Medicinal Chemistry最新文献

{"title":"Histone Deacetylase (HDAC) Inhibitors: Research and Therapeutic Applications in Cancer and Neurodegenerative Diseases: A Mini-review.","authors":"Yupeng Wu, Siyi Wu, Xin Wang, Hui Sun, Bin Cui","doi":"10.2174/0115734064505531260713070531","DOIUrl":"https://doi.org/10.2174/0115734064505531260713070531","url":null,"abstract":"<p><p>Cancer and neurodegenerative disorders remain major public health challenges worldwide. Increasing incidence across age groups, together with persistently high mortality in many settings, contributes to substantial socioeconomic burdens on individuals, families, and healthcare systems. Histone Deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histone tails. As a key post-translational modification, histone deacetylation modulates chromatin organization and gene transcription. In many contexts, HDACmediated deacetylation is associated with increased chromatin compaction, which may limit transcription-factor accessibility and reduce transcriptional output. Beyond chromatin regulation, HDACs have been implicated in cell-cycle progression, apoptosis, inflammation, immune responses, redox homeostasis, and neuronal development. Given their involvement in disease mechanisms, Histone Deacetylase Inhibitors (HDACis) have attracted attention as potential epigenetic therapeutics with pleiotropic effects. By counteracting aberrant deacetylation, HDACis may help restore acetylation-dependent transcriptional programs and reactivate genes implicated in disease. They may also affect dysregulated signaling pathways and have been reported to exhibit antiproliferative, anti-inflammatory, neuroprotective, and anticancer effects. Accumulating preclinical and emerging clinical evidence suggests that HDACis are being evaluated for therapeutic activity in a range of malignant and neurodegenerative diseases. This review summarizes recent advances in HDACis, with emphasis on structural classification, key chemical features, molecular mechanisms, and clinical translation in oncology and neurodegeneration. By integrating these aspects, the article aims to provide a conceptual reference for targeted drug discovery and rational combination strategies for these challenging conditions.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604822","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":"Drug Repurposing against the PurS Subunit of Phosphoribosylformylglycinamidine Synthase in Methicillin- and Oxacillin-Resistant Staphylococcus Aureus: In vitro and In silico Studies.","authors":"Faryal Ashraf, M Iqbal Choudhary, Muhammad Yousuf, Humaira Zafar, Atia Tul-Wahab","doi":"10.2174/0115734064472830260611114241","DOIUrl":"https://doi.org/10.2174/0115734064472830260611114241","url":null,"abstract":"<p><strong>Introduction: </strong>Staphylococcus aureus is the causative agent of mild to severe human infections. The exponential increase in resistance to available antibiotics has created the need to identify new drug targets and develop new drug candidates to combat bacterial infections. The PurS subunit of phosphoribosylformylglycinamidine synthase (synonym FGAM synthase) catalyzes the 4th step of the de novo purine biosynthesis in bacteria, including S. aureus. Purine nucleotides are essential in the bacterial life cycle and are required for growth and survival. Inhibition or disruption of FGAM synthase adversely affects the bacterial life cycle.</p><p><strong>Methods: </strong>This study reports cloning, expression, and purification (yield 16.08 mg/mL) of the PurS subunit of FGAM synthase from methicillin- and oxacillin-resistant Staphylococcus aureus, followed by interaction analysis of the PurS subunit with 50 US-FDAapproved drugs, using Saturation Transfer Difference (STD) NMR spectroscopy.</p><p><strong>Results: </strong>Among these drugs, tramadol HCl (1), nicotinamide (2), amoxicillin trihydrate (3), hydroxychloroquine sulphate (4), and phenylephrine HCl (5) showed interactions with the PurS subunit of FGAM synthase, using STD-NMR spectroscopy. All 50 drugs were also studied for their effects on thermal destabilization of the PurS subunit using differential scanning fluorimetry; among them, only nicotinamide (2) and drotaverine HCl (6) destabilized the PurS subunit of FGAM synthase. However, drug 6 interacted with the PurS subunit either irreversibly or with strong binding affinity, as no interactions in STD-NMR were observed. Therefore, drugs 1‒5, which showed interactions in STD-NMR, were further computationally studied, revealing comparable docking scores (-2.4 to 0.21) for complexes 1‒5 (PurS subunit, and drugs 1‒5), with substantial binding energies, supporting the experimental findings.