Drug Development Research最新文献

{"title":"Dioscin Reverses Drug Resistance via AKT/GSK3β-mediated P-gp Degradation and EMT Inhibition","authors":"Keqi Zhang,&nbsp;Jinzhu Zhao,&nbsp;Linlin Li,&nbsp;Zixin Wang,&nbsp;Xinyi Mao,&nbsp;Jie Yan,&nbsp;Shuhua Han,&nbsp;Mingjing He,&nbsp;Bingjie Bi,&nbsp;Qiang Xu,&nbsp;Cong Wang","doi":"10.1002/ddr.70366","DOIUrl":"https://doi.org/10.1002/ddr.70366","url":null,"abstract":"<div>\u0000 \u0000 <p>Tumor drug resistance and metastasis are leading causes of cancer‑related mortality, both of which are tightly governed by multiple signaling pathways. The AKT‑GSK‑3β axis is a critical regulator of tumor progression, mediating drug resistance and epithelial‑mesenchymal transition (EMT) through its downstream targets. Aberrantly activated AKT‑GSK‑3β signaling modulates the expression and degradation of the drug efflux pump P-gp, which expels chemotherapeutic agents, including paclitaxel (PTX), from cancer cells, resulting in chemotherapy failure and drug resistance. Moreover, hyperactivated AKT‑GSK‑3β signaling drives EMT, a key process closely linked to tumor metastasis and malignant progression. Dioscin (Dio), a natural steroidal saponin, exhibits significant anti‑tumor activity in multiple cancers. However, whether Dio reverses chemoresistance and inhibits tumor growth by targeting the AKT‑GSK‑3β pathway to promote P-gp degradation and suppress EMT remains elusive, which is the central focus of this study. To explore whether Dio enhances the sensitivity of drug-resistant cancer cells to PTX and inhibits cancer metastasis and the EMT process, as well as its potential mechanism(s). Paclitaxel-resistant TE-1/PTX and HeLa/PTX cells were subjected to SRB, colony formation, Rh123 accumulation, wound-healing, and Transwell assays to evaluate Dio's chemosensitizing, anti-EMT, and anti-metastatic effects. Network pharmacology, molecular docking, CETSA, and proteolysis assays verified a direct Dio-AKT1 interaction. Western blotting, Co-IP, and MG132 and MK2206 rescue experiments clarified AKT/GSK3β-dependent P-gp ubiquitin-proteasomal degradation and EMT suppression. HeLa/PTX xenograft models were generated; H&amp;E staining and immunoblotting were used to assess tumor growth, biosafety, and intratumoral protein profiles for in vivo validation. Dio sensitized PTX-resistant cells to paclitaxel, increased intracellular Rh123 accumulation, and inhibited cell migration and invasion. Mechanistically, Dio directly bound AKT1 to suppress AKT/GSK3β signaling, promoted ubiquitin-proteasomal degradation of P-gp, and reversed EMT by upregulating epithelial markers and repressing mesenchymal markers and EMT transcription factors. In vivo, Dio restrained xenograft tumor growth with negligible systemic toxicity, and intratumoral expression patterns of AKT/GSK3β, P-gp, and EMT-related proteins mirrored in vitro findings. Dio has the potential to be a safe and effective agent for drug-resistant cancer therapy.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753940","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":"Development of Phenoxyacetic Acid Hybrids With COX-2 Inhibitory Activity as Potential Anti-Neuroinflammatory Agents","authors":"Mohammad H. Alqarni,&nbsp;Mahmoud Abdelrahman Alkabbani,&nbsp;Aya Mohamed Ahmed Ibrahim,&nbsp;Ahmed I. Foudah,&nbsp;Tariq M. Aljarba,&nbsp;Aftab Alam,&nbsp;Hatem A. Abdel-Aziz,&nbsp;Mohamed K. Elgohary","doi":"10.1002/ddr.70363","DOIUrl":"https://doi.org/10.1002/ddr.70363","url":null,"abstract":"<div>\u0000 \u0000 <p>This research employs a molecular hybridization strategy to repurpose the pyrazoline scaffold <b>6a, 6c, 7a-c, 11a,</b> and <b>12b</b>, transforming it into a high-efficiency conjugate designed to tackle the multifaceted pathology of neuroinflammation and epilepsy. By integrating a selective phenoxyacetic acid moiety. Our findings identified compound <b>7c</b> as a potential lead candidate for the development of novel anticonvulsant agents. In vivo trials demonstrated that <b>7c</b> offers a superior therapeutic window compared to valproic acid, yielding 90% seizure protection in PTZ models and a remarkable 212.27% delay in seizure onset within the pilocarpine model, alongside 100% survival. Beyond mere symptomatic suppression, <b>7c</b> re-engineers the hippocampal environment by slashing glutamate-driven excitotoxicity by 64.23% and silencing the cytokine-glial activation axis (TNF-alpha, IL-6, GFAP, and Iba-1). Supported by ADME profile confirming optimal BBB permeability and molecular docking indicating a robust binding affinity of −10.3 kcal/mol, this study positions <b>7c</b> as a versatile, non-toxic, and repurposed-ready hybrid candidate for advanced neuroprotective intervention.