European Journal of Medicinal Chemistry最新文献

{"title":"Synthesis and biological evaluation of C-28-modified pyrazole-fused betulinic acid derivatives as potent antiosteoporosis agents","authors":"Tianzhen Zhao ,&nbsp;Shihui Li ,&nbsp;Guoyan Qiu ,&nbsp;Enqi Xiao ,&nbsp;Zijun Chen ,&nbsp;Qiaoli Liang ,&nbsp;Fan Yang ,&nbsp;Jie Tang ,&nbsp;Bo Wang ,&nbsp;Nian-Guang Li ,&nbsp;Wen-Wei Qiu ,&nbsp;Liang Chang","doi":"10.1016/j.ejmech.2025.118169","DOIUrl":"10.1016/j.ejmech.2025.118169","url":null,"abstract":"<div><div>A series of novel C-28 amino acid/amide conjugates and oligo(ethylene glycol)-modified C-2, C-3 pyrazole-fused betulinic acid derivatives were designed, synthesized, and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these, compound <strong>18</strong>, bearing a C-28 oligo(ethylene glycol) amino amide ester linkage, exhibited the most potent inhibitory activity. It demonstrated an IC₅₀ of 7.96 nM against RANKL-induced osteoclastogenesis in RAW264.7 cells, representing a 10-fold increase in potency compared to the <strong>XJ13</strong> (IC₅₀ = 0.08 μM) and achieved &gt;50 % inhibition at 0.01 μM. Importantly, the inhibitory effects of these compounds on RANKL-induced osteoclast differentiation were not attributed to cytotoxicity, as evidenced by the minimal cytotoxicity of compound <strong>18</strong> at 10 μM. Mechanistic studies showed that compound <strong>18</strong> could dose-dependently suppress the expression of osteoclast marker genes (TRAP, CTSK) and proteins (c-Fos, MMP-9). Furthermore, in an ovariectomized (OVX) mouse model, compound <strong>18</strong> (10 and 20 mg/kg, intraperitoneally, i.p.) dose - dependently prevented bone loss by improving key micro-CT parameters and decreasing serum bone resorption markers (CTx). Overall, compound <strong>18</strong> emerged as a highly promising candidate for the treatment of RANKL-driven osteoporosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118169"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the anti-leukemic efficacy of a curcuminoid in cellular and animal models","authors":"Vijayalakshmi Sudarshan ,&nbsp;P. Shyamjith ,&nbsp;Sujeet Kumar ,&nbsp;Febina Ravindran ,&nbsp;Nishith Teraiya ,&nbsp;Bibha Choudhary ,&nbsp;Subhas S. Karki","doi":"10.1016/j.ejmech.2025.118177","DOIUrl":"10.1016/j.ejmech.2025.118177","url":null,"abstract":"<div><div>Leukemia ranks as the tenth most common cause of cancer-related deaths, and significant side effects often limit current treatments. Curcumin, a lipophilic polyphenol, has garnered considerable attention for its therapeutic potential in addressing various conditions, including inflammation, diabetes, aging, and cancer, particularly leukemia. In this study, ten novel curcuminoids were synthesized and structurally characterized for integrity and purity using spectral techniques. Cytotoxic evaluation against the MOLT-4, HEK, EL4, YAC1 and L1210 cell lines identified one compound, <strong>(<em>3E,5E</em>)-3,5-bis((3-(4-chlorophenyl)-1-phenyl-1<em>H</em>-pyrazol-4-yl)methylene)piperidin-4-one (5e)</strong>, to be potent, demonstrating superior cytotoxic activity compared to curcumin. Mechanistic studies revealed that treatment with <strong>5e</strong> induced the production of reactive oxygen species (ROS), disrupted mitochondrial membrane potential, and promoted apoptosis, as confirmed by annexin-V-FITC/PI staining. Cell cycle analysis further showed significant accumulation in the sub-G₀/G₁ phase, consistent with apoptotic or necrotic cell death. <em>In vivo</em> studies using Dalton's Lymphoma models demonstrated that <strong>5e</strong> effectively reduced tumor volume with minimal systemic toxicity. Western blot analyses confirmed activation of the intrinsic apoptotic pathway, with significant upregulation of cytochrome <em>c</em> and cleaved caspase-3. Moreover, <strong>5e</strong> inhibited HDACs significantly <em>in vitro</em>, with activity greater than curcumin and comparable to trichostatin A, suggesting a target of anticancer action. Additionally, molecular docking studies suggested that <strong>5e</strong> acts as a potential HDAC8 inhibitor, correlating with its enhanced anticancer activity. Collectively, these findings establish compound <strong>5e</strong> as a promising curcuminoid analogue with potent cytotoxic and anti-proliferative effects against leukemia, highlighting its therapeutic potential.