Drug Development Research最新文献

{"title":"Contrastive Learning-Powered Ultrafast Genome-Wide Virtual Screening: The Rise of DrugCLIP","authors":"Jinwei Zhang","doi":"10.1002/ddr.70351","DOIUrl":"10.1002/ddr.70351","url":null,"abstract":"<div>\u0000 \u0000 <p>Virtual screening (VS) stands as a cornerstone of early-stage drug discovery, yet long-standing hurdles—including prohibitive computational cost and limited cross-target generalization—have long restricted its genome-wide application, especially with the rapid expansion of AlphaFold-predicted protein structures. Over the past 2 years, contrastive learning has emerged as a genuinely transformative paradigm, with DrugCLIP as a landmark implementation that reimagines virtual screening as fast embedding-based dense retrieval. This commentary offers a balanced overview of DrugCLIP's core innovations: its contrastive framework that aligns protein pocket and small-molecule representations, paired with GenPack for targeted pocket refinement of predicted structures. We synthesize recent benchmark results validating its performance relative to molecular docking and machine-learning baselines, recap wet-lab success stories across psychiatric and cancer-associated targets, and assess the real-world impact of the resulting GenomeScreenDB resource. We further place DrugCLIP in context with contemporary computational tools including RosettaVS, Deep Docking, and AF2-RAVE, highlight unresolved challenges such as translating binding predictions into functional activity and screening against tough PPI targets, and outline actionable avenues for future development. Taken together, this work illustrates how contrastive learning is quietly reshaping informatics-driven drug discovery and opening the undrugged genome to systematic exploration.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390177","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 Biological Evaluation of Chiral Urea and Thiourea Derivatives as Multitarget-Directed Anti-Alzheimer Agents","authors":"Sule Erol Gunal,&nbsp;Senel Teke Tuncel,&nbsp;İlke Demir,&nbsp;İpek Baysal,&nbsp;Gökçen Telli,&nbsp;Safiye Sag Erdem,&nbsp;Gulberk Ucar,&nbsp;Michaela Hanzlova,&nbsp;Kamil Musilek,&nbsp;İlknur Dogan,&nbsp;Nesrin Gokhan Kelekci","doi":"10.1002/ddr.70341","DOIUrl":"10.1002/ddr.70341","url":null,"abstract":"<p>A series of novel chiral urea and thiourea compounds were designed as multitarget-directed ligands for Alzheimer's disease and evaluated against hAChE, hBChE, and hMAO-B, with exploratory assessment of HSD10. These chiral compounds were synthesized and fully characterized, and their enantiopurity was confirmed via HPLC. Biological screening revealed that several of the 38 single-enantiomer derivatives exhibited potent triple inhibition of hAChE, hBChE, and hMAO-B. Biological screening revealed that a significant number of the 38 synthesized single-enantiomer urea and thiourea derivatives potent inhibition across the primary target panel. Among them, compounds <b>14</b><i><b>S</b></i> (<i>h</i>AChE: 0.08 μM, <i>h</i>BChE: 0.93 μM, <i>h</i>MAO-B: 0.02 μM), <b>23</b><i><b>R</b></i> (<i>h</i>AChE: 0.06 μM, <i>h</i>BChE: 0.74 μM, <i>h</i>MAO-B: 0.08 μM), <b>6</b><i><b>S</b></i> (<i>h</i>AChE: 0.08 μM, <i>h</i>BChE: 0.65 μM, <i>h</i>MAO-B: 0.08 μM), and <b>30</b><i><b>S</b></i> (<i>h</i>AChE: 0.04 μM, <i>h</i>BChE: 0.74 μM, <i>h</i>MAO-B: 0.19 μM) showed the most promising multitarget profiles. Compounds <b>6</b><i><b>S</b></i> and <b>23</b><i><b>R</b></i> also displayed anti-Aβ aggregation activity, whereas <b>12</b><i><b>S</b></i> combined dual hMAO-B/hAChE inhibition with antioxidant activity. Compounds <b>3</b><i><b>R</b></i> and <b>11</b><i><b>R</b></i> were found to be highly active against <i>h</i>MAO-B (0.03 μM and 0.06 μM, respectively) and <i>h</i>BChE (0.68 and 0.72 μM). HSD10 inhibition was limited overall, with only compound <b>26</b><i><b>S</b></i> showing moderate activity (52.2%) at higher micromolar concentration. Molecular docking and molecular dynamics simulations supported the proposed ligand-target interactions for the most active compounds. In addition, selected derivatives showed no acute cytotoxicity under the tested conditions in HepG2 cells and high permeability potential in the PAMPA-BBB assay. Based on their in vitro profiles, seven compounds (<b>3</b><i><b>R</b></i>, <b>6</b><i><b>S</b></i>, <b>11</b><i><b>R</b></i>, <b>12</b><i><b>S</b></i>, <b>14</b><i><b>S</b></i>, <b>23</b><i><b>R</b></i>, and <b>30</b><i><b>S</b></i>) were advanced to in vivo evaluation, and compounds <b>6</b><i><b>S</b></i>, <b>12</b><i><b>S</b></i>, and <b>23</b><i><b>R</b></i>, <b>30</b><i><b>S</b></i> produced significant improvements in the Morris Water Maze model. Collectively, these findings identify chiral urea and thiourea derivatives as promising lead structures for further anti-Alzheimer drug discovery.