Medicinal Chemistry最新文献

{"title":"DPP-IV and FAP-α as Targets of Drug Design: A Comparative Structural Analysis of Molecular Features and Biological Implications.","authors":"Michelle Cristiane Melo Reis Martins, Simone Queiroz Pantaleão, Eric Allison Philot, Yolanda Maria Barros Marcello, Patricia Gasparini, Sheila Cruz Araujo, Wítor Ribeiro Ferraz, Gustavo Henrique Goulart Trossini, Ana Ligia Scott, Kathia Maria Honorio","doi":"10.2174/0115734064442963260227222643","DOIUrl":"https://doi.org/10.2174/0115734064442963260227222643","url":null,"abstract":"<p><strong>Introduction/objective: </strong>This study aims to compare the structural and functional features of DPP-IV and FAP-α to identify ligand characteristics relevant to selective inhibition.</p><p><strong>Methods: </strong>To this end, we performed enzyme superposition, binding-site characterization, molecular docking, normal mode analysis, molecular dynamics simulations, and binding-site detection.</p><p><strong>Results and discussion: </strong>The analyses revealed distinct residue compositions in the binding pockets, indicating a more polar environment in DPP-IV and a more hydrophobic environment in FAP-α. Key interactions between DPP-IV and bioactive compounds included hydrogen bonds and π-π contacts involving Ser630, Tyr622, and Tyr666, which were associated with ligand regions, such as the trifluorophenyl and cyclohexylamine groups. Normal mode calculations revealed differences in functional motions among the biological targets under study, and molecular dynamics simulations confirmed ligand stability and the structural impact on binding sites.</p><p><strong>Conclusion: </strong>These findings highlight structural elements that can guide the design of more selective drug candidates for type 2 diabetes therapy.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839906","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 Influenza H1N1 Endonuclease Inhibitor <i>via</i> Virtual Screening and <i>In Vitro</i> Validation.","authors":"Shymaa Damfo","doi":"10.2174/0115734064458083260224071435","DOIUrl":"https://doi.org/10.2174/0115734064458083260224071435","url":null,"abstract":"<p><strong>Background: </strong>The H1N1 influenza pandemic remains a global health burden, causing acute respiratory illness and high mortality. The continuous emergence of therapeutically resistant strains necessitates the ongoing development of new, effective antiviral drugs.</p><p><strong>Materials and methods: </strong>This study employed a virtual screening approach to identify potential inhibitors from a fragment-based chemical library targeting the H1N1 polymerase acidic (PA) endonuclease, an enzyme crucial for the cap-snatching process and viral replication. Chemical fragments binding within the PA active site were identified through virtual screening, and the crystal violet assay, together with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, were subsequently used to experimentally validate inhibitory activity and cytotoxicity in Madin-Darby canine kidney (MDCK) cells.</p><p><strong>Results: </strong>A new chemical scaffold of triazole pyridine derivative that binds within the PA active site was found as a result of a fragment-based screening approach. In the crystal violet assay, the compound exhibited substantial inhibitory activity, with an IC50 value of 1.392 μM/mL. This potent antiviral activity is consistent with the virtual screening results, which showed a lower binding energy than the control. In addition, the cytotoxicity assay yielded a CC₂⁽ value of 495 μmol/mL, indicating a favourable selectivity index.</p><p><strong>Discussion: </strong>Compounds that inhibited the PA endonuclease in vitro decreased or abolished the influenza virus activity. This study identified a triazole-pyridine derivative as an inhibitor and characterised the key interacting residues involved in binding. The results indicate that binding affinity is determined by the nature of the interactions and the specific residues involved, rather than by the number of participating residues. The hit compound identified in this study demonstrated activity comparable to that of previously reported inhibitors, while exhibiting a more favourable safety profile, making it a promising candidate for further investigation as an antiviral agent.</p><p><strong>Conclusion: </strong>These findings demonstrate a successful virtual fragment-based screening method of novel inhibitors targeting the influenza polymerase endonuclease. This study suggests that triazole-pyridine derivatives can serve as promising lead compounds for the development of novel H1N1 influenza inhibitors, providing a valuable direction for next-generation influenza therapeutics.