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118177"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioisosterism: an approach to develop new anti-cancer agents","authors":"Akash Verma ,&nbsp;Digambar Kumar Waiker ,&nbsp;Prem Shanker Gupta ,&nbsp;Mohit Kumar ,&nbsp;Sushant Kumar Shrivastava","doi":"10.1016/j.ejmech.2025.118166","DOIUrl":"10.1016/j.ejmech.2025.118166","url":null,"abstract":"<div><div>Bioisosterism is a powerful strategy to develop novel drug molecules. This approach allows researchers to rationally design a drug molecule by replacing functional groups or atoms on a molecular scaffold with similar electronic or structural moieties to fine tune its biological activity. Thus, change in the structural properties enhances pharmacological properties such as selectivity, its binding affinity, metabolic stability and pharmacokinetics with minimized toxicity. In cancers, especially those that develop drug resistance become tolerant to most of the chemotherapeutics and targeted medications which is a bottle neck in the treatment. Thereby altering the existing pharmacophoric features of the molecule with its bioisosters can help in enhancing the selectivity, reducing the resistance and toxicity. In this review, we were mainly focused on collecting and compiling various classical and non-classical bioisosteric replacement strategies being considered to develop a new anticancer agent. Here we also emphasize and discuss some biological pathways that could be further utilized to understand the biology of the disease and to design and optimize a lead candidate. Overall, this review will be helpful for those researchers who are continuously involved in optimizing the existing molecules or drugs to develop next-generation therapeutics for cancer treatment.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118166"},"PeriodicalIF":5.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progress in small-molecule inhibitors of gasdermin D","authors":"Yixuan Shua ,&nbsp;Qianqian Wang ,&nbsp;Yuhang Wang ,&nbsp;Cheng Jiang","doi":"10.1016/j.ejmech.2025.118171","DOIUrl":"10.1016/j.ejmech.2025.118171","url":null,"abstract":"<div><div>As a key mediator of pyroptosis, Gasdermin D (GSDMD) drives pro-inflammatory cell death through caspase-mediated cleavage to form membrane pores, which is closely linked to the pathogenesis of sepsis, cancer, and autoimmune diseases. Recent advances in GSDMD inhibitor development primarily focus on key steps: blocking caspase-mediated cleavage, inhibiting N-terminal oligomerization, or disrupting pore formation. Examples include small-molecule drugs targeting Cys191/192 such as DMF, DSF, NSA, and NU6300, as well as molecules targeting other residues like mafenide, GI-Y1, and GI-Y2. The elucidation of high-resolution structures of caspase-GSDMD complexes and pore assembly mechanisms has facilitated the emergence of novel targeting strategies, providing a critical basis for rational design. Despite progress, challenges such as off-target effects and low clinical translation rates persist. Optimizing specificity and exploring disease-specific applications remain pivotal to advancing these inhibitors as therapeutic agents. Current research focuses on developing clinically translatable, highly effective, and safe GSDMD-targeted therapies through structure-guided optimization, drug repurposing, innovations in precision delivery systems, and synergistic mechanism approaches.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118171"},"PeriodicalIF":5.