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390245","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":"Benzimidazole-Based VEGFR-2 Inhibitors Inspired by Sorafenib: Synthesis, Biological Evaluation, and Mechanistic Insights","authors":"Mohamed Atia Dewidar,&nbsp;Heba Abdelrasheed Allam,&nbsp;Hatem A. Abdel-Aziz,&nbsp;Mohamed R. Elnagar,&nbsp;Noha M. Ibrahim","doi":"10.1002/ddr.70339","DOIUrl":"10.1002/ddr.70339","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based derivatives (<b>3a–k</b>, <b>5a–d</b>, <b>8a–g</b>, and <b>10a–d</b>) were rationally designed to incorporate the essential structural and pharmacophoric features required for effective VEGFR-2 inhibition, followed by their synthesis and biological evaluation. In vitro kinase assays demonstrated that the synthesized derivatives inhibited VEGFR-2 with IC₅₀ values ranging from 0.061 to 1.895 µM. Based on their enzymatic potency, the most active compounds (<b>3f</b>, <b>3h</b>, <b>3j</b>, <b>8d</b>, and <b>8g</b>) were further investigated for antiproliferative activity against HUVEC, MCF-7, and HepG2 cell lines. Among them, Compound <b>3f</b> exhibited IC₅₀ values of 13.34, 5.32, and 5.02 µM, respectively, showing activity comparable to sorafenib. Evaluation against normal MCF-10A and Vero cell lines indicated favorable biocompatibility and a reasonable selectivity profile. Mechanistic studies revealed that <b>3f</b> induced G2/M-phase arrest, promoted apoptosis, and suppressed cell migration, accompanied by a reduction in VEGFR-2 protein expression levels. Molecular docking suggested that the synthesized derivatives adopt a binding mode consistent with Type II VEGFR-2 inhibitors, while in silico ADME and toxicity predictions supported an acceptable toxicity profile and drug-like characteristics.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359948","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":"Luliconazole Potentiates Efficacy of Miltefosine Against Leishmania donovani","authors":"Niva Singh,&nbsp;Mansi Rani,&nbsp;Hara Prasad Mandal,&nbsp;Raju Yadav,&nbsp;Ashiq Hussain Bhat,&nbsp;Dayakar Alti,&nbsp;Shubhankar Kumar Singh","doi":"10.1002/ddr.70337","DOIUrl":"10.1002/ddr.70337","url":null,"abstract":"<div>\u0000 \u0000 <p>Visceral leishmaniasis is a vector-mediated parasitic disease caused by <i>Leishmania donovani</i>. Its treatment relies on chemotherapy with limited options. Existing drugs face significant challenges, including low efficacy, high relapse rates, toxicity, and cost. Therefore, exploring novel chemotherapeutic strategies identified as newer drugs targeting <i>L. donovani</i> CYP51 either alone or in combination with Miltefosine, which presents a promising alternative to current therapy. Here, we have evaluated the antileishmanial potential of an azole drug, luliconazole, which was previously demonstrated to target the sterol biosynthesis pathway in <i>Leishmania major</i>, in combination with conventional antileishmanial agents. Luliconazole exhibited significant inhibitory activity against both extracellular and intracellular <i>L. donovani</i>, with half-maximal inhibitory concentrations of 4.67 and 6.24 µM, respectively. Notably, the addition of miltefosine and luliconazole combinations resulted in a synergistic effect, reducing the effective doses by 3.26- and 5.62-fold compared to monotherapy with miltefosine and luliconazole, respectively. Conversely, the combination of luliconazole with Amphotericin B yielded antagonistic effects. A significant increase in nitric oxide by the parasite-infected macrophages after luliconazole treatment underscores its leishmanicidal potential. Evaluation of host cell cytotoxicity, hemolytic assays, and oxidative burst affirmed the safety of luliconazole. This study is limited to in vitro intracellular amastigote. These findings highlight the efficacy of luliconazole, particularly in combination with miltefosine. Further investigations including formulation development and in vivo validation, are needed to assess the translational potential. This is the first study to demonstrate that luliconazole enhances miltefosine efficacy against <i>L. donovani</i>.