Medicinal Chemistry最新文献

{"title":"Development of Pyrazole and Pyrazolo[4,5-b]pyridine Analogues with Potent Fungal Biofilm Inhibition Properties.","authors":"Mohammed Al-Ghorbani, Khulud M Al-Taisan, Mohammed Baashen, Lakshmi Jayaram, Ramith Ramu","doi":"10.2174/0115734064519687260917115009","DOIUrl":"https://doi.org/10.2174/0115734064519687260917115009","url":null,"abstract":"<p><strong>Introduction: </strong>Fungal infections continue to pose significant health risks because of two factors, which include drug resistance and the restricted availability of treatment options. Molecular hybridization has been an effective method for developing new drugs with improved therapeutic effects. Fused heterocyclic systems provide researchers with useful frameworks for synthesizing compounds that more effectively engage biological targets. The pyrazole and pyrazolo[ 4,5-b]pyridine derivatives have attracted significant scientific interest due to their multiple biological functions and their ability to be modified in various ways.</p><p><strong>Methods: </strong>The target compounds were prepared through cyclization of naphthalene hydrazide 1 with 2-cyano-N-aryl-acetamide 2a-d to give the key 5-amino-pyrazoles 3a-d. These compounds were then converted into pyrazolo[4,5-b]pyridine derivatives (5a, 5b, 5d, 7a-c) using various chemical routes. Spectroscopic methods (FT-IR, ¹H NMR, and ¹³C NMR) were used for structural identification. An ADMET analysis was conducted to assess the drug likeness and pharmacokinetics of each compound. Finally, the selected compounds were evaluated for antifungal activity against Candida albicans by assessing their ability to inhibit biofilm formation and filamentation. SEM and gene expression studies were conducted to investigate the mechanisms of action, while molecular docking analysis was performed to identify binding interactions with biofilm-associated proteins.</p><p><strong>Results: </strong>Compound 5a showed the highest inhibitory activity (IC50 = 16 μg/mL), with high biofilm inhibition (69%) and filamentation suppression compared to Fluconazole (IC50 = 8 μg/mL, 76.7%). SEM and gene expression data confirmed disruption of the biofilm matrix and the suppression of virulence-related genes. Docking analysis also provided evidence of high-affinity binding to several biofilm-associated proteins.</p><p><strong>Discussion: </strong>The significant biological activity of compound 5a can be explained by the chloro group present on the pyrazolo[4,5-b]pyridine system. On the other hand, compound 7a, despite containing similar groups, exhibited low activity, possibly due to bulky substituents that cause steric hindrance, preventing its interaction with the target molecules involved in fungal virulence. Thus, both biological and molecular docking studies confirm the suitability of compound 5a for use as an antifungal drug.</p><p><strong>Conclusion: </strong>This research has shown that the synthesized pyrazolo[4,5-b]pyridine derivatives showed high antifungal activity. Specifically, compound 5a has been identified as a lead candidate due to its high capacity to disrupt biofilm formation, suppress virulence factor production, and exhibit strong binding affinity for these proteins, thereby making it suitable for the development of future antifungal drugs.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168080","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":"Organotin (IV)-4-(2-Thienyl) Butyric Acid Complexes Synergize with Vitamins D and E to Inhibit Breast Cancer Cell Proliferation.","authors":"Syeda Saba Shah, Balquees Kanwal, Yasmeen Cheema, Warda Gul, Farzana Shaheen, Rumeza Hanif","doi":"10.2174/0115734064509559260927160057","DOIUrl":"https://doi.org/10.2174/0115734064509559260927160057","url":null,"abstract":"<p><strong>Introduction: </strong>Breast cancer (BC) treatment with conventional drugs is a medical challenge because of nonspecific targets, resistance, metastasis, and cancer relapse. Combination therapies incorporating bioactive compounds such as vitamins may enhance therapeutic efficacy and overcome these limitations. This study investigates the anticancer potential of organotin (IV) complexes in combination with vitamins D and E against key BC-associated molecular targets.</p><p><strong>Methods: </strong>Four organotin (IV) complexes; TBA-Ph₂ (C₂₈H₂₈O₄S₂Sn), TBA-Bu₃ (C20H36O2SSn), TBA-Bu₂ (C₂₄H₃₆O₄S₂Sn), and TBA-Me₃ (C₁₁H₁₈O₂SSn), were evaluated through molecular docking against breast cancer target proteins (AKT1, ER, EGFR, HER2, mTOR, and PI3K). Pharmacokinetic properties were predicted using SwissADME, toxicity profiles via ProTox-II, and drug-likeness through Molinspiration. The order of selected protein- ligand compounds was further analyzed using molecular dynamics simulations (CABS-flex 2.0). In vitro antioxidant activity was assessed spectrophotometrically, while antiproliferative activity was evaluated using MTT assays in MCF-7 (Estrogen-receptor positive) and MDAMB- 231 (basal-like breast cancer) cell lines.