity characteristics were investigated using Swiss ADME, ADMET Lab 2.0, and ProTox-3.0 tools. Furthermore, to observe the selective COX-2 inhibitory nature, a protein (bovine serum albumin (BSA)) denaturation study of the five best compounds with high binding affinities was conducted.</p><p><strong>Results: </strong>Nine diaryl ether derivatives were synthesized and characterized using 1H-NMR, 13C NMR, LC-MS, and FT-IR spectroscopy. Based on the docking score and pharmacokinetics, compound 12a showed a significant IC50 value of 39.24 μg/mL in the BSA denaturation assay. To screen the kinetic behavior of five selected compounds with high binding affinities (11a, 12a, 12b, 12c, and 13a) with COX-2, Molecular Dynamics (MD) simulations were performed for 100 ns. MD simulations and binding free energy calculations were performed to observe the stability of the best-docked EGFR-12a complex with a docking score of -9.5 kcal/mol.</p><p><strong>Conclusion: </strong>This study focused on the synthesis and biological analysis with theoretical explanations. Overall, diaryl ether derivatives are promising precursors for anti-inflammatory and anticancer drugs in the biomedical field.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of the PARP1 Inhibitors from Natural Compounds Using Structure-Based Virtual Screening and Bioactivity Evaluation.","authors":"Dabo Pan, Yaxuan Huang, Dewen Jiang, Xiaojie Jin, Mingkai Wu, Jianjun Luo, Yonghao Zhang","doi":"10.2174/0115734064350048241121110017","DOIUrl":"10.2174/0115734064350048241121110017","url":null,"abstract":"<p><strong>Background: </strong>PARP1 (poly ADP-ribose polymerase 1, also known as ADPRT1) plays a significant role in DNA repair and has become an attractive target for treating PARP1-related diseases, such as cancer.</p><p><strong>Objective: </strong>This study aimed to discover inhibitors targeting PARP1 from the phytochemicals of Huangbai (Phellodendron chinense Schneid.), Baixianpi (<i>Dictamnus dasycarpus</i> Turcz.), and Shechuangzi (<i>Cnidium monnieri</i> (L.) Spreng.).</p><p><strong>Methods: </strong>The chemical compositions of Huangbai, Baixianpi, and Shechuangzi were extracted from the HERB database. Next, a combination of molecular docking and PARP1 enzyme assay was used to identify PARP1 inhibitors from these chemical components. Finally, molecular dynamics simulation and binding free energy calculation were used to explore the detailed interaction mode of these inhibitors with PARP1.</p><p><strong>Results: </strong>A total of 507 chemical constituents of Huangbai, Baixianpi, and Shechuangzi were collected from the HERB database. Four potential PARP1 inhibitors were screened based on molecular docking and PARP1 enzyme assay. Demethyleneberberine exhibited strong PARP1 inhibitory activity with an IC₅₀ value of 2.0 ± 0.8 μM. The IC₅₀ values of the inhibitory activities of 8-hydroxy dictanmnine, meranzin hydrate, and osthol on PARP1 ranged from 44 μM to 76 μM. Molecular dynamics simulation and binding free energy calculation suggested that the nonpolar interaction energies of HIS862, GLY863, TYR889, TYR896, PHE897, and TYR907 played a primary role in the binding of inhibitors to PARP1.</p><p><strong>Conclusion: </strong>Integrating molecular simulation and bioactivity testing was found to be an effective approach for the rapid discovery of targeted PARP1 inhibitors. Demethyleneberberine demonstrated strong PRAP1 inhibitory activity and has a good prospect for development.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"57-66"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13284649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}