Bioorganic & Medicinal Chemistry最新文献

{"title":"Synthesis of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides and evaluation of their antitubercular activity.","authors":"Ojaswitha Ommi, Harshada Anil Bhalerao, Pradip Malik, Juned Ali, Deepanshi Saxena, Srinivas Nanduri, Rajesh Sonti, Arunava Dasgupta, Sidharth Chopra, Venkata Madhavi Yaddanapudi","doi":"10.1016/j.bmc.2025.118341","DOIUrl":"10.1016/j.bmc.2025.118341","url":null,"abstract":"<p><p>The rise of drug-resistant tuberculosis (TB) has created an urgent need to discover and develop new anti-mycobacterial agents. Herein, we report the synthesis and evaluation of a library of 1,3-diaryl substituted pyrazole-based imidazo[1,2-a]pyridine carboxamides as promising anti-TB agents. In preliminary screening, 10 out of 26 compounds displayed potent in vitro inhibition against Mtb H37Rv with a MIC value of 0.03 μg/mL, which is 17-fold more potent than the first-line TB drug streptomycin, 33-fold more potent than ethambutol, and equipotent with isoniazid and rifampicin. Encouragingly, most of these compounds exhibited a selectivity index (SI) >3333.3 and CC₅₀ values >100 μg/mL against Vero cells, indicating they are over 3000 times more toxic to M. tuberculosis than to mammalian cells and demonstrate absence of cytotoxicity at concentrations effective against TB (MIC = 0.03 μg/mL). Among them, 12a, 14a, and 14d demonstrated remarkable activity against drug-resistant strains of Mtb with an MIC of 0.03 μM. Time-kill kinetic studies revealed that 12a, 14a, and 14d exhibited bacteriostatic properties. Furthermore, 12a, 14a, and 14d demonstrated synergistic effects with the FDA-approved anti-TB drugs rifampicin (ƩFIC 0.093), ethambutol (ƩFIC 0.061), and moxifloxacin (ƩFIC 0.154-0.281), exhibiting bactericidal time-kill properties in combination with these drugs. Additionally, 12a, 14a, and 14d exhibited acceptable metabolic stability (CL_int 11.49-14.62 μL/min/mg microsomal protein), indicating effective drug levels and bioavailability. Also, 12a, 14a, and 14d showed stable interactions with QcrB in docking studies. These findings highlight 12a, 14a, and 14d as potential candidates for in vivo evaluation and further development as novel anti-tubercular drugs.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118341"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovering a potent and orally available imidazopyridine derivative as a BRD4 inhibitor: Enhancing antiproliferative activity against melanoma cells by mitigating P-gp substrate recognition.","authors":"Yuhei Horai, Naoki Suda, Shinsuke Uchihashi, Mayako Katakuse, Tomomi Shigeno, Takashige Hirano, Junichi Takahara, Tomoyuki Fujita, Yohei Mukoyama, Yuji Haga","doi":"10.1016/j.bmc.2025.118337","DOIUrl":"10.1016/j.bmc.2025.118337","url":null,"abstract":"<p><p>Bromodomain-containing protein 4 (BRD4), a crucial epigenetic regulator in cancer, has become a critical target for melanoma therapy. Herein, we investigated a strategy for enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. A compound that exhibits antitumor effects in a mouse melanoma xenograft model at doses lower than those required for previously reported compound 1 is required. Therefore, we focused on enhancing the antiproliferative activity of BRD4 inhibitors against melanoma cells. Our hypothesis state that mitigating P-glycoprotein (P-gp) substrate recognition can improve cell permeability and enhance cellular inhibitory activity. Thus, we reduced the hydrogen-bond donors (HBDs) of a benzimidazole core through N-alkylation. Using this approach, we successfully enhanced the cellular inhibitory activity by mitigating P-gp substrate recognition; however, the compounds derived from this approach exhibited poor metabolic stability. To overcome this issue, we used a scaffold-hopping strategy to identify core-lacking HBDs and discovered the imidazopyridine derivative 17. This compound exhibits potent antiproliferative activity against melanoma cells and good oral exposure. Thus, we conclude that mitigation of P-gp substrate recognition can effectively enhance cellular activity and identify favorable antitumor agents.