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775931","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":"A Perspective on Alzheimer's Therapeutics: A Multitarget Approach with Rho-associated Kinase and Histone Deacetylase Inhibitors.","authors":"Luís Felipe Ferreira Lopes, Heber Victor Tolomeu, Rafael Pinto Vieira","doi":"10.2174/0115734064452204260325102425","DOIUrl":"https://doi.org/10.2174/0115734064452204260325102425","url":null,"abstract":"","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775860","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":"Developing Safer Anticoagulant Candidates: Structure-Activity Relationship Studies of 5-Amino-Triazole-Based FXIIa Inhibitors.","authors":"Francis N Eze, Navneet Goyal, Rami A Al-Horani, Daniel K Afosah","doi":"10.2174/0115734064445872260209104404","DOIUrl":"10.2174/0115734064445872260209104404","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Factor XIIa (FXIIa), a serine protease in the intrinsic coagulation pathway, is primarily involved in thrombosis rather than hemostasis, making it an attractive target for safer anticoagulants with reduced bleeding risk. We previously reported a series of potent and selective triazole-based FXIIa inhibitors. To further advance this class, we evaluated sixteen additional derivatives of the lead inhibitor (1).</p><p><strong>Methods: </strong>FXIIa inhibition was assessed using a chromogenic substrate assay under physiological conditions. The new derivatives were structurally modified in two domains: the N1-benzoyl group and the C3-substituent. Kinetic characterization, selectivity profiling, and clotting assays were also performed.</p><p><strong>Results: </strong>We identified three molecules inhibiting FXIIa with more than 40% at 100 μM. Structure- activity analysis revealed superior activity of a halogenated benzoyl group at the N1- position over a 3-phenylpropanoyl substituent and highlighted the importance of meta-position halogenation. A methyl ester at the 3-position of the triazole ring was required for activity, as analogs lacking this group were inactive. Inhibitor 6 was the most potent compound, exhibiting an IC₂⁽ of 56 nM and ~100% efficacy. It demonstrated a marginal-to-high selectivity of 4- 8,900-fold selectivity for FXIIa over thrombin, FXIa, FXa, FIXa, and plasmin. Kinetic analysis suggested active-site binding with a covalent mode of inhibition. In coagulation assays, inhibitor 6 prolonged both prothrombin time and activated partial thromboplastin time, with a greater effect on aPTT.</p><p><strong>Discussion: </strong>These results define key structural determinants of FXIIa inhibition, including the importance of halogenated benzoyl substitution at N1 and a required methyl ester on the triazole scaffold. The high potency and selectivity of inhibitor 6 indicate effective engagement of the FXIIa active site with minimal off-target serine protease inhibition. Preferential prolongation of aPTT relative to PT is consistent with selective modulation of the intrinsic coagulation pathway.</p><p><strong>Conclusion: </strong>This study successfully identified a potent, selective, and covalent FXIIa inhibitor 6 and defined critical structure-activity relationships for the triazole-based chemotype. The findings validate the feasibility of developing FXIIa-targeted anticoagulants. Future work will focus on the rational design of next-generation inhibitors with enhanced potency and selectivity, further mechanistic studies, and in vivo profiling to advance therapeutic potential.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147674990","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":"Synthesis and Antiparasitic Action of 2-aryl-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazin-4-ones.","authors":"Fabiane Knepper Zehetmeyr, Cíntia Costa Vianna, Mariana Martino Maciel Coelho, Guilherme Porto Vargas, Ítalo Ferreira Leon, Natália Berne Pinheiro, Wilson Cunico","doi":"10.2174/0115734064447318260131145001","DOIUrl":"https://doi.org/10.2174/0115734064447318260131145001","url":null,"abstract":"<p><strong>Introduction: </strong>Haemonchus contortus (H. contortus) is a gastrointestinal nematode that causes significant economic losses in sheep farming. The increasing resistance to conventional anthelmintics such as albendazole, levamisole, and ivermectin highlights the urgent need for new therapeutic agents. In this context, the present work reports, for the first time, the synthesis of 1,3-benzothiazin-4-ones with ovicidal activity against H. contortus.