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and function analysis of novel antimicrobial peptides derived from Cathelicidin-DM: Insights into structure-function relationships","authors":"Ying Luo ,&nbsp;Zhan Dong ,&nbsp;Yaoqiang Shi ,&nbsp;Lei Wang ,&nbsp;Zhizhi Chen ,&nbsp;Shuo Yan ,&nbsp;Guanlin Wang ,&nbsp;Qinqin Han ,&nbsp;Jinyang Zhang ,&nbsp;Chao Li ,&nbsp;Yuzhu Song","doi":"10.1016/j.ejmech.2025.118173","DOIUrl":"10.1016/j.ejmech.2025.118173","url":null,"abstract":"<div><div>The increasing threat of bacterial drug resistance calls for effective solutions, and antimicrobial peptides (AMPs) hold great promise. However, the connection between their structure and function remains unclear. The study of the structure-function relationship and other basic issues of AMPs is a guarantee for the development of safe, effective and clear mechanism of therapeutic drugs or active biomaterials. The aim of this study was to develop new antimicrobial candidate molecules and further elucidate the structure-function relationship of AMPs. In this study, more than 20 AMPs derived from Cathelicidin-DM were designed in terms of sequence size, amino acid composition, amphiphilicity and amidation. And then the antimicrobial activity in vitro/vivo, structure of peptides, safety and stability assessment, antimicrobial mechanism, anti-inflammatory activity, and in vivo toxicity were evaluated, and the relationship between structure and function of AMPs was analyzed. The results showed that the hydrophobicity amino acid substitution is of great significance to improve the biological activity of AMPs. Overall, our research uncovers the potential link between the function and structure of AMPs, laid the foundation for the development of AMPs drugs and biomaterials.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118173"},"PeriodicalIF":5.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance","authors":"Zeren Sun ,&nbsp;Mengxuan Hu ,&nbsp;Jie Xu ,&nbsp;Bingxin Zhai ,&nbsp;Yuchen Zhang ,&nbsp;Wenbin Zhang ,&nbsp;Boning Wang ,&nbsp;Runyuan Wang ,&nbsp;Zheqi Hu ,&nbsp;Yungen Xu ,&nbsp;Qihua Zhu ,&nbsp;Yi Zou","doi":"10.1016/j.ejmech.2025.118164","DOIUrl":"10.1016/j.ejmech.2025.118164","url":null,"abstract":"<div><div>PARP1 is a well-established therapeutic target in cancer treatment, based on the principle of synthetic lethality. However, the development of drug resistance has significantly compromised the antitumor efficacy of PARP1 inhibitors, exemplified by resistance mediated through c-Met amplification. In this study, we report the development of a novel PARP1/c-Met dual inhibitor derived from the benzofuran-7-carboxamide moiety of the PARP1 inhibitor Mefuparib. Compared with compound <strong>16</strong> obtained in the previous study, compound <strong>S12</strong> was identified as a highly potent dual inhibitor with lower molecule weight and better solubility, demonstrating robust inhibitory activity against both PARP1 (IC₅₀ = 21.8 nM) and c-Met (IC₅₀ = 30.2 nM). Importantly, <strong>S12</strong> exhibited remarkable anti-tumor efficacy in the HCT116OR xenograft models, suggesting that targeting both PARP1 and c-Met represents an effective therapeutic strategy to overcome PARP1 inhibitor resistance mediated by c-Met amplification.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118164"},"PeriodicalIF":5.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, molecular modeling, biological and pharmacokinetic evaluation of hydroxy pyrimidinones and pyrimidinediones as novel LDHA inhibitors","authors":"Horrick Sharma ,&nbsp;Ty Elliott ,&nbsp;Amery Good ,&nbsp;Pragya Sharma ,&nbsp;Somrita Mondal ,&nbsp;Lerin Luckett Chastain ,&nbsp;Michael A. Ihnat","doi":"10.1016/j.ejmech.2025.118156","DOIUrl":"10.1016/j.ejmech.2025.118156","url":null,"abstract":"<div><div>There is compelling evidence that increased LDHA expression and lactate accumulation promote tumor progression, particularly in patients with basal/quasi-mesenchymal (QM) tumor subtypes that exhibit a glycolytic phenotype. Despite efforts to develop small-molecule inhibitors, no LDHA inhibitor is currently available in the clinic, and advancing