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118337"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging and anti-aging strategies: A review of past and future therapeutics.","authors":"Yuqing Wei, Baichen Xiong, Zuoaoyun Song, Sheng Zhong, Na Zheng, Ao Zhang, Yao Chen, Haopeng Sun","doi":"10.1016/j.bmc.2025.118340","DOIUrl":"10.1016/j.bmc.2025.118340","url":null,"abstract":"<p><p>Aging is a progressive degenerative state characterized by a gradual loss of physiological fitness, resulting in deteriorated functions and susceptibility to age-related diseases. With the progress of research on aging and age-related mechanisms, identifying effective anti-aging drugs has become a key focus. In this review, we summarize aging and its related signaling pathways and targets, mainly including clearance of senescent cells, NAD⁺ augmentation, anti-inflammatory and anti-oxidant defense, dysfunction of proteostasis and activation of telomerase. Furthermore, we collect advanced research progress of anti-aging agents and other strategies to delay aging and age-related diseases, and ultimately ameliorate lifespan and healthspan. Finally, we review anti-aging research and discuss potential strategies for aging intervention.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118340"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Click conjugation of trivalent mannosyl glycocluster with human serum albumin to generate a cell targeting delivery vehicle.","authors":"Yu-Fan Zhou, Hui Xu, Dan-Yang Chen, Xi-Le Hu, Guo-Rong Chen, Tony D James, Xiao-Peng He","doi":"10.1016/j.bmc.2025.118335","DOIUrl":"10.1016/j.bmc.2025.118335","url":null,"abstract":"<p><p>The exploitation of glycans as targeting agents to construct delivery materials has proved useful for targeted disease diagnosis and therapy. To achieve effective targeting, multivalent glycosides are prepared to enhance avidity with sugar receptors. In this study, we designed and synthesized a new trivalent mannoside (Man₃-PEG₃-N₃) bearing an azido unit. This azido mannosyl glycocluster was used to conjugate with cyclooctyne-modified human serum albumin (HSA) through strain-promoted click chemistry. Mass spectroscopic analysis validated the successful construction of the glycocluster-conjugated HSA, and a fluorescence titration assay indicated that the resulting conjugate is capable of accommodating an environmentally sensitive dye.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"118335"},"PeriodicalIF":3.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting fungal biofilms: design, synthesis, biological and in silico studies of novel N-(5-undecyl-1,3,4-oxadiazol-2-yl)benzamide derivatives against Candida albicans","authors":"A.C. Kumar ,&nbsp;Madalambika ,&nbsp;P.M. Bharathkumar ,&nbsp;Priyanka R. Patil ,&nbsp;J. Rangaswamy ,&nbsp;Ramith Ramu ,&nbsp;K.B. Vilas Gowda ,&nbsp;Nagaraja Naik","doi":"10.1016/j.bmc.2025.118425","DOIUrl":"10.1016/j.bmc.2025.118425","url":null,"abstract":"<div><div>The inhibition of fungal biofilm formation has garnered significant attention as a promising therapeutic strategy against fungal infections. In this study, a series of N-(5-undecyl-1,3,4-oxadiazol-2-yl)benzamide derivatives <strong>5(a–o)</strong> were synthesized as novel biofilm inhibitors targeting <em>Candida albicans</em>, utilizing the well-known biological activities linked with the oxadiazole nucleus. The in vitro antifungal activity of all derivatives was evaluated using the broth microdilution method, with fluconazole serving as the reference drug. Notably, compound <strong>5e</strong> exhibited potent activity, with a minimum inhibitory concentration (MIC) of <strong>7</strong> μ<strong>g/mL</strong> and a minimum fungicidal concentration (MFC) of <strong>32</strong> μ<strong>g/mL</strong>, outperforming the standard drug (MIC: 8 μg/mL; MFC: 64 μg/mL). Biofilm and hyphal filament inhibition assays further revealed that compound <strong>5e</strong> achieved <strong>86.29 %</strong> inhibition of biofilm formation and <strong>72.30 %</strong> inhibition of fungal filamentation. Additionally, RT-PCR analysis demonstrated that treatment with compound <strong>5e</strong> significantly downregulated the expression of key biofilm genes, including ALS1, ALS3, and HWP1. Scanning electron microscopy (SEM) of <em>C. albicans</em> treated with <strong>5e</strong> confirmed substantial inhibition of biofilm formation compared to both untreated controls and the fluconazole-treated group. Screening of compound <strong>5e</strong> for blood compatibility by hemolytic assay revealed <strong>4.83 %</strong> cell lysis at <strong>1125</strong> μ<strong>g/mL</strong>, and cytotoxicity assay on human HEK293 cell line demonstrated that compound <strong>5e</strong> was non-toxic to normal cells at the tested concentrations. Furthermore, molecular docking studies to investigate the potential binding interactions of the lead compound, along with ADMET analysis, were performed to assess pharmacokinetic and bioavailability profiles. The enhanced bioactivity of compound <strong>5e</strong> is associated with the presence of an ortho-substituted hydroxy group, a 1,3,4-oxadiazole core, and a long hydrophobic alkyl chain, which collectively improve target binding, membrane interaction, and antifungal effectiveness. These findings suggest that compound <strong>5e</strong> is a promising candidate for the development of next-generation antifungal agents to combat drug-resistant <em>Candida albicans</em> infections.