</p><p><strong>Methods: </strong>Compounds 5a-d were synthesized via a one-pot reaction between 1-(2-aminoethyl) pyrrolidine 1, substituted arylaldehydes 2 (4-CH3 2a, 2-NO2 2b, 4-NO2 2c, 4-OCH3 2d), and thiosalicylic acid 3. Structural characterization was confirmed by ¹H and 13C NMR spectroscopy and GC-MS analysis. Anthelmintic activity was assessed through H. contortus egg-hatching inhibition assays. All compounds exhibited measurable inhibitory effects, at least at the highest concentrations tested (40, 20, 10, 5, 2.5, and 1.25 μg·mL⁸¹).</p><p><strong>Results: </strong>These compounds were obtained in moderate yields (31-54%), and their structures were confirmed by GC-MS and 1D/2D NMR data. Formation of the benzothiazinone ring was supported by the characteristic H2 and C2 signals (δ 5.93-6.08 and 61.6-62.3 ppm), along with the lactam carbonyl resonance at δ 163.7-164.1 ppm.</p><p><strong>Discussion: </strong>Four novel 1,3-benzothiazin-4-ones (5a-d) were synthesized via a threecomponent one-pot reaction in moderate yields. The electronic and positional effects of the aryl substituents may influence the ovicidal activity against H. contortus, although these hypotheses require experimental validation in future mechanistic studies. All molecules displayed activity at concentrations lower than those required for the reference drug, thiabendazole (20 μg·mL⁸¹; 99.103 μM).</p><p><strong>Conclusion: </strong>The results indicate that these benzothiazinone derivatives represent promising scaffolds for the development of new anthelmintic candidates. Compound 5c - 2-(2- nitrophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazine-4-one - exhibited the highest activity at 40 μg·mL⁸¹ (104.3 μM), inhibiting egg hatching by 39-45%.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675003","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":"Evaluating the Anti-tumor and Anti-inflammatory Efficacy of Natural Compounds Targeting TNFRs Using Computational Methods.","authors":"Hatice Akkaya, Aydın Özmaldar","doi":"10.2174/0115734064466725260330210728","DOIUrl":"https://doi.org/10.2174/0115734064466725260330210728","url":null,"abstract":"<p><strong>Introduction/objectives: </strong>The tumor necrosis factor (TNF) superfamily includes cytokines that play a role in biological functions such as cell cycle regulation, cell death, and inflammatory responses. The main objective of this research is to investigate the effects of naturally occurring compounds on the TNF receptor family using in silico methods, thereby revealing their potential for anticancer and anti-inflammatory activity.</p><p><strong>Methods: </strong>In this study, the drug affinity, receptor interactions, and pharmacokinetic properties of the compounds used were evaluated, and the analysis was completed with molecular docking, molecular dynamics simulations, and binding free energy calculations.</p><p><strong>Results: </strong>Computational analyses revealed that boswellic acid forms strong and stable interactions with TNFR1, TNFR2, and CD95. Berberine was identified as another candidate showing strong affinity with CD40. The analyses suggest that cysteine-rich key structural regions play a significant role in the stability of ligand-receptor complexes.</p><p><strong>Discussions: </strong>The data obtained in our study indicate that boswellic acid and berberine have the ability to interact with TNFRs and affect multiple targets. The previously reported antiinflammatory and anti-cancer properties of these compounds are consistent with our current findings. On the other hand, the possibility that the in silico approaches used may not fully reflect the receptor activation processes or unexpected interactions should not be overlooked. Therefore, the results obtained at this stage must be confirmed by experimental methods.</p><p><strong>Conclusions: </strong>The analysis results indicate that boswellic acid and berberine, which possess anti- inflammatory and anticancer properties, can be multi-target agents by interacting with the TNFR family.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675023","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, Synthesis, and Antimicrobial Evaluation of Novel Triazole-Acetamide-Linked Thiadiazole Hybrids.","authors":"Nour El-Huda Daoud, Ulviye Acar Çevik, Ülküye Dudu Gül, Zafer Asım Kaplancıklı","doi":"10.2174/0115734064437065251129131536","DOIUrl":"https://doi.org/10.2174/0115734064437065251129131536","url":null,"abstract":"<p><strong>Introduction: </strong>Infections caused by multidrug-resistant bacteria and fungi pose an increasing global threat, underscoring the urgent need for new drugs with novel structures and mechanisms of action.