</p><p><strong>Results: </strong>Docking analysis revealed favorable molecular association of the organotin (IV) compound in combination with vitamins D and E, particularly against AKT1 and mTOR, accompanied by bond energies extending from -6.2 to -9.3 kcal/mol. Molecular dynamics modeling confirmed the reliability of the TBA-Bu₃-AKT1 complex. ADMET analysis indicated that TBA-Bu₃ falls under toxicity class IV, exhibiting no blood-brain barrier permeability and good gastrointestinal absorption, while vitamin E demonstrated low toxicity (class V) and favorable bioactivity. In vitro studies showed that TBA-Bu₃ exhibited potent anticancer activity against MCF-7 cells (IC₅₀ = 6.954 μM), surpassing cisplatin (IC₅₀ = 8 μM), while displaying comparatively lower antiproliferative activity in MDA-MB-231 (IC₅₀ = 16.41 μM). Additionally, TBABu₃ reduced cell survival in a dose-dependent manner and demonstrated notable antioxidant activity.</p><p><strong>Discussion: </strong>The potent activity of TBA-Bu₃ may be linked to its strong interactions with AKT1 and mTOR and its modulation of oxidative stress. Its enhanced effect in combination with vitamins D and E suggests a synergistic mechanism, while its selective cytotoxicity and favorable ADMET profile support its potential as a promising anticancer candidate for further studies.</p><p><strong>Conclusion: </strong>The findings suggest that TBA-Bu₃, particularly in combination with vitamins D and E, exhibits significant anticancer potential against MCF-7 breast cancer. Its favorable binding affinity, stability, pharmacokinetic profile, and selective cytotoxicity highlight its promise as a potential therapeutic candidate for further preclinical investigation.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111733","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":"Design, Discovery, Synthesis, Molecular Docking, MD Simulation, and In Vitro Biological Evaluation of Thiazolidinedione-Clubbed Benzimidazole Hybrids as Potential Anticancer Agents.","authors":"Pragya Dubey, DharamPal Pathak, Archana Sharma, Satyam Sharma, Garima Chauhan, Md Azhar Iqbal, Rajeev Taliyan, Shobha Kumari","doi":"10.2174/0115734064490624260925075551","DOIUrl":"https://doi.org/10.2174/0115734064490624260925075551","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Breast cancer is a major global health issue. A new series of thiazolidinedione-benzimidazole hybrid derivatives (TBZ1-15) was developed and tested for anticancer properties against the MCF-7 breast cancer cell line using the MTT assay. Among these compounds, TBZ-13 showed the greatest cytotoxicity, with an IC₂⁽ of 35 μM.</p><p><strong>Method: </strong>To further elucidate its mechanism of action, TBZ-13 was subjected to multiple in vitro assays, including colony formation, Hoechst staining, reactive oxygen species (ROS) generation, cell migration, and propidium iodide (PI) staining. The results demonstrated that TBZ- 13 significantly inhibits clonogenic survival and cell migration, while inducing pronounced nuclear condensation and fragmentation, confirming apoptosis. Moreover, TBZ-13 caused a marked increase in intracellular ROS levels, indicating that oxidative stress-mediated cytotoxicity is a leading mechanism of cytotoxicity.</p><p><strong>Results and discussion: </strong>Notably, TBZ-13 outperformed the reference drug troglitazone in suppressing metastatic potential and promoting cancer cell death. Molecular docking studies were conducted to investigate interactions with peroxisome proliferator-activated receptor gamma (PPAR-γ), a key target implicated in tumor progression, angiogenesis, and metastasis. The crystal structure of human PPAR-γ (PDB ID: 1FM9; resolution 2.10 Å) was used for docking analysis. TBZ-13 displayed favorable binding conformations with critical hydrogen bonding interactions involving Tyr473, His323, and Ser289. Overall, these findings suggest that TBZ-13 is a promising anticancer lead candidate for further development.</p><p><strong>Conclusion: </strong>The study focuses on breast cancer, a leading cause of death globally, introducing a series of thiazolidinedione-benzimidazole hybrid derivatives (TBZ1-15) evaluated for anticancer activity against the MCF-7 cell line. TBZ-13 showcased the highest cytotoxicity with an IC₂⁽ of 35 μM. Subsequent in vitro assays revealed that TBZ-13 inhibits cell migration and clonogenic survival, induces apoptosis through nuclear condensation, and increases reactive oxygen species (ROS), indicating oxidative stress as its cytotoxic mechanism.