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316293","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":"Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease","authors":"Vinod Ugale,&nbsp;Nissi Sharon,&nbsp;Chandradip Salunkhe,&nbsp;Jotiram Salunkhe,&nbsp;Deepak Lokwani,&nbsp;Kalpesh Patil,&nbsp;Pedavenkatagari Narayana Reddy,&nbsp;Prasad Kulkarni","doi":"10.1002/ddr.70338","DOIUrl":"10.1002/ddr.70338","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)−4<i>H</i>-chromene derivatives <b>4</b>(<b>a-n</b>) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound <b>4 m</b> has shown highest inhibitory potency against AChE (AChE, IC₅₀ = 1.08 µM; BuChE, IC₅₀ = 82.59 µM). The prototype compound (<b>4 m</b>) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound <b>4 m</b> was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with <b>4 m</b> have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound <b>4 m</b> alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of <b>4 m</b> at cholinesterase enzymes. Taken together, these findings supported the emergence of <b>4 m</b> as a potential cholinesterase inhibitor for the treatment of AD.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293850","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 Sulfonamide-Based Thiazolidine-2,4-Dione Derivatives as VEGFR-2 and Tumor-Associated hCA IX Inhibitors With Hypoxia-Targeted Anti-Colorectal Cancer Activity","authors":"Haytham O. Tawfik,&nbsp;Mohammed A. Dahab,&nbsp;Mohamed R. Elnagar,&nbsp;Andrea Ammara,&nbsp;Mahmoud S. Elkotamy,&nbsp;Maha-Hamadien Abdulla,&nbsp;Khayal Al-Khayal,&nbsp;Mohamed Fares,&nbsp;Alessio Nocentini,&nbsp;Claudiu T. Supuran,&nbsp;Wagdy M. Eldehna","doi":"10.1002/ddr.70333","DOIUrl":"10.1002/ddr.70333","url":null,"abstract":"<div>\u0000 \u0000 <p>Given their critical roles in tumor progression and hypoxia adaptation, concurrent inhibition of carbonic anhydrase IX (hCA IX) and vascular endothelial growth factor receptor-2 (VEGFR-2) is a viable therapeutic approach. This study rationally developed, synthesized, and biologically assessed a novel class of thiazolidinedione-benzenesulfonamide hybrids as possible dual hCA IX/VEGFR-2 inhibitors. A number of agents, including <b>4a</b>, <b>4b</b>, <b>4e</b>, <b>4g</b>, <b>6a</b>, and <b>6b</b>, showed strong hCA IX inhibition (<i>K</i>_I = 15.0–37.9 nM), outperforming the reference inhibitor acetazolamide (<i>K</i>_I = 25 nM) and displaying better selectivity indices. Moreover, these substances efficiently suppressed VEGFR-2, with IC₅₀ values ranging from 0.055 to 1.080 µM. Under both normoxic and hypoxic conditions, biological evaluation demonstrated strong anti-proliferative activity against colorectal cancer cell lines (HT-29 and HCT-116). Compound <b>4g</b> stood out as the most promising candidate among the investigated derivatives, showing greater activity to 5-fluorouracil during hypoxia and comparable potency under normoxia (IC₅₀ = 5.89 vs. 26.66 µM). In hypoxic conditions, <b>4g</b> significantly enhanced the cytotoxicity of 5-fluorouracil, increasing its activity by more than sevenfold. <b>4g</b> caused cell-cycle arrest at the G₁/G₂/M phases, raised pro-apoptotic markers (caspase-3, caspase-9, and BAX), downregulated the anti-apoptotic protein Bcl-2, and dramatically enhanced apoptotic cell death (total apoptosis: 37.78%), according to mechanistic studies. The persistent binding of <b>4g</b> inside the zinc-containing active site of hCA IX and the ATP-binding pocket of VEGFR-2 was validated by molecular docking and molecular dynamics simulations. Additionally, favorable pharmacokinetic and drug-likeness features were shown by in silico ADME research. All of these results point to compound <b>4g</b> as a promising mechanism-based dual VEGFR-2/hCA IX inhibitor with strong anti-colorectal cancer action, especially in hypoxic tumor microenvironment circumstances.