</p><p><strong>Discussion: </strong>The current study focuses on FGAM synthase, a potential drug target in S. aureus. This is the first report on the identification of drugs that bind the PurS subunit of FGAM synthase using STD-NMR, DSF, and molecular docking. Drugs 1‒6 can be considered potential hits for further studies for drug discovery against infections caused by methicillin- and oxacillin-resistant S. aureus.</p><p><strong>Conclusion: </strong>These five hits merit further biochemical and mechanistic studies to validate their therapeutic potential against methicillin- and oxacillin-resistant S. aureus infections.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604866","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 Critical Review of Tetramethylpyrazine: Diseases and Derivatives.","authors":"Jie Fan, Sixun Zeng, Yingxian Liu, Hang Xu, Wangping Ma, Fenghua Zhang","doi":"10.2174/0115734064473152260514071623","DOIUrl":"https://doi.org/10.2174/0115734064473152260514071623","url":null,"abstract":"<p><p>As the primary active constituent of the traditional Chinese medicinal herb Ligusticum chuanxiong, Tetramethylpyrazine (TMP) has demonstrated broad therapeutic potential across multiple disease areas. Its clinical applications span cardiovascular and cerebrovascular disorders, oncology, hepatorenal protection, and respiratory diseases. The mechanisms of action involve antiplatelet aggregation, anti-inflammatory, antioxidant, and anti-apoptotic effects, as well as modulation of autophagy and multiple signaling pathways. Despite its pleiotropic efficacy, the clinical utility of TMP is constrained by unfavorable pharmacokinetic properties, including rapid metabolism and limited oral bioavailability. To overcome these limitations, researchers have developed various TMP derivatives, which exhibit significantly improved metabolic stability and enhanced pharmacological activity. This review summarizes recent advances in TMP and its derivatives over the past five years, aiming to provide insights for the future development of novel TMP-based therapeutics.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604814","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":"Investigating the Bioactivity of Indole-Based Oxadiazole Derivatives: Design, Synthesis, and Anti-Inflammatory Activities.","authors":"Siyuan Ma, Jiayi Cai, Zixuan Yang, Mengping Guo, Jian-Guo Fu, Chi-Ming Liu","doi":"10.2174/0115734064499405260624073822","DOIUrl":"10.2174/0115734064499405260624073822","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) exert their pharmacological effects by inhibiting Cyclooxygenase (COX) enzymes and are widely used in the treatment of inflammation. The new potential anti-inflammatory agents of indolebased oxadiazole derivatives were developed.</p><p><strong>Methods: </strong>A structure-activity relationship study of 62 indomethacin derivatives was designed, synthesized, and tested for COX-2 inhibition and anti-inflammatory activity in vitro. The structures were confirmed by 1H-NMR, 13C-NMR, and ESI-MS. Drug-likeness and pharmacokinetic properties were predicted by PreADME. Molecular docking was conducted to explore the binding interactions of these compounds with COX-2.</p><p><strong>Results: </strong>Compounds 4a and 4f exhibited superior COX-2 inhibitory activity compared to indomethacin and celecoxib at a concentration of 500 nM. Compounds 4a and 4f (0.0001-1 μM) showed no cytotoxicity while inhibiting COX-2 in the Raw264.7 cell line. Molecular docking results indicated that compounds 4a and 4f have affinity and interaction with COX-2.</p><p><strong>Conclusion: </strong>Compounds 4a and 4f show selective COX-2 inhibition as potent antiinflammatory agents for the treatment of inflammatory diseases. Molecular docking studies have shown high affinity for COX-2, and the pharmacokinetic properties suggest that 4f can be categorized as a drug-like compound. Compounds 4a and 4f can be considered for further investigation.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430709","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":"Evaluation of the Anticancer Potential of Nitro-Benzimidazole Derivatives in Breast Cancer.","authors":"Ayşe Büşranur Celik, Kezban Ucar Cifci, Merve Akdag, Sema Nur Agca, Levent Gulum, Musa Ozil, Yusuf Tutar","doi":"10.2174/0115734064480556260605205509","DOIUrl":"https://doi.org/10.2174/0115734064480556260605205509","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds have attracted considerable interest in medicinal chemistry due to their broad pharmacological properties and anticancer potential. This study aimed to investigate the anticancer activity, selectivity, and molecular mechanisms of novel nitro-benzimidazole derivatives in luminal and Adriamycin-resistant breast cancer cell lines.