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137309","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":"Pyrazinone Derivatives in Medicinal Chemistry: SAR Insights and Emerging Therapeutic Applications.","authors":"Neetu Agrawal, Priya Kushwah, Shilpi Pathak","doi":"10.2174/0115734064519985260907100959","DOIUrl":"https://doi.org/10.2174/0115734064519985260907100959","url":null,"abstract":"<p><p>Pyrazinones remain a comparatively underexplored class of nitrogen heterocycles, despite their recurrence in bioactive natural products and their emergence as a privileged scaffold engaging viral polymerases, kinases, proteases, and G-protein-coupled receptors. Unlike prior reviews, typically confined to a single therapeutic class or to synthetic methodology alone, this review is the first to integrate the natural occurrence, synthetic access, structure-activity relationships, and clinical translatability of pyrazinone derivatives within a single framework, and in doing so identifies structural determinants that recur across nine otherwise unrelated therapeutic areas rather than being specific to any one target. Three such determinants emerge consistently: halogenation at C-3/C-5 improves potency and metabolic stability across kinase, protease, and antifungal series alike; hydrogen-bond donor/acceptor substituents are well tolerated at N-1/C-6 but sharply disruptive when placed adjacent to the lactam at N-3/C-2, reflecting a conserved role for this region in target recognition; and lipophilic extensions at N-1/C-6 raise cellular potency at the recurring cost of selectivity. Inherent limitations are critically examined, including lactam-lactim tautomeric equilibria, challenges in regioselective functionalization, and the trade-off between aqueous solubility and membrane permeability, alongside ADMET considerations such as metabolic stability and off-target toxicity. A central finding of this synthesis is that, across almost every therapeutic class surveyed, reported activity data remain confined to in vitro measurements, without matching pharmacokinetic or translatability data, indicating that the principal bottleneck to clinical progression is evaluative rather than a shortage of potent chemical matter. Clinically relevant examples, including the antiviral drug favipiravir and the clinical-stage candidates RWJ-671818 and BI 730357, nonetheless demonstrate that this bottleneck is surmountable and illustrate the scaffold's translational potential. Recent advances, emerging resistance mechanisms, and future directions, including multi-target-directed ligand design, structure-based optimization, and AI-assisted drug design, are also discussed. By consolidating this fragmented literature into a single cross-scaffold structure-activity framework and by pinpointing where pharmacokinetic and toxicological characterization, rather than potency optimization, most limits clinical translation, this review provides a practical, decisionoriented resource for researchers designing the next generation of pyrazinone-based therapeutics.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012572","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":"Nitrogen-Containing Heterocycles in Antibacterial Drug Discovery: Recent Advances and Structure-Activity Relationships.","authors":"Xiaoqing Zhu, Ping Zhang, Xueyu Wang, Meiran Jiao, Hui Sun, Bin Cui","doi":"10.2174/0115734064511285260901071524","DOIUrl":"https://doi.org/10.2174/0115734064511285260901071524","url":null,"abstract":"<p><p>Antibiotic resistance has become a major global public health challenge, creating an urgent need for the development of new antimicrobial agents. This article reviews the latest research on nitrogen-heterocyclic antimicrobial agents, including pyrazole, imidazole, triazole, thiazole, indole, and quinolone. The article analyzes synthetic strategies, antibacterial activities, and structure-activity relationships for various derivatives. Eight key antibacterial scaffolds, namely compounds 21aa, 30a, 40, 63S, 91, 105, 123, and 127a, were identified as exhibiting outstanding performance. Future research should focus on evaluating the in vivo pharmacodynamics, pharmacokinetics, clinical translation challenges, and safety of these key antibacterial scaffolds, thereby promoting the clinical translation of nitrogen-heterocyclic antibacterial candidate drugs.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148969949","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":"Computer-Aided Design of Novel Acrylamido Derivatives as Potential Oral Antidiabetic Agents.","authors":"Ahmet Mesut Şentürk, Abdulilah Ece, Süreyya Ölgen","doi":"10.2174/0115734064513164260828103027","DOIUrl":"https://doi.org/10.2174/0115734064513164260828103027","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Due to the significant problem of the pharmacokinetic properties of available oral antidiabetic drugs, it is necessary to focus on developing novel oral agents. This study utilized in silico methods to design novel GLP-1 receptor agonists as potential oral antidiabetic drugs based on the most promising studies in the literature. In the framework of available studies, novel methyl (S, E)-3-(4-substitutedphenyl)-2-(3-(3,4-dichlorophenyl) acrylamido)propanoate and (E)-3-(4-(2-(3-(3,4-dichlorophenyl)acrylamido) ethyl) phenyl) propanoic acid derivatives were designed as GLP-1 agonists.