</p><p><strong>Methods: </strong>A new series of triazole-thiadiazole hybrid derivatives (7a-7i) was designed, synthesized, and structurally characterized using 1H NMR and 13C NMR spectroscopy. The antimicrobial efficacy of the synthesized compounds was evaluated in vitro against a panel of clinically significant, resistant bacterial and fungal strains.</p><p><strong>Results: </strong>Compound 7a demonstrated the highest potency against E. coli with a MIC of 3.90 μg/mL, followed by compound 7b (7.81 μg/mL) and compound 7e (31.25 μg/mL). Antifungal screening revealed moderate activity against the resistant strains C. krusei ATCC 6258 and C. albicans ATCC 24433. Compound 7a inhibited C. krusei with an MIC of 62.5 μg/mL, while compounds 7e and 7h exhibited MIC values of 125 μg/mL against both fungal strains.</p><p><strong>Discussion: </strong>Preliminary Structure-Activity Relationship (SAR) analysis suggests that small, hydrophobic alkylamine substituents significantly enhance antimicrobial activity. In silico ADMET profiling supported the biological findings, indicating that all compounds fall within acceptable drug-likeness criteria. Among them, compound 7b emerged as the most promising lead, exhibiting high oral absorption, good solubility, and permeability, and the lowest predicted cardiotoxicity risk.</p><p><strong>Conclusion: </strong>These results suggest that triazole-thiadiazole hybrids, particularly compound 7b, represent a promising scaffold for the development of new antimicrobial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147609257","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":"Cancer continues to be a major global health challenge, driving the need for innovative and precise therapeutic approaches. Protein kinases, which orchestrate vital cellular functions including cell division, survival, and metastasis, are frequently altered in malignancies, positioning them as highly promising targets for cancer treatment. Kinase inhibitors (KIs) have emerged as a powerful class of targeted therapies, demonstrating enhanced effectiveness and reduced systemic toxicity compar.","authors":"Himanchal Sharma, Atul Pratap Singh, Divya Pathak, Dhananjay Taumar, Vatan Chaudhary, Shamim","doi":"10.2174/0115734064404334251024112120","DOIUrl":"https://doi.org/10.2174/0115734064404334251024112120","url":null,"abstract":"<p><p>Cancer continues to be a major global health challenge, driving the need for innovative and precise therapeutic approaches. Protein kinases, which orchestrate vital cellular functions including cell division, survival, and metastasis, are frequently altered in malignancies, positioning them as highly promising targets for cancer treatment. Kinase inhibitors (KIs) have emerged as a powerful class of targeted therapies, demonstrating enhanced effectiveness and reduced systemic toxicity compared to traditional chemotherapy. This review explores the involvement of kinases in cancer development, with a focus on critical signalling cascades, such as MAPK, PI3K-AKT, and JAK-STAT. Kinase inhibitors are categorized based on their action mechanisms-ATPcompetitive, allosteric, reversible, and irreversible. Additionally, the review delves into medicinal chemistry approaches, including rational drug design, identification of pharmacophores, and insights from structure-activity relationship (SAR) analyses. Clinical use and pharmacological profiles of approved kinase inhibitors are highlighted, alongside ongoing challenges like therapeutic resistance and drug-induced toxicities, particularly affecting the heart and liver. To address these issues, recent efforts emphasize the design of advanced inhibitors, combination regimens, and novel drug delivery platforms. Cutting-edge strategies, such as PROTAC technology, dual-target agents, and artificial intelligence-guided drug discovery, are gaining momentum. Furthermore, the integration of personalized medicine is reshaping the selection and optimization of kinase-based therapies. In summary, although kinase inhibitors have significantly advanced cancer treatment, overcoming resistance, toxicity, and interpatient variability remains critical. Future progress hinges on the continued evolution of precision oncology and next-generation therapeutic innovations to maximize their clinical potential.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494054","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":"Monoamine Oxidase Regulation and Inhibition of Aging and Neurodegenerative Diseases.","authors":"Papanotas Ilias, Dimitra Litina Hadjipavlou","doi":"10.2174/0115734064433856251118094747","DOIUrl":"https://doi.org/10.2174/0115734064433856251118094747","url":null,"abstract":"","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444180","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 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}