</p><p><strong>Methods: </strong>A series of benzimidazole derivatives was synthesized and evaluated using in silico pharmacokinetic analyses. Cytotoxicity was assessed by MTT assay in MCF-7, adriamycinresistant MCF-7 (MCF-7/Adr), and normal human fibroblast cells CCD-1072sk. The most active compound was further investigated by RT-qPCR-based gene expression and pathway enrichment analyses, flow cytometry-based evaluation of apoptosis and cell cycle distribution, fluorescence-based morphological analyses, and gene-metabolite interaction analysis.</p><p><strong>Results: </strong>Among the tested compounds, SN-1 exhibited the strongest antiproliferative activity, with IC₂⁽ values of 4.86 ± 0.27 μM in MCF-7 cells and 8.62 ± 1.51 μM in MCF-7/Adr cells, along with a high selectivity index. SN-1 significantly induced apoptosis and caused cell cycle arrest at the G2/M phase in MCF-7 cells and at the G0/G1 phase in MCF-7/Adr cells. Gene enrichment and metabolite interaction analyses revealed modulation of apoptosis-, cell cycle-, and metabolism-related pathways, including associations with glycerol, ATP, and ADP.</p><p><strong>Discussion: </strong>These findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways. The observed effects on resistant cells further indicate the therapeutic potential of SN-1 in overcoming chemotherapy resistance.</p><p><strong>Conclusion: </strong>The nitro-benzimidazole derivative SN-1 exhibits strong and selective anticancer effects in both drug-sensitive and chemoresistant breast cancer cells by modulating apoptosis, cell cycle progression, and key metabolic pathways.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376290","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> Evaluation of the Antibacterial Potential of the Cyclic Tetrapeptide Tentoxin Derived from <i>Alternaria alternate</i>.","authors":"Vera S Zayats, Siyamak N Shahab","doi":"10.2174/0115734064488134260611223851","DOIUrl":"https://doi.org/10.2174/0115734064488134260611223851","url":null,"abstract":"<p><strong>Introduction/objective: </strong>The main objective of this study is to test <i>in silico</i> the previously unexplored antimicrobial activity of the tetrapeptide tentoxin. To investigate its efficacy, in silico molecular docking was performed to analyze its interactions with key resistancerelated proteins, specifically FusB and the bacterial IMPDH, a validated target for antibiotic development.</p><p><strong>Methods: </strong>Ligand preparation and quantum chemical analysis of tentoxin were performed using DFT at the CAM-B3LYP/TZVP level of theory. Molecular docking was executed via Auto- DockVina, while ADMET profiles were predicted using the Deep-PK platform. Protein-ligand interactions were characterized through computational visualization tools to assess binding modes and stability.</p><p><strong>Results: </strong>For FusB, a binding energy of -9.1 kcal/mol with an inhibition constant of 0.213 μM was obtained. For bacterial IMPDH, a binding energy of -7.3 kcal/mol with an inhibition constant of 4.449 μM was obtained.</p><p><strong>Discussion: </strong>These findings represent the first evidence of tentoxin's potential as a bacterial inhibitor. The strong binding to FusB and IMPDH suggests a specific mechanism of action, confirming that the compound effectively targets key bacterial proteins.</p><p><strong>Conclusion: </strong>These results provide a theoretical foundation for subsequent <i>in vitro</i> studies of tentoxin against a broad spectrum of bacteria, including multidrug-resistant strains. Our findings highlight the potential of natural fungal metabolites as a scaffold for developing novel antibacterial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376247","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":"ZN002: A Novel Natural Product Small Molecule Inhibitor Targets the Coxsackie-Adenovirus Receptor (CAR) to Control Coxsackie B3 Viral Proliferation.","authors":"Ashish Kumar, Harish C Chandramoorthy","doi":"10.2174/0115734064452781260507102053","DOIUrl":"https://doi.org/10.2174/0115734064452781260507102053","url":null,"abstract":"<p><strong>Introduction: </strong>The Coxsackie Adenovirus Receptor (CAR), encoded by the CXADR gene, facilitates entry of Coxsackie group B virus (CVB) and adenoviruses into host cells. Infections caused by CVB, particularly CVB3, are associated with severe complications, such as meningoencephalitis and cardiomyopathy. Currently, no specific antiviral therapy is available. This study aimed to identify novel lead compounds targeting CVB3 using an integrated in silico and in vitro approach.