new chemical space is needed. In our earlier studies, we identified hits, containing a novel hydroxy pyrimidinone motif, including <strong>ZINC2783354</strong> and <strong>ZINC4978206</strong>, against LDHA. In this study, we performed pharmacokinetic evaluation and <em>in vivo</em> metabolic profiling of our starting hit to inform the design of new analogs, leading to the identification of pyrimidinedione as a new chemotype with LDHA inhibitory activity. The most promising compound, <strong>HP19</strong>, inhibited LDHA with IC₅₀ of 5.2 μM, demonstrated lactate inhibition, and reduced H3K18 lactylation. <strong>HP19</strong> resulted in a drastic reduction in ATP levels and inhibited proliferation of PANC-1 cells with IC₅₀ of 22.7 μM. The antiproliferative effects of <strong>HP19</strong> in PANC-1 cells were mediated by G1/S cell cycle arrest and induction of apoptosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118156"},"PeriodicalIF":5.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antibacterial evaluation of 5-(3-nitrophenyl)-N′-arylisoxazole-3-carbohydrazide derivatives against carbapenem-resistant Acinetobacter baumannii","authors":"Rani Bandela ,&nbsp;Rohini Ramesh Tupare ,&nbsp;Deepanshi Saxena ,&nbsp;Rahul Maitra ,&nbsp;Swechchha singh ,&nbsp;Anuradha Singampalli ,&nbsp;Sri Mounika Bellapukonda ,&nbsp;Pardeep Kumar ,&nbsp;Bulti Bakchi ,&nbsp;Shruti Polshettiwar ,&nbsp;Srinivas Nanduri ,&nbsp;Sidharth Chopra ,&nbsp;Venkata Madhavi Yaddanapudi","doi":"10.1016/j.ejmech.2025.118154","DOIUrl":"10.1016/j.ejmech.2025.118154","url":null,"abstract":"<div><div>The gram-negative coccobacillus <em>Acinetobacter baumannii,</em> a WHO critical priority pathogen and member of ESKAPE pathogen panel, threatens global health due to its substantial association with hospital-acquired infections as well as resistance exhibited to last-resort antibiotics, such as colistin, tigecycline and carbapenems. Thus, urgent drug discovery and development is essential, targeting <em>Acinetobacter baumannii,</em> especially carbapenem-resistant <em>Acinetobacter baumannii</em> (CRAB)<em>.</em> In this context, we report the design, synthesis and anti-bacterial evaluation of a new collection of 5-(phenyl)-<em>N′</em>-arylisoxazole-3-carbohydrazides for their effectiveness against various bacterial pathogen panels. Amongst the various compounds synthesised, <strong>7j, 7l, 7n, 7o, 7p,</strong> and <strong>16</strong> exhibited significant antibacterial activity against CRAB, with minimum inhibitory concentrations (MIC) 0.5–2 <em>μ</em>g/mL. Compound <strong>7l</strong> demonstrated the highest antibacterial effectiveness, with a 0.5 <em>μ</em>g/mL MIC. Additional testing revealed that these compounds were non-toxic to Vero cells and displayed high selectivity indices. Furthermore, they were effective against clinical isolates of multidrug-resistant <em>Acinetobacter baumannii</em> (MDR-AB), with compound <strong>7l</strong> showing bactericidal effects when paired with Rifampicin, as supported by time-kill kinetic studies. 3D QSAR confirms <strong>7l</strong>s increased activity comes from good steric fit, ideal electrostatics, strategic hydrophobic placement, and precise H-bond acceptor/donor positioning, and <strong>7l</strong> complies with Lipinski's rule of five. The molecular target for these compounds is not known, though <em>in silico α</em>-fold modelling indicate that KatG may be the probable target. However in-depth mechanistic studies need to be done to validate these <em>in silico</em> predictions, based on which <strong>7l</strong> may be further optimised as a promising candidate targeting CRAB.