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293859","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":"Bacterial mRNA Vaccines: Programming Immunity Against Antimicrobial Resistance","authors":"Rui Liao,&nbsp;Mingxing Luo,&nbsp;Fating Yang,&nbsp;Lifeng Xu,&nbsp;Jingjing Zhang,&nbsp;Weijun Zhang,&nbsp;Shan Guan,&nbsp;Yi Zhang,&nbsp;Ping Luo,&nbsp;Ping Cheng,&nbsp;Jing Yang,&nbsp;Yang Li,&nbsp;Qian Wang","doi":"10.1002/ddr.70335","DOIUrl":"10.1002/ddr.70335","url":null,"abstract":"<div>\u0000 \u0000 <p>The relentless rise of antimicrobial resistance poses a critical threat to global health, urgently demanding the development of antibacterial vaccines. Messenger RNA (mRNA) technology, validated during the COVID-19 pandemic, offers a powerful platform of fast development and flexibility. However, its application against bacterial pathogens remains an emerging frontier due to the structural complexity of bacterial antigens, challenges in achieving effective mucosal and cellular delivery, and the need to elicit balanced Th1/Th17-dominated immune responses for durable protection. Progress in antigen design, mRNA engineering, and lipid nanoparticle (LNP) delivery has enabled early preclinical success against <i>Mycobacterium tuberculosis</i>, <i>Pseudomonas aeruginosa</i>, and <i>Streptococcus pneumoniae</i>. Yet, challenges such as complex antigen expression, mucosal targeting, and immune durability persist. This review provides a brief overview of recent advances in bacterial mRNA vaccine design, including antigen selection, mRNA engineering, and delivery platform optimization. Additionally, we summarize current preclinical progress across key bacterial pathogens and highlight emerging strategies that integrate AI-guided antigen discovery, synthetic biology, and next-generation delivery systems to accelerate clinical translation. Finally, we highlight the prospects of bacterial mRNA vaccines by integrating synthetic biology, AI-driven antigen prediction, and advanced delivery systems. These cutting-edge technologies hold the promise of overcoming existing barriers, ultimately establishing mRNA vaccines as a viable and powerful strategy to curb the tide of antibiotic-resistant infections.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276602","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 Quinoline Tethered Thiadiazole/Thiazole Derivatives as Potent Tyrosinase Inhibitors With Promising Anti-Toxoplasma gondii Agents: Design, Synthesis, and Computational Analysis","authors":"Ahmed Sabt,&nbsp;Maciej Chyb,&nbsp;Aladdin M. Srour,&nbsp;Adrian Bekier,&nbsp;Hanaa Farag,&nbsp;Moataz A. Shaldam,&nbsp;Hoda Atef Abdelsattar Ibrahim,&nbsp;Asmaa Saleh,&nbsp;Justyna Gatkowska,&nbsp;Huda R. M. Rashdan,&nbsp;Jarosław Dziadek","doi":"10.1002/ddr.70334","DOIUrl":"https://doi.org/10.1002/ddr.70334","url":null,"abstract":"<div>\u0000 \u0000 <p>Toxoplasmosis, caused by the protozoan parasite <i>Toxoplasma gondii</i>, remains a serious global health concern, largely because current treatments with sulfonamides and pyrimethamine are toxic and increasingly ineffective due to rising drug resistance. In response, this study describes the design, synthesis, and laboratory evaluation of novel hybrid molecules that merge a quinoline backbone with either thiadiazole (compounds <b>8a</b>–<b>e</b>) or thiazole (compounds <b>12a</b>–<b>d</b>) bioactive groups to develop safer and more effective therapies. Cytotoxicity tests on mouse (L929) and human (Hs27) fibroblast cell lines revealed distinct safety profiles: the thiadiazole hybrids (<b>8a</b>–<b>e</b>) were significantly toxic to host cells, whereas the thiazole-based versions (<b>12a</b>–<b>d</b>) were much safer, with several showing no toxicity even at 250 µg/mL. When tested against <i>T. gondii</i>, the quinoline-thiazole hybrids proved the most effective. Notably, <b>12b</b> and <b>12c</b> achieved IC₅₀ values of 0.40 and 0.52 µg/mL, respectively, better than the reference drug pyrimethamine (IC₅₀ = 0.74 µg/mL). Compound <b>12c</b> emerged as the top candidate, with an excellent selectivity index (SI) of 71.0 in human Hs27 cells. Further mechanistic work showed that <b>12c</b> strongly inhibits tyrosinase, a potential parasitic target. Kinetic studies revealed a mixed-type inhibition mechanism, with an IC₅₀ of approximately 5 µM, 10 times more potent than kojic acid (48 µM), a standard inhibitor. Molecular docking and dynamics simulations confirmed stable binding between <b>12c</b> and tyrosinase. Together, these findings underscore the therapeutic promise of the quinoline-thiazole scaffold, particularly compound <b>12c</b>, as a lead for developing targeted, low-toxicity anti-toxoplasmosis drugs. The results are expected to expand the existing toolkit of small molecules targeting the parasite and reinforce the importance of molecular hybridization in drug development. Additional research is needed to clarify how these compounds work and to assess their effectiveness in living organisms in order to fully unlock their potential as anti-parasitic drugs.