</p><p><strong>Materials and methods: </strong>A diversity-based High-Throughput Virtual Screening (HTVS) of a Zn-based natural compound library was conducted, followed by Molecular Dynamic Simulation (MDS) to assess binding stability. Top hits were evaluated using in vitro Micro Tissue Culture Antiviral Assays (MTCA), including Direct Pre-infection Incubation (DPI), Pre-Treatment Assay (PTA), and Viral Adsorption Assay (VAA) in HEp-2 cells. MTT assay was performed to assess cytotoxicity.</p><p><strong>Results: </strong>Among the top five hits, ZN-002 [2-(3,4-dimethylphenyl) cyclohexa-2,5-diene-1,4- dione] showed strong binding affinity (< -5.0 kcal/mol) with stable interactions spanning residues Pro25 to Gln50 of the CAR protein. MDS confirmed binding stability over 100 ns. ZN- 002 demonstrated dose-dependent antiviral activity at 10-15 μM concentrations, effectively inhibiting 1, 10, and 100 TCID50 of CVB3 in multiple assay formats without cytotoxicity.</p><p><strong>Discussion: </strong>ZN-002 interferes with the CAR-virus interaction interface, likely hindering viral entry into host cells. The compound's robust binding and broad antiviral efficacy across varying viral loads underscore its potential. The absence of cytotoxicity further supports its candidacy for therapeutic development. This dual in silico-in vitro validation platform accelerates earlystage antiviral discovery.</p><p><strong>Conclusion: </strong>ZN-002 represents a promising lead molecule against CVB3, warranting further evaluation through in vivo studies to explore its potential as a novel antiviral agent.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361624","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":"2-Quinolinone Derivatives as Dual Cholinesterase Inhibitors: Experimental and Computational Insights.","authors":"Ece Oğuz, Pınar Güller","doi":"10.2174/0115734064499561260531131802","DOIUrl":"https://doi.org/10.2174/0115734064499561260531131802","url":null,"abstract":"<p><strong>Background: </strong>Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two cholinesterases that play important roles as therapeutic targets in the cholinergic system associated with neurodegenerative diseases such as Alzheimer's disease.</p><p><strong>Objective: </strong>The purpose of this study was to assess the in vitro inhibitory potencies of 2- quinolinone derivatives against hAChE and hBuChE and to estimate the interaction types in silico. Besides, drug-likeness characteristics (ADME) and density functional theory (DFT) calculations of the compounds were used to support the in vitro inhibition studies.</p><p><strong>Methods: </strong>IC50-[inhibitor] graphs and Lineweaver-Burk graphs were generated. Molecular docking studies were performed by AutoDock. While ADME properties were predicted by SwissADME, DFT calculations of the compounds were made by ORCA software.</p><p><strong>Results: </strong>QU4 and QU6 were found to be the most effective inhibitors of AChE and BuChE with Ki values of 35.672±9.75 μM and 13.38±3.5 μM, respectively. The binding energy of QU3 against hAChE was estimated as -7.51 kcal/mol, while QU2 exhibited a binding energy of -9.11 kcal/mol against BuChE; these values are more negative than that of the reference inhibitor tacrine for both enzymes. Additionally, according to drug-likeness analysis, the derivatives except QU7 showed high blood-brain barrier permeability.</p><p><strong>Discussion: </strong>The results suggest that QU4 and QU6 derivatives may have potential for cholinesterase inhibition.</p><p><strong>Conclusion: </strong>Overall, the findings of this study guide the development of more potent and selective inhibitors by appropriate structural modifications of the 2(1H)-quinolinone skeleton.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258674","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> and <i>in vitro</i> Analysis of Secondary Metabolites of <i>Pleurotus djamor</i> Against Targets of <i>Haemonchus contortus</i>.","authors":"Eyra Ortiz-Perez, Jose M Quintero-Solano, Jesús Antonio Pineda-Alegría, Fernanda Robles-Inclan, Liliana Aguilar-Marcelino, Gildardo Rivera","doi":"10.2174/0115734064467947260602065231","DOIUrl":"https://doi.org/10.2174/0115734064467947260602065231","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Haemonchosis is a gastrointestinal disease caused by the nematode Haemonchus contortus, a serious problem in sheep farming worldwide. Benzimidazole drugs are used as treatment; however, their ineffectiveness and resistant strains indicate a need for new therapeutic options. Therefore, this project aimed to determine the possible mode of action and nematicidal activity of secondary metabolites of the mushroom Pleurotus djamor against H. contortus.