Drug Development Research最新文献

{"title":"Design, Synthesis, and Biological Evaluation of 8-Phenyl-THIQ as Antidepressive Agents","authors":"Xiaopeng Wei,&nbsp;Fan Yang,&nbsp;Nuo Xu,&nbsp;Xingyu Huang,&nbsp;Wei Qiao","doi":"10.1002/ddr.70156","DOIUrl":"https://doi.org/10.1002/ddr.70156","url":null,"abstract":"<div>\u0000 \u0000 <p>The structural modification and derivatization of natural products represent an essential pathway for pharmaceutical innovation in the management of depression. The 8-phenyl tetrahydroisoquinoline, as a parent core, was obtained from magnoflorine by a structural simplification strategy. The present report details the synthesis and antidepressant activity studies of 8-phenyl-THIQ analogs. Among them, compounds <b>1e</b> and <b>1j</b> exhibited significant antidepressant activity in addition to high synthetic accessibility and adequate predictive ADME/T properties.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012258","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":"Triazole-Pyrimidine Hybrids as EGFR Inhibitors via Synthesis, In Silico, In Vitro, and In Vivo Evaluation as Anticancer Agents","authors":"Rahul Dubey,&nbsp;Shankar Gupta,&nbsp;Rajveer Singh,&nbsp;Shivani Chandel,&nbsp;Shubham Thakur,&nbsp;Mehdi Irani,&nbsp;Ghanshyam Das Gupta,&nbsp;Vivek Asati","doi":"10.1002/ddr.70154","DOIUrl":"https://doi.org/10.1002/ddr.70154","url":null,"abstract":"<div>\u0000 \u0000 <p>The epidermal growth factor receptor (EGFR) is a common diver gene for lung cancer (NSCLC), which leads to an increasing death rate worldwide. This study reports the design, synthesis, and biological evaluation of triazole-clubbed pyrimidine derivatives (<b>RDa</b>–<b>RDm</b>) as potential anticancer agents. Thirteen compounds were synthesized and screened against the A549 lung cancer cell line. <b>RDg</b> emerged as the most potent derivative, exhibiting an IC₅₀ of 15.70 µM, compared with the standard drug erlotinib (IC₅₀ = 10.10 µM). Notably, all derivatives displayed moderate to excellent anticancer activity at 100 µM, with IC₅₀ values ranging from 15.70 to 88.27 µM. <b>RDg</b>, characterised by a 4-chlorophenyl group, demonstrated strong in vitro activity and induced cell-cycle arrest at the sub-G0 phase. In vivo study using the Ehrlich ascites carcinoma (EAC) mouse model confirmed the superior anticancer efficacy of <b>RDg</b>. At a 5 mg/kg dose, <b>RDg</b> achieved a 52% reduction in tumour volume and 54% reduction in tumour weight compared with erlotinib 26% tumour volume reduction. Furthermore, <b>RDg</b> demonstrated a 90% tumour inhibition rate compared with erlotinib 75%, attributed to its enhanced cellular uptake and sustained release properties. In silico analyses provided insights into <b>RDg</b> mechanism of action, revealing strong interactions with EGFR binding sites, including hydrogen bonding with Met-793 and π-sulphur interaction with Met-790. Molecular dynamics simulations demonstrated <b>RDg</b> stabilising effect on EGFR, as evidenced by reduced protein flexibility and compact conformational space. The combination of promising in vitro, in vivo and in silico results showed <b>RDg</b> may be used as a lead compound for further development of novel compounds as EGFR inhibitors.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012260","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":"Isolation, Purification, and Preparation of Taxinine-Loaded Liposomes for Improved Anti-Hepatocarcinogenic Activity","authors":"Qilong Wang,&nbsp;Xiaowen Wang,&nbsp;Qinyang Hua,&nbsp;Feng Shi,&nbsp;Xia Jiang,&nbsp;Minjie Gong,&nbsp;Tingyuan Li,&nbsp;Jiaying Li,&nbsp;Elmurat Toreniyazov,&nbsp;Jiangnan Yu,&nbsp;Michael Adu-Frimpong,&nbsp;Xia Cao,&nbsp;Ximing Xu","doi":"10.1002/ddr.70143","DOIUrl":"https://doi.org/10.1002/ddr.70143","url":null,"abstract":"<div>\u0000 \u0000 <p>Liver cancer is the fourth most deadly cancer worldwide, but existing treatment options are insufficient, thus highlighting the urgent need for new therapeutic agents. Taxanes, known for their anticancer properties, provide a promising