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753979","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, X-Ray Crystallographic Characterization, Anticholinesterase and Antioxidant Evaluation, and Molecular Modeling of Novel Dispiroindene-Pyrrolidine Derivatives as Multifunctional Anti-Alzheimer Agents","authors":"Aisha A. Alsfouk,&nbsp;Riham A. El-Shiekh,&nbsp;Benson M. Kariuki,&nbsp;Eman Sabry,&nbsp;Mohamed G. Abouelenein,&nbsp;Asmaa Saleh,&nbsp;Mahmoud G. A. Saleh,&nbsp;Aladdin M. Srour","doi":"10.1002/ddr.70361","DOIUrl":"10.1002/ddr.70361","url":null,"abstract":"<p>A novel series of 5-chloro-<i>N</i>-alkyl-1′,1″-dimethyl-4′-aryldispiro[indene-2,3′-pyrrolidine-2′,3″-indoline]−1,2″(3<i>H</i>)-diones (<b>4a–r</b>) was rationally designed and synthesized via a one-pot multicomponent reaction of <i>N</i>-alkylated 5-chloroisatin derivatives, 2-(arylmethylidene)−2,3-dihydro-1<i>H</i>-inden-1-ones (<b>2a–i</b>), and sarcosine (<b>3</b>). To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives <b>4b</b>, <b>4f</b>, and <b>4o</b> emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC₅₀ = 0.91 ± 0.02, 0.89 ± 0.01, and 0.74 ± 0.01 µM, respectively; donepezil IC₅₀ = 0.68 ± 0.005 µM) alongside significant BChE inhibition (IC₅₀ = 10.19 ± 0.16, 9.59 ± 0.08, and 9.11 ± 0.01 µM, respectively; donepezil IC₅₀ = 2.97 ± 0.01 µM). The structure of the most active derivatives (<b>4b</b>, <b>4f</b>, and <b>4o</b>) was further confirmed by X-ray crystallographic analysis. In addition, antioxidant evaluation of compounds <b>4b</b>, <b>4f</b>, and <b>4o</b> demonstrated that derivative <b>4f</b> possessed the most superior radical scavenging profile (IC₅₀ = 23.18 ± 0.33 µM), representing approximately a 5.5-fold enhancement in potency relative to ascorbic acid (IC₅₀ = 128.20 ± 0.82 µM). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood–brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti-Alzheimer agents.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700813","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}

{"title":"Applications of Bioinorganic Nano-Based Delivery Systems—Diagnostics and Therapeutics","authors":"Frank Ssengooba,&nbsp;Jubilee Andrew,&nbsp;Donald Fernandes","doi":"10.1002/ddr.70276","DOIUrl":"10.1002/ddr.70276","url":null,"abstract":"<p>Nanotechnology has emerged as a promising avenue for producing nanomedicines as alternatives to conventional drugs. Many organic nanoparticles, such as liposomes used in formulations like Doxil, Onivyde, and Marqibo, are approved by the Food and Drug Administration (FDA) and instrumental in treating various types of cancers. However, due to the many challenges associated with these formulations, alternative delivery systems have been explored, particularly those derived from inorganic sources. In particular, bioinorganic nano-based delivery systems (BNDSs) such as gold, silver, platinum, silicon-based, metal oxide and hybrid nanoparticles have been found to be useful in treating cancer and infectious and noncommunicable diseases. This review presents the most commonly used BNDSs, providing an in-depth discussion on their use as therapeutic and imaging agents, the challenges associated with their use and current trends and future perspectives in their development for enhancing efficacy.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668151","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}

{"title":"GRP78 Drives NSCLC Stemness and EMT via a SIX1/β-Catenin Signaling Axis","authors":"Guoping Tong,&nbsp;Huanyu Qi","doi":"10.1002/ddr.70359","DOIUrl":"10.1002/ddr.70359","url":null,"abstract":"<div>\u0000 \u0000 <p>Non-small cell lung cancer (NSCLC) exhibits stem-like characteristics that drive tumor aggressiveness and treatment resistance. The molecular chaperone Glucose-Regulated Protein 78 (GRP78) is substantially elevated in NSCLC compared to normal tissues and cell lines. In clinical samples, GRP78 protein levels correlated with advanced tumor stage and lymph node metastasis. Pharmacological inhibition of GRP78 using BAPTA-AM and GRP78-IN-3 significantly suppressed NSCLC cell viability while promoting apoptosis. The inhibitors effectively attenuated cell migration by downregulating matrix metalloproteinases and reversed epithelial-mesenchymal transition by modulating key cadherin expression profiles. Importantly, GRP78 inhibition substantially reduced cancer stem cell markers and impaired spheroid formation capability. Genetic knockdown of GRP78 in A549 and H1975 cells recapitulated the effects of pharmacological inhibition, reducing cell migration, reversing EMT, attenuating stemness, and suppressing β-catenin signaling. Conversely, GRP78 overexpression in A549 and H1975 cells induced opposite effects, promoting mesenchymal markers, enhancing stemness proteins, and increasing spheroid size. Mechanistic studies revealed that this anti-tumor activity operates through suppression of β-catenin signaling mediated by SIX1, as evidenced by SIX1-overexpression rescue experiments. These findings demonstrate that GRP78 acts as a key regulator of NSCLC stemness and metastatic potential by coordinating epithelial plasticity and stemness pathways, positioning it as a promising therapeutic target for NSCLC treatment.