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118425"},"PeriodicalIF":3.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The epigenetic landscape of kinetoplastid parasites: From histone post-translational modifications to emerging therapeutic strategies","authors":"Inès Jacquet ,&nbsp;Romain Paoli-Lombardo ,&nbsp;Patrice Vanelle ,&nbsp;Nicolas Primas","doi":"10.1016/j.bmc.2025.118377","DOIUrl":"10.1016/j.bmc.2025.118377","url":null,"abstract":"<div><div>Kinetoplastids are parasites which cause various neglected tropical diseases. A hallmark feature of their genomic composition is the presence of polycistronic transcription, a phenomenon that involves the transcription of multiple genes into a single mRNA molecule, along with unconventional modes of gene regulation. In these organisms, histone variants and post-translational modifications play pivotal roles in modulating chromatin structure and transcriptional activity. This review provides a comprehensive overview of histone variants and post-translational modifications identified across <em>Leishmania</em> spp., <em>Trypanosoma cruzi</em>, and <em>Trypanosoma brucei</em>, detailing both the diversity of modifications and their known functional roles. This review also focuses on the writers, erasers, and readers proteins, including available three-dimensional structural data, to better understand their contribution to chromatin regulation, cell cycle progression, and parasite adaptation. Concurrently, this review offers a synopsis of therapeutic endeavors that have targeted these pathways, emphasizing the outcomes of <em>in silico</em>, <em>in vitro</em> and <em>in vivo</em> studies. This comprehensive review underscores the potential of unraveling kinetoplastid epigenetic mechanisms as a promising avenue for developing innovative treatments against these major human pathogens.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118377"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel Aurora B inhibitor using the AI-driven drug screening and docking-based traditional screening","authors":"Jiayuan Ye ,&nbsp;Nan Chen ,&nbsp;Yixiang Zhu ,&nbsp;Yana Xu ,&nbsp;Chenghao Pan ,&nbsp;Yaojiang Xu","doi":"10.1016/j.bmc.2025.118423","DOIUrl":"10.1016/j.bmc.2025.118423","url":null,"abstract":"<div><div>Aurora B, a subtype of Aurora kinases that functions as a serine/threonine kinase, playing a vital role in the process of mitosis, is often overexpressed in certain tumor cells leading to tumorigenesis and progression. Therefore, the development of small molecule inhibitors targeting Aurora B holds promise for providing new options for some cancer patients. In this study, we efficiently screened 4 compounds from MCE compound database using a combination of machine learning-based screening and structure-based screening. The results showed that 2 compounds exhibited strong Aurora B inhibitory activity in a homogeneous time-resolved fluorescence (HTRF) assay, indicating a high hit rate for this screening method. Among them, compound <strong>4</strong> demonstrated optimal inhibitory activity against Aurora B, with an IC₅₀ value of 15.54 nM, comparable to Aurora B inhibitors that have entered clinical trials. <em>In vitro</em> experiments indicated that compound <strong>4</strong> effectively inhibited Huh-7 and Huh-6 cells, with IC₅₀ values of 0.9 μM and 1.8 μM, respectively. Molecular dynamics simulation results revealed that the compound binds to the ATP binding pocket of Aurora B, forming hydrogen bond interactions with Glu171 and Glu220, salt bridges with Asp234 and Glu177, and a pi-cation interaction with Arg97. In summary, by integrating multi-modal screening approaches, we successfully identified a potent Aurora B inhibitor with <em>in vitro</em> antitumor activity, providing lead compounds for subsequent drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118423"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, in-silico and in-vitro evaluation of quinoline-chromene hybrids as dual topoisomerase inhibitors","authors":"Anjali Saxena ,&nbsp;Noimul Hasan Siddiquee ,&nbsp;Mohammad Hasan Shahariar ,&nbsp;Subhrajit Biswas ,&nbsp;Andrew M.Lynn ,&nbsp;Biswajit Saha","doi":"10.1016/j.bmc.2025.118422","DOIUrl":"10.1016/j.bmc.2025.118422","url":null,"abstract":"<div><div>Quinoline and chromene scaffold are recognized to possess anticancer