avenue for intervention. In this study, a tetracyclic taxane compound with antitumor activity (taxinine) was extracted and isolated from <i>Taxus chinensis</i> (<i>T. chinensis</i>) seeds. It was then formulated into liposomes using lecithin, cholesterol, and D-<i>α</i>-tocopheryl polyethylene glycol succinate (TPGS) as excipients to enhance its solubility and antitumor efficacy. The isolation of taxinine was achieved through ultrasound-assisted ethanol extraction, followed by silica gel column chromatography, MTT activity screening, and recrystallization. Afterward, the structure of taxinine was confirmed using nuclear magnetic resonance and mass spectrometry. Taxinine liposomes were prepared via the thin film dispersion method, while the particle size, polydispersity index, zeta potential, and encapsulation efficiency of the nanoliposomes were discovered to be 186.76 ± 0.08 nm, 0.226 ± 0.012, −44.34 ± 0.77 mV, and 93.75 ± 1.29%, respectively. They also showed good stability with a release rate of 85.77% ± 2.43% in phosphate-buffered solution (PBS, pH 7.4). Toxicity tests conducted on zebrafish larvae indicated that taxinine liposomes were safe in vivo. Tissue distribution study showed that the concentration of taxinine liposomes increased to varying degrees in tissues (especially liver). In vitro experiments demonstrated that taxinine liposomes significantly enhanced the inhibitory effect of taxinine on HepG2 cell growth. Overall, the nanoliposomal formulation improved the anti-liver cancer activity of taxinine, thus suggesting its potential as a therapeutic agent.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012259","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":"Lazertinib: A Cardio-Safer Alternative to Osimertinib for Epidermal Growth Factor Receptor L858R/T790M Double-Mutant Tyrosine Kinase Resistant Non-Small Cell Lung Cancer","authors":"Chandrakant S. Gawli,&nbsp;Narendra R. Nagpure,&nbsp;Bhatu R. Patil,&nbsp;Nobuaki Ochi,&nbsp;Nagio Takigawa,&nbsp;Harun M. Patel","doi":"10.1002/ddr.70153","DOIUrl":"https://doi.org/10.1002/ddr.70153","url":null,"abstract":"<div>\u0000 \u0000 <p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with “epidermal growth factor receptor (EGFR)” mutations playing a pivotal role in tumor progression and carcinogenesis. “Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs),” such as Osimertinib, have significantly improved treatment outcomes by overcoming resistance mechanisms like the T790M mutation. However, Osimertinib's clinical application is limited by cardiotoxicity concerns, necessitating safer alternatives. Lazertinib, a structurally optimized third-generation EGFR-TKI, exhibits superior selectivity for mutant EGFR while sparing wild-type EGFR, thereby reducing off-target toxicities. This current opinion highlights the pharmacological properties of Lazertinib, its enhanced binding interactions, and its efficacy in overcoming resistance while demonstrating an improved safety profile. Comparative analyses reveal that Lazertinib offers stronger inhibition of key EGFR mutations, superior pharmacokinetics, and lower cardiotoxicity risks compared to Osimertinib. Additionally, Lazertinib's improved central nervous system (CNS) penetration enhances its therapeutic potential in patients with brain metastases. As ongoing clinical trials further elucidate its role, Lazertinib emerges as a promising next-generation EGFR inhibitor, offering a safer and more effective alternative for NSCLC treatment.