Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Worm-like gold nanocrystals fabricated using a self-assembling peptide and inducing cell death upon exposure to near infrared light","authors":"Soo-Ang Ahn ,&nbsp;Kazutoshi Ishida ,&nbsp;Ryuki Watanabe ,&nbsp;Takahito Imai ,&nbsp;Masayuki Yamasaki ,&nbsp;Kin-ya Tomizaki","doi":"10.1016/j.bmcl.2025.130472","DOIUrl":"10.1016/j.bmcl.2025.130472","url":null,"abstract":"<div><div>Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to synthesize these nanorods, the highly cytotoxic compound cetyltrimethylammonium bromide (CTAB) is required. In the present study, to overcome this difficulty, we developed a method for synthesizing CTAB-free nanocrystals in the form of gold nanoworms (GNWs) using a self-assembling peptide exhibiting a positively-charged nuclear localization signal (NLS) sequence. We investigated the photothermal conversion performance of the GNWs and their ability to induce cell death under NIR irradiation. Based on transmission electron microscopy observations, the NLS-GNWs were determined to be approximately 80 nm in length and 9 nm in width. Their photothermal conversion efficiency was estimated to be 0.27 ± 0.06. Interestingly, in the absence of NLS-GNWs, following three cycles of NIR light exposure for 5 min at an intensity of 5 W/cm² separated by 10 min intervals, no significant change in cytotoxicity of HeLa cells was observed compared with the control. However, in the presence of NLS-GNWs, the cell viability after the first, second and third cycles was approximately 25 %, 18 % and 10 %, respectively. The intracellular localization of NLS-GNWs was also investigated using fluorescein labelled-NLS-GNWs, and it was found that many of the GNWs were present at the nuclei of the HeLa cells. The positively-charged NLS-GNWs are thought to have been attracted to the relatively acidic surfaces of the cancer cells.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130472"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511470","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":"Late-stage functionalization of Cycloastragenol and anti-inflammatory study","authors":"Yong Wang ,&nbsp;Yingchuan Que ,&nbsp;Yi Gu ,&nbsp;Jia Xia ,&nbsp;Yi Dong ,&nbsp;Lumin Tang ,&nbsp;Shan Mou ,&nbsp;Gang Chen","doi":"10.1016/j.bmcl.2025.130442","DOIUrl":"10.1016/j.bmcl.2025.130442","url":null,"abstract":"<div><div>Cycloastragenol (CAG), a bioactive compound from Huangqi, exhibits anti-inflammatory properties but has poor water solubility. This study enhanced CAG's solubility via C3-position modifications, synthesizing phosphorylated, sulfonated, and glycosylated derivatives with improved solubility. The phosphorylated derivative (<strong>11a</strong>) excelled in suppressing nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. Further investigation revealed that both CAG and <strong>11a</strong> effectively reduced levels of pro-inflammatory cytokines IL-6 and TNF-α, suggesting their anti-inflammatory effects are mediated through these pathways. Our findings indicate that chemical modifications can successfully enhance the solubility of CAG without compromising its bioactivity, with derivative <strong>11a</strong> emerging as a particularly promising candidate for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130442"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367242","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":"An efficient approach to flavan-4-ols via radiolysis and their inhibitory activity against cytokine production","authors":"Gyeong Han Jeong ,&nbsp;Ha-Yeon Song ,&nbsp;Hanui Lee ,&nbsp;Byung Yeoup Chung ,&nbsp;Kyung-Bon Lee ,&nbsp;Hyoung-Woo Bai","doi":"10.1016/j.bmcl.2025.130464","DOIUrl":"10.1016/j.bmcl.2025.130464","url":null,"abstract":"<div><div>Facile structural modification of naringin (<strong>1</strong>) induced by γ-irradiation produced five novel hydroxymethylated flavan-4-ols, namely, narinflavans A (<strong>2</strong>), B (<strong>3</strong>), C (<strong>4</strong>), D (<strong>5</strong>), and E (<strong>6</strong>). The structures of the newly synthesized flavan derivatives were determined through comprehensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, whereas their absolute configurations were confirmed by electronic circular dichroism (ECD) spectroscopy. The new unusual flavan derivatives <strong>4</strong> and <strong>5</strong> containing a hydroxymethyl, instead of a ketone moiety, exhibited significantly modulated inhibitory effects on cytokine production than the parent compound. These results highlight γ-irradiation as an efficient one-step approach to generate structurally novel flavan-4-ols with biological functions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130464"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470317","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 telomerase for