</p><p><strong>Methods: </strong>Molecular docking, molecular dynamics simulations, and ADME analysis were applied to clarify the structure-activity relationship of compounds. Compounds were evaluated against specific protein targets, including the glucagon-like peptide-1 receptor, the extracellular domain of the GLP-1 receptor, the extracellular domain of the human calcium-sensing receptor, the human maltase-glucoamylase enzyme, and the human dipeptidyl peptidase IV enzyme.</p><p><strong>Results: </strong>Despite the various results obtained on the specific molecule and target, protein-ligand interactions of compounds were found to be strongly comparable to native ligands. Compound 3 and compound 8 showed very similar binding energies compared to the native ligands against the 6X19 and 3C5T protein targets, respectively, and exhibited similar stability in a biological environment.</p><p><strong>Discussion: </strong>The computational results indicated that the molecules have significant binding properties. Therefore, it would be appropriate to test compounds 3 and 8 for antidiabetic efficacy due to their strong and stable binding properties.</p><p><strong>Conclusion: </strong>The computatıonal results revealed that compounds 3 and 8 are potential compounds for their anti-diabetic activities.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970007","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":"Uracil-Quinazoline Hybrids: Cytotoxicity, Docking, MD, and DFT Studies.","authors":"Mahkameh Moradimehrabadi, Sara Sadeghian, Alireza Poustforoosh, Leila Emami, Soghra Khabnadideh","doi":"10.2174/0115734064514052260819104552","DOIUrl":"https://doi.org/10.2174/0115734064514052260819104552","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer remains a major cause of mortality worldwide; therefore, research continues to focus on the development of more effective therapeutic agents.</p><p><strong>Methods: </strong>In this study, the cytotoxic effects of a series of uracil-quinazoline hybrids were evaluated against A549 (lung cancer) and HepG2 (hepatocellular carcinoma) cell lines using the MTT assay.</p><p><strong>Results: </strong>The biological results demonstrated that several of the studied hybrids exhibited significant cytotoxic activity against both A549 and HepG2 cell lines compared to the reference drugs Erlotinib (IC50 = 35.5 ± 0.4 μM for A549; 13.1 ± 0.2 μM for HepG2) and Cisplatin (IC50 = 15.4 ± 1.6 μM for A549; 15.9 ± 1.8 μM for HepG2). Among the studied hybrids, compound 3f showed the highest anti-proliferative activity against A549 cells, with an IC50 value of 5.4 ± 1.3 μM, while compounds 3g and 3i displayed superior cytotoxic activity against HepG2 cells, with IC50 values of 6.9 ± 3.0 μM and 3.3 ± 1.7 μM, respectively. Molecular docking studies and Molecular Dynamics (MD) simulations revealed that the binding interactions of the active hybrids within the Cyclin-Dependent Kinase 2 (CDK2) active site were consistent with the biological findings, suggesting CDK2 as a potential molecular target. Furthermore, Density Functional Theory (DFT) calculations were performed to theoretically evaluate the Frontier Molecular Orbital (HOMO and LUMO) energy levels, chemical reactivity, and molecular stability of selected hybrids.</p><p><strong>Discussion: </strong>These findings highlight the therapeutic potential of uracil-quinazoline hybrids, particularly compounds 3f, 3g, and 3i, as potent inhibitors of lung and liver cancer cell growth, with activities superior to those of standard drugs. The consistency between experimental cytotoxicity results, molecular docking, MD simulation, and DFT analyses supports CDK2 as a plausible molecular target and provides insight into the structure-activity relationships governing their anticancer effects. This integrated computational-experimental approach strengthens the rationale for further development of these hybrids as targeted anticancer agents.</p><p><strong>Conclusion: </strong>These findings provide a strong foundation for future optimization and in vivo evaluation of uracil-quinazoline derivatives as targeted cancer therapeutics.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906772","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":"Pyrimidine Derivatives as Anticancer Agents: Structural Insights and SAR Studies.","authors":"Balasubramanian Narasimhan, Ashu Sapra","doi":"10.2174/0115734064503567260817161010","DOIUrl":"https://doi.org/10.2174/0115734064503567260817161010","url":null,"abstract":"<p><p>The structural variety and associated biological potential of pyrimidine derivatives have made them attractive to medicinal chemists. Due to the various biological activities of Pyrimidine derivatives and structural derivatives of DNA, many researchers have been prompted to explore this area. Substituted Pyrimidine derivatives have a broad range of pharmacological applications, including antimicrobial, anticancer, and anti-inflammatory activities. The pyrimidine ring and its fused derivatives, which