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012315","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":"Theaflavins Inhibit Proliferation and Glycolysis of Colorectal Cancer Cells by Downregulating DDIT4","authors":"Huanqing Li,&nbsp;Songhua Bei,&nbsp;Yanqing Mo,&nbsp;Li Feng","doi":"10.1002/ddr.70151","DOIUrl":"https://doi.org/10.1002/ddr.70151","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) is a common malignancy often characterized by metastasis and poor prognosis. This study attempts to ascertain the anticancer impacts of theaflavin (TF) on CRC cells and examine the fundamental molecular mechanisms, focusing on the function of <i>DDIT4</i> in CRC progression. This study utilized RNA sequencing for gene expression profiling, differential expression analysis, and Venn diagram analysis for overlapping genes. Protein interactions were explored, while cell viability was evaluated using colony formation assays and Cell Counting Kit-8 (CCK-8). Flow cytometry was employed for apoptosis analysis, and Transwell assays measured cell migration and invasion. ATP synthesis, lactate production, and glucose uptake were analyzed to evaluate metabolic changes, with protein and RNA expression identified by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). This study reveals that TF effectively inhibits CRC cell invasion, migration, and proliferation in a dose- and time-dependent manner. TF induces apoptosis by suppressing the antiapoptotic protein Bcl-2 and enhancing proapoptotic proteins (Cleaved Caspase-3, Bax, and Caspase-9). Through bioinformatics analysis, <i>DDIT4</i> was identified as a key target gene. Additionally, correlation analysis highlighted a positive relationship between DDIT4 and the glycolysis/gluconeogenesis pathway. TF downregulates <i>DDIT4</i> expression, which suppresses CRC cell proliferation and glycolysis. Moreover, <i>DDIT4</i> overexpression partially reverses the suppressive impacts of TF on glycolysis and cell viability. These observations imply that TF suppresses CRC progression by targeting <i>DDIT4</i> and regulating glycolytic activity, highlighting its promise as a medicinal substance for the treatment of CRC.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990764","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":"Effects of a Dendritic Cell Vaccine Loaded With Whole Tumor Antigen on Bladder Cancer Model in hu-PBL-SCID Mice","authors":"Bin Wang,&nbsp;Kai Wu,&nbsp;Yu Cui,&nbsp;Xuebing Han,&nbsp;Tianjun Xing","doi":"10.1002/ddr.70157","DOIUrl":"https://doi.org/10.1002/ddr.70157","url":null,"abstract":"<div>\u0000 \u0000 <p>The aim of this study was to establish a humanized immune system model in severe combined immunodeficient (SCID) mice, assess dendritic cell (DC) phenotype, and evaluate the therapeutic efficacy of a DC-based vaccine in a bladder cancer model. Bladder cancer was induced in SCID mice by injection of T24 cells, followed by human peripheral blood leukocyte (hu-PBL) inoculation to reconstitute the human immune system. DCs were generated in vitro by culturing hu-PBL for 5 days and matured on the eighth day. The DC vaccine was produced by coculturing with whole tumor antigen which was purified through freezing and melting T24 cells. The therapeutic efficacy of a DC vaccine was evaluated by administering the vaccine to SCID mice at Weeks 5 and 6 after T24 cell injection. Immune reconstitution, phenotype of DCs, tumor weight, and matrix metalloproteinase-7 (MMP-7) mRNA expression were assessed. All SCID mice successfully developed bladder cancer, confirmed as urothelial carcinoma. After hu-PBL inoculation, human IgG was detectable in mouse serum at Week 5, and spleen weight increased over time, indicating successful human immune system reconstitution. Phenotypic analysis of DCs showed high expression of maturation markers, including CD1a (78.07% ± 9.43%), CD80 (60.11% ± 20.50%), and CD83 (46.82% ± 14.15%), indicating functional and mature DCs. Therapeutic intervention with the DC vaccine significantly reduced tumor weight and MMP-7 mRNA expression, with statistical significance (<i>p</i> = 0.0004 for tumor weight and <i>p</i> = 0.0008 for MMP-7). This study successfully established a humanized immune system model in SCID mice and demonstrated that a DC-based vaccine effectively inhibits tumor growth in a bladder cancer model. These results support the potential of DC vaccines as a promising immunotherapeutic strategy for bladder cancer.