lung cancer: design and synthesis of acridine hybrids with in vitro and in vivo evaluation","authors":"Keerti Vishwakarma,&nbsp;Rajdeep Dey,&nbsp;Hardik Bhatt","doi":"10.1016/j.bmcl.2025.130465","DOIUrl":"10.1016/j.bmcl.2025.130465","url":null,"abstract":"<div><div>Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecular target; however, the clinical translation of its inhibitors has been limited. In this study, we employed a rational design approach that integrated pharmacophore modeling, virtual screening, QSAR, and molecular docking to develop acridine–thiadiazole hybrids as potential telomerase inhibitors. Guided by pharmacophore-based virtual screening and 3D-QSAR studies, 32 derivatives were synthesized through an optimized route for synthesis and evaluated for anticancer activity. Several compounds displayed potent sub-micromolar cytotoxicity against A549 lung cancer cells with minimal toxicity toward Vero cells. Among them, compound <strong>28</strong> emerged as the most potent, exhibiting nanomolar activity and strong telomerase inhibition, while compounds <strong>21</strong>, <strong>29</strong>, and <strong>39</strong> also demonstrated significant efficacy. Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic survival, and telomerase suppression. <em>In vivo</em> evaluation in a benzo[<em>a</em>]pyrene-induced lung cancer model further validated the therapeutic potential of these hybrids, showing reduced tumor burden, restoration of antioxidant balance, and preservation of lung architecture. Collectively, these findings highlight acridine–thiadiazole hybrids, particularly compound <strong>28</strong>, as promising, selective telomerase inhibitors for lung cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130465"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487402","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":"Lysine-reactive tag system for cell-surface protein labeling via N-acyl-N-alkyl sulfonamide chemistry","authors":"Vikram Thimaradka,&nbsp;Tomonori Tamura,&nbsp;Itaru Hamachi","doi":"10.1016/j.bmcl.2025.130470","DOIUrl":"10.1016/j.bmcl.2025.130470","url":null,"abstract":"<div><div>Target-selective and site-specific incorporation of a desired functionality into a membrane protein endogenously expressed in cells is a great challenge in chemical biology. Here, we describe a versatile strategy for <!--> <!-->covalent chemical modification of short peptide tag-fused membrane proteins expressed in cells. This method is based on the recognition-driven reaction of a lysine-containing short histidine tag (KH6 or H6K sequence) and a binuclear nickel (II)-nitrilotriacetic acid (BisNi²⁺-NTA) complex probe containing a lysine-reactive <em>N</em>-acyl-<em>N</em>-alkyl sulfonamide (NASA). Our reactive peptide tag system enabled the selective modification of cell-surface proteins with affinity tags or fluorescent probes through a simple one-step protocol. In this study, we fused the KH6 or H6K tag to cell-surface proteins such as Neuroligin-1, epidermal growth factor receptor (EGFR), and Neurexin-1β, and achieved selective chemical modification of these proteins in live cells. Furthermore, we demonstrated that our short peptide tag allows efficient labeling not only when introduced at the protein termini but also when incorporated internally.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130470"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493798","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":"Precision engineering of adalimumab fab variants enhances TNF-α neutralization and structural stability","authors":"Abida Khan ,&nbsp;Abdullah R. Alzahrani ,&nbsp;Zia Ur Rehman ,&nbsp;Syeda Huma H. Zaidi ,&nbsp;Abdul Hai ,&nbsp;Maha M. Al-Bazi ,&nbsp;Abeer A. Banjabi ,&nbsp;Mohd Imran","doi":"10.1016/j.bmcl.2025.130475","DOIUrl":"10.1016/j.bmcl.2025.130475","url":null,"abstract":"<div><div>The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-α) plays a substantial role in the advancement of various autoimmune diseases and is mostly suppressed by the monoclonal antibody adalimumab (Humira). This study utilized a rational <em>in-silico</em> method to design and optimize adalimumab Fab mutants with enhanced TNF-α binding affinity. A total of 512 mutants were produced with a Python automation script and FoldX. Eight mutants were selected for further analysed based on their stability (ΔG). The humanness ratings of the chosen variations were computed, demonstrating that they preserved similar human-like attributes. The anticipated expression in <em>E. coli</em> was elevated, with values between 0.93 and 0.94, as evidenced by the solubility analysis, which was analogous to the control (adalimumab) result of 0.94. Molecular docking revealed that all mutants displayed negligible RMSD values (≤ 0.001 Å) and uniform interface residues. FreeSASA and MM/GBSA studies were conducted to