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269128","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":"Selenium-Containing 1,4-Naphthoquinone Derivatives Trigger Reactive Oxygen Species and Apoptosis in Triple-Negative Breast Cancer Cells","authors":"Eduardo Angulo-Elizari,&nbsp;Asif Raza,&nbsp;Hannah Johnson,&nbsp;Nuria Martínez-Sáez,&nbsp;Ignacio Encío,&nbsp;Arun K. Sharma,&nbsp;Carmen Sanmartín,&nbsp;Daniel Plano","doi":"10.1002/ddr.70332","DOIUrl":"https://doi.org/10.1002/ddr.70332","url":null,"abstract":"<p>Cancer ranks as a leading cause of death worldwide, demanding new affordable therapies. Nature offers a diverse array of bioactive scaffolds, including 1,4-naphthoquinone, which serves as a precursor for numerous natural and synthetic compounds with potent antitumor properties. Selenium, an essential trace element, has shown significant potential in medicinal chemistry when incorporated into organic molecules. In this study, we synthesized 24 novel selenium-containing derivatives based on menadione (series A) and 1,4-naphthoquinone (series B), incorporating selenium as selenoester and selenocyanate functionalities. Initial cytotoxic screening at 25 and 10 µM against four cancer cell lines (MDA-MB-231, PC-3, HTB-54 and HCT-116) identified five active compounds, with <b>B2</b> and <b>B8</b> exhibiting the highest potency and selectivity against breast cancer cells. Further biological evaluation via the NCI Developmental Therapeutics Program confirmed their apoptosis induction and antiproliferative activity through reactive oxygen species (ROS) production. Molecular dynamics simulations additionally suggest that <b>B2</b> and <b>B8</b> may act as topoisomerase II alpha inhibitors. These results position compounds <b>B2</b> and <b>B8</b> as promising candidates for breast cancer therapy, paving the way for further investigation into their potential as chemotherapeutic agents.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269129","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":"A Medicinal Chemistry Perspective on Anticonvulsant Drug Design: Targets, Mechanisms, and Spiro Compounds","authors":"Ghada Abdel Hamid,&nbsp;Ghada F. Elmasry,&nbsp;Samir M. El-Moghazy,&nbsp;Walaa Hamada Abd-Allah","doi":"10.1002/ddr.70317","DOIUrl":"10.1002/ddr.70317","url":null,"abstract":"<div>\u0000 \u0000 <p>The neurological condition known as epilepsy is typified by frequent, unprovoked seizures brought on by aberrant or excessive synchronized neuronal activity in the brain. It can arise from various causes, including brain injury, tumors, infections, immune disorders, or congenital anomalies. However, in many patients, the underlying cause remains unknown. Epileptic seizures are broadly classified into two types: generalized and focal (or partial) seizures. Generalized seizures involve electrical discharges that affect the entire brain, while focal seizures are confined to a specific region. The World Health Organization (WHO) estimates that 50 million individuals worldwide suffer from epilepsy, with low- and middle-income nations accounting for over 80% of cases. In spite of the development of numerous antiepileptic drugs (AEDs), about 30% of individuals with epilepsy suffer from drug-resistant epilepsy (DRE), where seizures remain uncontrolled by current treatments. As a result, the search for new anticonvulsants with improved efficacy and reduced toxicity is a paramount demand. However, target-based drug discovery approaches are relatively uncommon due to limited understanding of the molecular pathways involved in epilepsy and the complex mechanisms of action of most existing AEDs. In this review, we investigate the characteristics of anticonvulsant drugs, the classification of epileptic seizures, the mechanisms through which these drugs exert their effects and spiro compounds with anticonvulsant activity.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 4","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257636","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}