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999048","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":"Exploring the Topoisomerase II Inhibitory Potential of Steroidal Drugs as a Recommended Mechanism of Action for Their Anticancer Activity: In Silico and In Vitro Assessments","authors":"Ahmed A. Al-Karmalawy,&nbsp;Mohamed E. Eissa,&nbsp;Ayman Abo Elmaaty,&nbsp;Tarek A. Yousef,&nbsp;Arwa Omar Al Khatib,&nbsp;Radwan Alnajjar,&nbsp;Faten Farouk,&nbsp;Amany Belal,&nbsp;Abdullah Yahya Abdullah Alzahrani,&nbsp;Marwa Sharaky","doi":"10.1002/ddr.70152","DOIUrl":"https://doi.org/10.1002/ddr.70152","url":null,"abstract":"<div>\u0000 \u0000 <p>Herein, and based on the pharmacophoric features of doxorubicin (Dox); 133 steroids were screened to assess their ability to act as TOP II inhibitors for the discovery of those with promising anticancer activity. The cytotoxic inhibitory concentration 50 (IC₅₀) of the investigated steroids was determined against H1299, CaCo2, MDA-MB-468, and FaDu cancer cell lines and compared to Dox. Fluticasone propionate and fusidic acid exhibited the most potent antiproliferative effect against the MDA-MB-468 with IC₅₀ values of 10.4 ± 0.7 and 10.6 ± 1.7 μM, respectively. On the other hand, the outstanding antitumor members (beclomethasone dipropionate, fluticasone propionate, prednisolone, dexamethasone, and fusidic acid) were further investigated for their TOP II inhibitory potentials. Where the protein expression of TOP II was downregulated by 0.79, 0.76, and 0.67-fold change for fusidic acid, fluticasone propionate, and dexamethasone, respectively, compared to the control. Besides, the examined steroidal candidates were subjected to a molecular docking study towards the TOP II receptor in comparison to Dox and the co-crystallized ligand (EVP) as references. Moreover, molecular dynamics (MD) simulations were conducted on the aforementioned steroids along with Dox and EVP for 200 ns to validate the docking results. Consequently, steroids, in particular fusidic acid, fluticasone propionate, and dexamethasone, can be regarded as promising lead compounds targeting TOP II for cancer treatment along with their typical anti-inflammatory effects.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990765","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":"Targeted Inhibition of NOTCH2 and Importin-β Promotes Osteogenic Differentiation of Osteosarcoma Cells","authors":"Zhiyuan Wei,&nbsp;Yan Chen,&nbsp;Guoshi Liu,&nbsp;Siyu Deng,&nbsp;Zhiyong Wang,&nbsp;Fan Zou","doi":"10.1002/ddr.70158","DOIUrl":"https://doi.org/10.1002/ddr.70158","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteosarcoma (OS) is a common malignant bone tumor, frequently associated with impaired osteogenic differentiation of tumor cells. Recent studies have suggested that the NOTCH signaling pathway plays a crucial role in maintaining tumor cell stemness and may influence their differentiation status. This study investigates the role of NOTCH2, a key receptor in the NOTCH family, in regulating osteogenic differentiation in OS. By analyzing public datasets, we compared the expression patterns and functional relevance of NOTCH1-4 in OS and identified NOTCH2 as the most significant. Using MG-63 and Saos-2 OS cell lines, we found that NOTCH2 silencing suppressed cell proliferation, invasion, and stem-like properties, while promoting osteogenic differentiation under inductive conditions. This was accompanied by increased expression of osteogenic markers. Further experiments demonstrated that Importazole, an Importin-β inhibitor, blocked the nuclear translocation of NOTCH2. Treatment with Importazole alone inhibited OS cell proliferation and invasion, reduced stem-like features, and enhanced osteogenic differentiation. When combined with NOTCH2 knockdown, Importazole exerted a synergistic effect, further inhibiting tumor progression and promoting differentiation. In vivo, xenograft models confirmed that the combination treatment more effectively suppressed tumor growth and induced osteoblast-like characteristics compared to either intervention alone. These findings indicate that NOTCH2 is a critical regulator of OS cell behavior, and that targeting NOTCH2 - especially in combination with Importazole - may offer a promising therapeutic strategy to promote differentiation and suppress tumor progression in OS.