activities but their synergistic potential has never been studied extensively. Our present work investigated a selectively designed series of quinoline-chromene hybrids using an integrative approach combining computational and experimental evaluations. Molecular docking experiments performed on topoisomerase I (3QX3) and II (4FM9) showed high binding affinities with lead molecules 6c, 6l, and 6j having greater efficacy in comparison to standard agents camptothecin and amsacrine. Moreover, molecular dynamics simulations confirmed the stability of the complexes of the ligand and the protein with low RMSD values and positive MM-GBSA binding free energies. ADMET profiling predicted high oral bioavailability, metabolic stability, and tolerable levels of toxicity with encouraging drug-like behavior. Seven of these hybrids were experimentally assessed for cytotoxicity in several cancer cell lines (HepG2, Hep3B, HCT-116, and MCF-7) and showed selective behavior in relation to normal cells (HEK-293 cells). Notably, the compounds 6c and 6l showed sub-micromolar IC₅₀ values and strong dual topoisomerase I/II inhibition and verified their mode of action. Structure-activity relationship (SAR) analysis showed that substituents with an electron-donating effect increased π–π stacking and hydrogen bonding and associated well with enhanced potency and selectivity. Collectively, these results position quinoline–chromene hybrids as important leads in anticancer treatment and emphasize the advantages of scaffold hybridization in attaining efficient, selective, and mechanistically established inhibition of the topoisomerase.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118422"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-embedded photoswitching PROTAC for spatiotemporal tubulin degradation","authors":"Wenpei Zhang ,&nbsp;Huagong Zeng ,&nbsp;Meng Xu ,&nbsp;Ziqing Zhang ,&nbsp;Xinyue Pan ,&nbsp;Jiaqi Li ,&nbsp;Tianzi Xu ,&nbsp;Jie He ,&nbsp;Qiuyuan Duan ,&nbsp;Shujun Huang ,&nbsp;Yirong Lin ,&nbsp;Fengyang Zhang ,&nbsp;Yeran Li ,&nbsp;Jieqing Liu","doi":"10.1016/j.bmc.2025.118414","DOIUrl":"10.1016/j.bmc.2025.118414","url":null,"abstract":"<div><div>This study developed a novel light-switchable proteolysis-targeting chimera (PROTAC) by integrating azobenzene-modified combretastatin A4 (Azo-CA4) as a photocontrollable tubulin ligand. In contrast to conventional light-regulated PROTACs that modulate linker conformation, our strategy embeds the photoswitch directly within the target protein ligand (Azo-CA4). Under 365 nm UV light, Azo-CA4 isomerizes to its cis-configuration, enabling high-affinity tubulin binding and subsequent ubiquitin-proteasome-dependent degradation. The lead compound AC2 exhibited pronounced light-dependent antitumor activity against triple-negative breast cancer (MDA-MB-231 cells), with a 15-fold enhancement in potency (IC₅₀ = 4.05 ± 0.13 μM under UV vs. 63.64 μM in the dark). Furthermore, AC2 exhibited minimal toxicity in normal breast epithelial cells (MCF-10A) under both light and dark conditions (IC₅₀ &gt; 100 μM), highlighting its favorable selectivity. Mechanistic analyses established reversible β-tubulin degradation, ubiquitin-proteasome system (UPS) dependency (inhibited by MG132), and robust ternary complex formation (binding energy: −5.96 kcal/mol). ADMET profiling indicated moderate membrane permeability (Log <em>P</em>_o/w = 3.19) but this permeability limited oral bioavailability, attributable to its high-molecular-weight (645 Da) and poor solubility. This ligand-embedded approach enhances spatiotemporal precision while mitigating off-target toxicity, establishing a novel therapeutic paradigm for targeted cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118414"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the potential of new acetylated unsaturated Oxindole derivatives as multi-target inhibitors for BACE1 and BuChE","authors":"Catarina A. Montargil ,&nbsp;Mariana Pinto ,&nbsp;Rosa Resende ,&nbsp;Elisabete P. Carreiro ,&nbsp;Alfonso T. García-Sosa ,&nbsp;Armanda E. Santos ,&nbsp;Anthony J. Burke","doi":"10.1016/j.bmc.2025.118419","DOIUrl":"10.1016/j.bmc.2025.118419","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60–70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules – some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules <strong>12a</strong> underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (<strong>3a</strong>, <strong>3b</strong>, <strong>3i</strong> and <strong>12a</strong>) have shown moderate BuChE inhibitory activity.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118419"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}