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668177","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":"Targeting CDK-2 With Novel Indole-Pyrazole Hybrids: Discovery of Potent Anticancer Agents Supported by Mechanistic and In Silico Studies.","authors":"Wagdy M Eldehna, Zainab M Elsayed, Mohamed R Elnagar, Yasser M Omar, Maha-Hamadien Abdulla, Abdulrahman M Saleh, Abdelrahman R Shalabi, Diaaeldin M Elimam, Suliman Alshamari, Mohamed Fares, Haytham O Tawfik","doi":"10.1002/ddr.70357","DOIUrl":"10.1002/ddr.70357","url":null,"abstract":"<p><p>The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin-dependent kinase-2 (CDK-2). ¹H NMR, ¹³C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK-2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub-micromolar IC₅₀ values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC₅₀ = 0.716 µM) as the most potent inhibitor (IC₅₀ = 0.536 µM), followed by compound 9 g (IC₅₀ = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT-116, and MCF-7 was further assessed. In addition to having an enhanced selectivity index for normal MCF-10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF-7 cells (IC₅₀ = 6.78 µM), surpassing Roscovitine (IC₅₀ = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S-phase population, markedly promoted apoptosis, and caused G1 and G2/M cell-cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP-binding pocket of CDK-2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug-like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK-2-targeted anticancer agents.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":"e70357"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705816","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}

{"title":"Alternative Splicing in Cyclin-Dependent Kinase 4/6 Inhibitor Resistance in Estrogen Receptor-Positive Breast Cancer.","authors":"Yuqiu Cui, Jia Xie, Jiale Cai, Yue Si, Hairong Huang, Shiyi Yu, Haibo Sun","doi":"10.1002/ddr.70354","DOIUrl":"10.1002/ddr.70354","url":null,"abstract":"<p><p>Breast cancer is one of the leading causes of cancer-related deaths among women worldwide, with estrogen receptor-positive (ER+) breast cancer being the most common subtype. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become a crucial therapeutic approach for this type of cancer. However, ER+ breast cancer frequently develops resistance to CDK4/6i, limiting therapeutic efficacy. Alternative splicing is a key post-transcriptional regulatory mechanism that may drive such resistance. In this review, we comprehensively analyzed the literature on the molecular mechanisms and key signaling pathways associated with CDK4/6i resistance in ER+ breast cancer and introduced the role of alternative splicing, with a particular focus on its function in tumor drug resistance. Available evidence suggests that splicing dysregulation may influence resistance through multiple pathways, including cell-cycle control, epithelial-mesenchymal transition, growth factor and RAS/MAPK signaling, and immune-related programs. Recent work has also suggested that reduced expression of the splicing regulator NSRP1 may be associated with CDK4/6i resistance through altered NSD2 splicing and activation of interferon signaling, although this mechanism currently requires further independent validation. Collectively, these findings support alternative splicing as a promising but still evolving area of investigation in CDK4/6i resistance. This work provides deeper insights into the role of alternative splicing in CDK4/6i resistance and offers a theoretical foundation for developing novel therapeutic approaches. Future research may focus on developing drugs that precisely modulate specific splicing events or combining CDK4/6i with splicing modulators to reverse or delay resistance.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":"e70354"},"PeriodicalIF":4.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705784","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}