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118154"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of adamantyl derivatives as potent and selective TRPM2 inhibitors with significantly reduced hERG liability","authors":"Tinghao Lu ,&nbsp;MeiJie Dai ,&nbsp;Kaiyue Ying ,&nbsp;Xianhao Dong ,&nbsp;Wanglin Qu ,&nbsp;Peichen Pan ,&nbsp;Wei Yang ,&nbsp;Xiangnan Zhang ,&nbsp;Peilin Yu ,&nbsp;Hongbin Zou","doi":"10.1016/j.ejmech.2025.118172","DOIUrl":"10.1016/j.ejmech.2025.118172","url":null,"abstract":"<div><div>Ischemic stroke remains a leading cause of mortality worldwide. Transient receptor potential melastatin 2 (TRPM2), a calcium-permeable channel involved in ischemia–reperfusion injury, has emerged as a promising target. We previously reported an effective TRPM2 inhibitor <strong>D10</strong>, but subsequent human ether-à-go-go-related gene (hERG) inhibition assays revealed comparable micromolar activity against both channels, indicating a narrow safety window. Further strategic optimization of the hERG safety profile led to the development of <strong>LC4</strong>, featuring a newly installed adamantyl group. Comprehensive characterization, including calcium imaging, electrophysiological, and pharmacokinetic studies, demonstrated that <strong>LC4</strong> exhibited enhanced TRPM2 inhibition, reduced hERG liability, retained selectivity, and improved metabolic stability. In a transient middle cerebral artery occlusion (tMCAO) model, <strong>LC4</strong> reduced the infarct volume and oxidative-stress level significantly. These results suggest that <strong>LC4</strong> could be a promising preclinical candidate for treatment of ischemic stroke.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118172"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 in vitro assessment of di-/tri-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes for antiplasmodial and anticancer use","authors":"Mohit K. Tiwari ,&nbsp;Malgorzata Kucinska ,&nbsp;Agnieszka Zgoła-Grześkowiak ,&nbsp;Marziyeh Raeispour ,&nbsp;Marek Murias ,&nbsp;Philippe Grellier ,&nbsp;Łukasz Marczak ,&nbsp;Tomasz Goslinski","doi":"10.1016/j.ejmech.2025.118159","DOIUrl":"10.1016/j.ejmech.2025.118159","url":null,"abstract":"<div><div>In the present article, a library of novel non-symmetrical <em>di-</em>/<em>tri</em>-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes (<strong>5a</strong>-<strong>m</strong>) has been prepared from methyltrioxorhenium(VII) complex-catalysed two-step one-pot direct oxidation approach. The <em>in vitro</em> antiplasmodial and cytotoxic potentials of all non-symmetrical <em>di-</em>/<em>tri</em>-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxanes (<strong>5a-m</strong>) have been assessed against the chloroquine-resistant FcB1 strain of <em>Plasmodium falciparum</em>, HeLa, A549 and A2780 cancer cells. The <em>in vitro</em> biological assessment has afforded eight <em>di-</em>/<em>tri</em>-methoxy-aryl-substituted mono-spiro-1,2,4,5-tetraoxane derivatives (<strong>5b</strong>-<strong>e</strong>, <strong>5g</strong>, <strong>5i</strong>, <strong>5k</strong>-<strong>l</strong>) with nanomolar antiplasmodial activity (IC₅₀ = 34–91 nM and Selectivity Index = 109–2900). Along with this, two <em>tri</em>-OMe-aryl substituted mon-spiro-1,2,4,5-tetraoxane analogues (<strong>5i</strong> and <strong>5l</strong>) have also shown dual potency with strong antiplasmodial (<strong>5i</strong>, IC₅₀ = 46 nM; <strong>5l</strong>, IC₅₀ = 48 nM), and <em>in vitro</em> micromolar cytotoxicity against the A2780 ovarian cancer (<strong>5i</strong>, IC₅₀ = 3.82 <em>μ</em>M; <strong>5l</strong>, IC₅₀ = 1.98 <em>μ</em>M) and HeLa cells (<strong>5i</strong>, LD₅₀ = 10.85 <em>μ</em>M; <strong>5l</strong>, LD₅₀ = 5.8 <em>μ</em>M). In addition, potential drug-target interactions prediction for representative compounds (<strong>5d</strong>, <strong>5i</strong>, and <strong>5l</strong>) has been examined using different computational-based techniques. Through this study, the selective incorporation of functionalized <em>di-</em>/<em>tri</em>-methoxy-aryl moieties on the mon-spiro-1,2,4,5-tetraoxane skeleton has proved efficient in improving the overall biological activities of the resulting molecules.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"300 ","pages":"Article 118159"},"PeriodicalIF":5.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}