</p><p><strong>Methods: </strong>Four pharmacological targets were selected to assess the binding affinity of the major secondary metabolites by molecular docking and molecular dynamics simulations. Subsequently, the nematicidal activity of selected compounds was evaluated using larval mortality assays.</p><p><strong>Results: </strong>Molecular docking analysis determined an affinity of 5,6-dimethoxy-1(3H)-isobenzofuranone (DIB) and veratryl alcohol (VA) for phosphoethanolamine N-methyltransferase (PMT1 and PMT2). Nevertheless, molecular dynamics simulations revealed that only the PMT1-DIB complex displayed greater stability than the control. In the in vitro evaluation, VA induced dose-dependent larval mortality, reaching 55% at 5 mg/mL, while CAF was inactive. No synergistic effect was observed with the combination of VA and CAF.</p><p><strong>Discussion: </strong>The stable interaction observed between DIB and PMT1 suggests that this enzyme may represent a promising anthelmintic target in H. contortus. In contrast, the biological activity exhibited by VA despite its unstable binding profile indicates the possible involvement of alternative molecular targets or pathways. Nevertheless, additional biochemical and experimental studies are required to further elucidate the underlying mechanisms of action.</p><p><strong>Conclusion: </strong>These findings highlight PMT1 as a promising pharmacological target and suggest that DIB and VA may contribute to the anthelmintic activity of P. djamor metabolites against H. contortus.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258736","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":"Indole-2-carboxylic Acid Hydrazones and Hydroxamic Acid Derivatives: Synthesis and Evaluation of Biological Properties.","authors":"Pavel Tiuleanu, Ivan V Ivanov, Irina P Andreeva, Vitaly G Grigorenko, Lybov G Dezhenkova, Alexey M Egorov, Andrey E Shchekotikhin","doi":"10.2174/0115734064493020260523211527","DOIUrl":"https://doi.org/10.2174/0115734064493020260523211527","url":null,"abstract":"<p><strong>Introduction: </strong>The indole nucleus is considered a privileged pharmacophore in medicinal chemistry. Indole-2-carboxylic acid derivatives are valued for their antiproliferative and antibacterial properties, including the potential to overcome drug resistance. This study aimed to synthesize novel salicylidene hydrazones of indole-2-carboxylic acid and evaluate their potential as metallo-β-lactamase (NDM-1) inhibitors and antiproliferative agents alongside previously reported indole-2-carboxylic acid derivatives.</p><p><strong>Methods: </strong>A novel series of salicylidene hydrazones of indole-2-carboxylic acid was synthesized with potential as metallo-β-lactamase inhibitors in mind. All compounds were evaluated for their inhibitory activity against NDM-1 and tested for antiproliferative potency against human chronic myelogenous leukemia K-562 cells and the multidrug-resistant (MDR) subline K- 562/4. Doxorubicin and previously reported indole derivatives (1, 5, 6) were used as reference compounds.</p><p><strong>Results: </strong>Unlike the parent acid 1, the novel derivatives showed weak NDM-1 inhibition (IC50 > 50 μM). In contrast, salicylidene hydrazones 4a-g demonstrated strong antiproliferative activity (IC50 = 0.15-0.80 μM). This effect was particularly pronounced against the MDR subline K- 562/4. Notably, the IC50 values for several derivatives were up to 50-fold lower than that of doxorubicin against resistant cells. Hydrazide 3, hydrazones 4h and 4i, thiosemicarbazide 5, and hydroxamic acids 6a-c showed moderate antiproliferative activity (IC50 = 2.4-13.3 μM).</p><p><strong>Discussion: </strong>The weak NDM-1 inhibition confirms that a free 2-carboxyl group is critical for binding within the enzyme's active site. However, converting this scaffold into salicylidene hydrazones significantly enhances antiproliferative potency. It also effectively enables the circumvention of P-glycoprotein (P-gp) mediated efflux in MDR leukemia cells.</p><p><strong>Conclusion: </strong>Indole-2-carboxylic acid salicylidene hydrazones emerged as promising scaffolds for developing new anticancer agents. They exhibit potent activity against leukemia cells, particularly against the P-gp-overexpressing MDR subline K-562/4.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258761","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}