{"title":"TrxR Inhibition and Nrf2–FOXO3 Modulation by Repurposed Drugs: A Redox Strategy to Reverse Cancer Multidrug Resistance","authors":"Charan Singh Pawar,&nbsp;Nagarajan Rajendra Prasad","doi":"10.1002/ddr.70358","DOIUrl":"https://doi.org/10.1002/ddr.70358","url":null,"abstract":"<div>\u0000 \u0000 <p>A common cause of multidrug-resistant (MDR) cancer is imbalanced redox signaling, which reduces the effectiveness of chemotherapy and promotes regrowth of cancer cells. Amplification of thioredoxin reductase (TrxR) and activation of the Keap1–Nrf2–FOXO3 pathway may contribute to enhanced drug efflux, strengthens antioxidant defenses, and resistance to oxidative stress-induced apoptosis in certain tumors. Redox-based drug repurposing offers a promising strategy to overcome MDR by targeting these shortcomings. Repurposing drugs including metformin, auranofin, brusatol, and natural polyphenols increase reactive oxygen species (ROS) and make MDR cells more sensitive to chemotherapy via modulation and inhibiting Nrf2 or TrxR. Nanotechnology advancements and combination of repurposed drugs with anticancer drugs, ferroptosis inducers may improve tumor selectivity while lowering systemic toxicity. Preclinical experiments show effectiveness by suppressing antioxidant pathways, inhibiting efflux pump function, and delivering drugs in a redox-responsive manner. Next-generation tumor-selective delivery systems, adaptive clinical trial designs, and biomarker-driven patient classification based on TrxR expression or Keap1/Nrf2 mutations are the main areas of focus. Translation into clinical practice could be accelerated by combining specific redox profiling, nanocarrier technologies, and pharmacokinetics. For MDR cancer, redox-targeted drug repurposing is an effective, precision-based strategy for recovering chemosensitivity and enhancing treatment outcomes.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617187","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":"RETRACTION: Reprogramming the Tumor Microenvironment: Calebin A as a Polyphenolic Paradigm Shift in Controlling Inflammation, Stemness, and Resistance in Colorectal Cancer","authors":"","doi":"10.1002/ddr.70356","DOIUrl":"10.1002/ddr.70356","url":null,"abstract":"<p><b>RETRACTION</b>: Anonymous, “Reprogramming the Tumor Microenvironment: Calebin A as a Polyphenolic Paradigm Shift in Controlling Inflammation, Stemness, and Resistance in Colorectal Cancer,” <i>Drug Development Research</i> 87, no. 2 (2026): e70230, https://doi.org/10.1002/ddr.70230.</p><p>The above article, published online on 28 January 2026 in Wiley Online Library (onlinelibrary.wiley.com), has been retracted by agreement between the Editor-in-Chief, Steven Fletcher; and Wiley Periodicals LLC. An investigation by the publisher found that the paper was submitted by a fraudulent third-party who used a fake email address to impersonate the corresponding author. The named authors did not consent to the submission or publication of the article. Therefore, a decision has been made to retract this article. Since the authors were listed without their consent and under false pretenses, their names have been removed from the article's author list.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70356","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148600331","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}

{"title":"Two Novel 1,4-Naphthoquinone Derivatives as Potent Agents Against Multidrug-Resistant Staphylococcus aureus and Pathogenic Gram-Positive Bacteria","authors":"HyunChan Song,&nbsp;Haena Lee,&nbsp;Ji-Hyun Yoon,&nbsp;Hyunkyung Choi,&nbsp;Hakwon Kim,&nbsp;Ki-Young Kim","doi":"10.1002/ddr.70353","DOIUrl":"10.1002/ddr.70353","url":null,"abstract":"<p>Drug-resistant bacteria such as Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and Quinolone-resistant <i>S. aureus</i> (QRSA), are a growing problem, creating a need for the development of novel antimicrobial agents. In this study, we designed and synthesized two novel 1,4-naphthoquinone derivatives, <b>LHN-1034</b> and <b>LHN-1035,</b> and evaluated their antibacterial efficacy. Both compounds exhibited great antimicrobial activity against a group of Gram-positive bacteria, including MRSA and QRSA, with Minimum Inhibitory Concentrations (MICs) ranging from 50 to 100 µM. Mechanism studies revealed that the antibacterial effect is oxygen-dependent. The compounds act as redox-cycling agents that induce intracellular reactive oxygen species (ROS), which disrupts cell membrane integrity and leads to cell lysis. In silico assessments predict low intestinal absorption and skin permeability, suggesting these compounds are suited for topical application. In conclusion, <b>LHN-1034</b> and <b>LHN-1035</b> are candidates for developing topical agents against resistant Gram-positive infections.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520145","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}