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935101","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":"Sestrin2 Regulates Mitochondrial Function and Autophagy via Nrf2/SIRT3 Signaling to Ameliorate Hypoxia/Reoxygenation-Induced Rat's Cardiomyocyte Injury","authors":"Tong Liu,&nbsp;Jiajie Kong,&nbsp;Zhaobin Li,&nbsp;Shuqiang Xi,&nbsp;Lei Liu","doi":"10.1002/ddr.70150","DOIUrl":"https://doi.org/10.1002/ddr.70150","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitigating myocardial ischemia-reperfusion (I/R) injury poses a significant challenge, necessitating the exploration of novel therapeutic targets. Sestrin2 (Sesn2), a stress-induced protein, has emerged as a potential candidate for attenuating I/R injury, yet its precise mechanisms remain elusive. The role of Sesn2 was investigated using an in vitro model of H9C2 cardiomyocytes subjected to hypoxia-reoxygenation (H/R). Sesn2 expression was modulated through overexpression techniques, and cellular responses, including cell viability, inflammatory factor production, mitochondrial function, oxidative stress, autophagy, and apoptosis, were assessed. Furthermore, the role of the Nrf2/SIRT3 signaling pathway in the mechanism was explored via treating cells with Nrf2 inhibitor ML385. Sesn2 overexpression significantly improved cell viability, attenuated inflammatory factor production, preserved mitochondrial function, and mitigated oxidative stress in H/R-exposed cardiomyocytes. Additionally, Sesn2 enhanced autophagy and modulated the Nrf2/SIRT3 signaling pathway. Moreover, Sesn2-mediated protection was reversed upon inhibition of Nrf2 signaling, underscoring the importance of this pathway in Sesn2-induced protection. Our findings may elucidate the mechanism of Sesn2-mediated protection and highlight its potential as a therapeutic target to ameliorate H/R-induced cardiomyocyte injury.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915103","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 the Enzymatic Site of Botulinum Neurotoxin Type E With 8-Hydroxyquinolinol–Based Inhibitors: In Silico, In Vitro, and In Vivo Evaluation","authors":"Priyanka Sonkar,&nbsp;Vinita Chauhan Kushwah,&nbsp;Surabhi Agnihotri,&nbsp;Deeksha Disoriya,&nbsp;Manorama Vimal,&nbsp;Ram Kumar Dhaked","doi":"10.1002/ddr.70148","DOIUrl":"https://doi.org/10.1002/ddr.70148","url":null,"abstract":"<div>\u0000 \u0000 <p>Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and effective active/passive prophylaxis available for the treatment. Therefore, it is highly desirable to develop a potential antidote to counter botulinum neurotoxicity. In this study, ~800 molecules were mined by a structure similarity search from open databases and docked into the pocket of the catalytic domain of botulinum toxin type E using AutoDock 4.2. Twenty-four small molecules with the best scoring function were selected and evaluated using in vitro and in vivo assays. Among these, two molecules, NSC1011 and NSC1012, were identified as inhibiting the catalytic activity of BoNT/E, with IC₅₀ values of 31.25 ± 1.0 μM and 55.45 ± 5.2 μM and <i>K</i>_D of 5.54E−07 and 6.51E−06 M, respectively. To find inhibitors that can reverse the neurotoxicity more effectively, we have derived and synthesized 12 analogs of NSC1011. These compounds showed higher inhibition than the parent molecules, with IC₅₀ and <i>K</i>_D values of 4.375 ± 2.3 µM and 1.61E−08 M (C25.12) and 10.25 ± 3.0 µM and 4.70E-08 M (C25.9). Compounds C25.9 and C25.12 completely protected mice in premixed doses and led to significant extension in survival of up to 60 h with therapeutic treatment. This study showed that these 8-HQ derivatives had the potency to inhibit BoNT/E by interacting with the active site. Further studies could lead to the development of undiscovered postexposure therapeutics against this deadly neurotoxin.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144894099","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}