identify the top three candidates (Antibody-98, Antibody-354, and Antibody-374), which were subsequently confirmed by molecular dynamics simulations. Antibody-374 (yellow) and Antibody-98 (green) exhibit negligible variations (∼0.2–0.3 nm). Relative to the control, all three mutants demonstrated an elevation in total buried surface area (BSA), with Antibody-354 displaying the greatest measurement (5434.06 Å<span><span>²</span></span>). Antibody-98 exhibited 14–15 hydrogen bonds, which were sustained at about 8–10 bonds for the majority of the simulation. Antibody-354 exhibited a range of 6–8 number of hydrogen bonds, while Antibody-374 had a robust contact with 6–10 hydrogen bonds. In the binding free energy examination utilizing MM/GBSA, Antibody-374 exhibited the most advantageous ΔG_total (−36.67 kcal/mol), succeeded by Antibody-98 (−30.07 kcal/mol) and Antibody-354 (−25.47 kcal/mol). These antibodies surpassed the wild-type docked model (−24.80 kcal/mol) and the native crystal complex (−25.46 kcal/mol). The enhancements were ascribed to particular point mutations, namely G28S, R90E, Y96W (light chain), and W53Y/F, L102I/V (heavy chain), which augmented molecular interactions and complex stability. This study demonstrated the capability of computational antibody engineering to generate Fab variants with enhanced binding affinity and stability for TNF-α. These findings thus offer significant insights for the advancement of future biologic therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130475"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530293","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":"Coumarin–benzimidazole hybrids: Design, synthesis and identification of potential anticancer agents","authors":"C.G. Arya ,&nbsp;Neethu Mariam Thomas ,&nbsp;Munugala Chandrakanth ,&nbsp;Anoop Kallingal ,&nbsp;P.G. Amrutha ,&nbsp;M.S. Sivapriya ,&nbsp;Ramesh Gondru ,&nbsp;Janardhan Banothu","doi":"10.1016/j.bmcl.2025.130444","DOIUrl":"10.1016/j.bmcl.2025.130444","url":null,"abstract":"<div><div>A series of coumarin–benzimidazole conjugates (<strong>6a–p</strong>) was designed and synthesized <em>via</em> a polyphosphoric acid (PPA)-mediated condensation of <em>o</em>-phenylenediamine derivatives with coumarin-3-carboxylic acids. The <em>in vitro</em> anticancer activity of all conjugates was evaluated against lung (A549) and breast (MCF7) cancer cell lines. Except for hybrids <strong>6l</strong> (A549) and <strong>6c</strong> (MCF7), all compounds exhibited notable cytotoxicity toward both cell lines, with IC₅₀ values ranging from 0.85 ± 0.07 to 48.01 ± 0.45 μM. Among them, the unsubstituted derivative <strong>6b</strong> emerged as the most potent compound, showing IC₅₀ values of 0.85 ± 0.07 μM (A549) and 1.90 ± 0.08 μM (MCF7). Compounds <strong>6a</strong>, <strong>6c</strong>, and <strong>6g</strong> also demonstrated strong activity against A549 cells, with IC₅₀ values of 1.86 ± 0.19 μM, 1.05 ± 0.09 μM, and 2.23 ± 0.13 μM, respectively. Furthermore, the potent conjugates <strong>6b</strong> and <strong>6g</strong> were found to be non-toxic toward Vero cells (LD₅₀ &gt; 100 μM), indicating selective cytotoxicity toward cancer cells. <em>In silico</em> molecular docking studies suggested that the activity of compound <strong>6b</strong> against both cell lines may result from inhibition of sphingosine kinase 1 (SK1), whereas the potency of <strong>6g</strong> against A549 cells could be attributed to cyclin-dependent kinase 2 (CDK2) inhibition. These computational predictions warrant further validation through target-specific biological assays. ADMET analysis further revealed that conjugate <strong>6b</strong> possesses favorable pharmacokinetic properties, supporting its potential as a promising lead for future anticancer drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130444"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336141","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":"Exploration of imidazothiazole and imidazopyrimidine carboxamides for enhanced antitubercular activity","authors":"Oluseye K. Onajole ,&nbsp;Shichun Lun ,&nbsp;Dakoju Ravi Kishore ,&nbsp;Anđela Savić ,&nbsp;Alexis Morales ,&nbsp;Alfredo Guzman ,&nbsp;Ethan Schmidt ,&nbsp;Adela Lazzara ,&nbsp;Gianna Fajardo ,&nbsp;Daniel P. Jamieson ,&nbsp;A. Jean-Luc Ayitou ,&nbsp;William R. Bishai","doi":"10.1016/j.bmcl.2025.130447","DOIUrl":"10.1016/j.bmcl.2025.130447","url":null,"abstract":"<div><div>Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are limited safe therapeutics available to combat multidrug- and extensively drug-resistant (MDR and XDR, respectively) strains of TB, hence the race to find highly effective antitubercular drug candidates with little to no side effects. Herein, we report on the design, synthesis, and biological evaluation of 33 novel heterobicyclic (imidazothiazole- and