include pyrazolo[3,4-d]pyrimidine, pyrido[2,3- d]pyrimidine, quinazoline, and furo[2,3-d] pyrimidine, have generated a great deal of attention due to the high variety of biological potential that they possess. In addition, fused pyrimidines are intended as bioisosteres of purines. As a result, numerous substances, including pyrimidines and fused pyrimidine derivatives, have demonstrated promising anticancer potential. The emergence of multidrug resistance in cancer cells has significantly reduced the effectiveness of numerous anticancer drugs, posing a challenge to cancer treatment. To avoid this issue, researchers are continuously focusing on target-based drug discovery as a promising pathway for developing novel anticancer agents with improved efficacy and selectivity. Specifically, this review will explore various pyrimidine derivatives, examining positional substitutions and fusion with other heterocyclic rings to elucidate how these compounds interact with molecular targets involved in cancer development and progression. By understanding these interactions, researchers can design more potent pyrimidine -based drugs with better target selectivity. Moreover, the review will also explain the structure-activity relationships of various pyrimidine derivatives, providing insights into the structural features that contribute to their anticancer activity. In the past few years, numerous novel pyrimidine derivatives have been developed and studied for their anticancer activities. The primary objective of this review is to evaluate the structureactivity relationship (SAR) of pyrimidine derivatives developed as anticancer agents over the past decade.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891831","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":"Arylsulfonylaminopyridines as Potential Epac Inhibitors: Design, Synthesis and Effects on Myocardial Strips.","authors":"Tatiana Vorobeva, Grigory Mokrov, Valeriy Stolyaruk, Daniel Malikin, Andrey Pantileev, Alexey Rebeko, Anna Maksimenko, Iosif Tsorin, Sergey Kryzhanovskii, Vladimir Dorofeev","doi":"10.2174/0115734064504072260724092027","DOIUrl":"https://doi.org/10.2174/0115734064504072260724092027","url":null,"abstract":"<p><strong>Introduction: </strong>Exchange proteins directly activated by cyclic AMP (Epac) represent a promising therapeutic target for developing novel cardiotropic agents. Epac-dependent signaling regulates intracellular calcium dynamics, intercellular coupling, and the contractile function of cardiomyocytes. Preclinical studies have demonstrated the potential of Epac2 inhibitors for the treatment of cardiovascular diseases (CVDs).</p><p><strong>Methods: </strong>New potential Epac protein inhibitors from the series of arylsulfonylaminopyridines were designed using pharmacophore modeling, molecular docking, ADMET analysis, and molecular dynamics. The compounds were synthesized via the reaction of N-substituted aminopyridines with arylsulfonyl chlorides. The potential cardiotropic activity of the synthesized compounds was evaluated ex vivo using a model of an isolated rat atrial myocardial strip.</p><p><strong>Results: </strong>Pharmacophore-based design led to novel aminopyridine derivatives predicted to interact with Epac2. Computational studies suggested stabilization of the inactive conformation of Epac2. Ex vivo experiments revealed changes in myocardial contractility that are consistent with the proposed hypothesis of Epac2 involvement, although further studies are required to establish direct target engagement.</p><p><strong>Discussion: </strong>A key objective of this study was to refine the ligand-binding pocket of Epac2, as preliminary in silico analyses revealed discrepancies with previously reported models. In parallel, the potential for PKA-independent Epac2 involvement was assessed using ZMEI-26 in a forskolin-based experimental setup. The combined computational and functional data suggest possible Epac2 engagement and are consistent with the proposed mechanism, although further studies are required to confirm direct target interaction.</p><p><strong>Conclusion: </strong>A new series of aminopyridine derivatives was created using molecular modeling methods as potential Epac2 inhibitors. During the synthesis, 11 compounds (coded ZMEI) were obtained, several of which (ZMEI-3, ZMEI-15, ZMEI-18, ZMEI-19, ZMEI-22, ZMEI-26, and ZMEI-14) demonstrated the ability to reduce the automaticity and contractility of isolated rat myocardial strips.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808814","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":"From Docking Scores to Biological Relevance: Strengthening Experimental Validation in Medicinal Chemistry Research.","authors":"Vipan Kumar","doi":"10.2174/0115734064521007260729061037","DOIUrl":"https://doi.org/10.2174/0115734064521007260729061037","url":null,"abstract":"","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808756","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}