imidazopyrimidine-containing) carboxamide derivatives for their antitubercular properties. These compounds were designed based on reported anti-TB properties of indole-2-carboxamides, imidazo[1,2-<em>a</em>]pyridine-3-carboxamides, and imidazo[2,1-<em>b</em>]pyrimidine-5-carboxamides derivatives. This effort led to the discovery of compounds <strong>21</strong> (imidazothiazole-based) and <strong>37</strong> (imidazopyrimidine-based), which showed excellent anti-TB activity against susceptible, MDR, and XDR-TB strains (MIC: 0.2–6.36 μM). Compound <strong>21</strong> also displayed excellent drug-like properties based on its pharmacokinetic profiles and is void of cytotoxicity to Vero cells at the highest tested concentration. Importantly, compounds <strong>21</strong> and <strong>37</strong> were found to be inactive against selected non-TB forming mycobacteria (MIC: &gt;40 μM) and bacteria (both gram-negative and gram-positive microorganisms), indicating their selectivity for <em>Mycobacterium tuberculosis</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130447"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353221","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":"Gallium Hematoporphyrin inhibits Mycobacteroides abscessus in vitro, including biofilm formation and stability","authors":"Seoung-ryoung Choi ,&nbsp;Bradley E. Britigan ,&nbsp;Prabagaran Narayanasamy","doi":"10.1016/j.bmcl.2025.130466","DOIUrl":"10.1016/j.bmcl.2025.130466","url":null,"abstract":"<div><div>The nontuberculous mycobacterial (NTM) pathogen, <em>Mycobacteroides abscessus</em>, can cause severe pulmonary infections. Emerging multidrug resistance to current antibiotics poses significant challenges for treatment of <em>M. abscessus</em> infections. Thus, new antibiotics are needed, preferably ones that target new microbial pathways. Earlier, we examined the <em>in vitro</em> inhibitory activities of several gallium compounds, Ga(NO₃)₃, GaCl₃, gallium <em>meso</em>-tetraphenylporphyrin (GaTP) and gallium nanoparticles (GaNP), against intra- and extracellular <em>M. abscessus</em>. We have previously shown that these gallium compounds function by disrupting microbial iron/heme acquisition and utilization. Here, we explored an alternative therapeutic approach using gallium hematoporphyrin (GaHP), a toxic heme analogue. GaHP inhibited growth of clinical <em>M. abscessus</em> isolates, with MICs in range of 0.5 and 1 μg/ml. GaHP was more active than rifampin against <em>M. abscessus</em>, showed synergism with clarithromycin, and induced ROS formation in <em>M. abscessus</em>. GaHP also inhibited biofilm formation of both smooth and rough <em>M. abscessus</em> colony morphotypes. GaHP also disrupted preformed biofilms by both <em>M. abscessus</em> morphotypes. Hence, GaHP could be a potential lead compound for development of anti-NTM agents that targets heme-metabolism of <em>M. abscessus</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130466"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463284","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":"LXH254 hybrid with adamantane: synthesis and in vitro evaluation of 2,4,6-trisubstituted pyridine derivative Z-001 containing adamantyl moiety as a novel B-RAF inhibitor","authors":"Wei Fan ,&nbsp;Meina Li ,&nbsp;Yeming Wang","doi":"10.1016/j.bmcl.2025.130481","DOIUrl":"10.1016/j.bmcl.2025.130481","url":null,"abstract":"<div><div>In this study, 2,4,6-trisubstituted pyridine derivative <strong>Z-001</strong> containing adamantyl moiety was designed through the hybridization strategy of LXH254 and adamantane. A new and effective synthetic route was established to achieve the synthesis of <strong>Z-001</strong> through four step reactions, starting from commercially available 3-bromo-4-methylaniline and (2,6-dichloropyridin-4-yl) boronic acid. Besides, <strong>Z-001</strong> was evaluated inhibitory activity against B-RAF kinase with IC₅₀ value of 37.80 nM by ADP-Glo kinase assay, and it was found that <strong>Z-001</strong> was a more potent B-RAF inhibitor than Vemurafinib (IC₅₀ = 78.52 nM). Furthermore, molecular docking simulations showed that <strong>Z-001</strong> bound to DFG-out/C-helix-in conformation in the B-RAF kinase, and formed three hydrogen bonds with GLU501, ASP594 and CYS532, respectively. It was worth noting that the adamantane alcohol of <strong>Z-001</strong> was very suitable for matching the cavities near the solvent exposed region, which was filled with adamantyl moiety and effectively utilized in the docking model. The binding mode between <strong>Z-001</strong> and B-RAF kinase provided a reasonable explanation for <strong>Z-001</strong> as a potential B-RAF kinase inhibitor.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"131 ","pages":"Article 130481"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585582","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}