Bioorganic & Medicinal Chemistry Letters最新文献_第2页

Dioscin attenuates hyperlipidemia by dual modulation of intestinal triglyceride and cholesterol absorption 薯蓣皂苷通过肠道甘油三酯和胆固醇吸收的双重调节来减轻高脂血症。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-31 DOI: 10.1016/j.bmcl.2025.130531

Jufeng Sun , Yixiao Wang , Rufei Wang , Yuan Yao , Jiarui Wang , Guojun Pan , Renshuai Zhang , Xiaoguang Zhao

Dioscin, a natural steroidal saponin derived from Dioscorea species, has been reported to exhibit lipid-lowering activity despite its extremely low oral bioavailability. This study aimed to elucidate whether dioscin exerts its lipid-lowering effects through intestinal mechanisms. Using both high-fat diet (HFD)-induced and acute lipid-challenge rat models, dioscin significantly reduced plasma triglyceride (TG) and total cholesterol (TC) levels, indicating an inhibitory effect on intestinal lipid absorption. In vitro assays demonstrated that dioscin inhibited pancreatic triglyceride lipase (PTL) activity with moderate potency and suppressed Niemann-Pick C1-Like 1 (NPC1L1)-mediated cholesterol uptake in Caco-2 cells. Surface plasmon resonance (SPR) analysis and molecular docking suggested direct interactions between dioscin and both PTL and NPC1L1, suggesting that dioscin interferes with intestinal lipid absorption through mechanisms involving TG hydrolysis and cholesterol transport. These findings provide mechanistic insight into the intestinal lipid-lowering activity of dioscin and highlight its potential as a natural lead compound for the development of safe and intestine- restricted lipid-lowering agents.

薯蓣皂苷是一种从薯蓣属植物中提取的天然甾体皂苷，尽管其口服生物利用度极低，但据报道具有降脂活性。本研究旨在阐明薯蓣皂苷是否通过肠道机制发挥其降脂作用。在高脂饮食（HFD）诱导和急性脂质挑战大鼠模型中，薯蓣皂苷显著降低血浆甘油三酯（TG）和总胆固醇（TC）水平，表明其对肠道脂质吸收有抑制作用。体外实验表明，薯蓣皂苷能适度抑制胰腺甘油三酯脂肪酶（PTL）活性，抑制cco -2细胞中Niemann-Pick C1-Like 1 （NPC1L1）介导的胆固醇摄取。表面等离子体共振（SPR）分析和分子对接表明，薯蓣皂苷与PTL和NPC1L1均存在直接相互作用，表明薯蓣皂苷通过TG水解和胆固醇转运等机制干扰肠道脂质吸收。这些发现为薯蓣皂苷的肠道降脂活性提供了机制见解，并突出了其作为天然先导化合物开发安全和肠道限制降脂剂的潜力。

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引用次数: 0

Second generation PSMA-targeted turn-on probe for imaging cargo release in prostate cancer cells 第二代psma靶向开启探针用于成像前列腺癌细胞中的货物释放。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-31 DOI: 10.1016/j.bmcl.2025.130530

Nooshin Mesbahi , Brenna C. McAllister , Hosog Yoon , Aaron T. Hendricksen , Melody D. Fulton , Leslie A. Caromile , Clifford E. Berkman

Targeted payload release in cancer cells can be modulated by tuning both the linker, spacer, and the payload chemistries. In previous studies, a PSMA-targeted probe incorporating a 7-amino-4-methylcoumarin (AMC) payload and a PEG linker resulted in predominant payload release in the lysosome (pH ∼5.0). Here, we introduce a second-generation PSMA-targeted turn-on probe with a shorter, hydrophobic linker and a 7-hydroxy-4-methylcoumarin (HMC) payload. Based on pH-dependent kinetic studies, the HMC payload exhibits faster cleavage at a slightly higher pH (pH 5.5), suggesting an earlier release—potentially more in early endosomes than lysosomes. Our results demonstrate that subtle changes in linker and payload structures can alter intracellular release kinetics, offering improved control over the cellular release site, which is critical for optimizing targeted therapeutic and imaging strategies in prostate cancer cells.

癌细胞中的靶向有效载荷释放可以通过调节连接器、间隔器和有效载荷化学物质来调节。在先前的研究中，psma靶向探针结合了7-氨基-4-甲基香豆素（AMC）有效载荷和PEG连接物，导致溶酶体（pH ~5.0）中主要的有效载荷释放。在这里，我们介绍了第二代psma靶向开启探针，该探针具有更短的疏水连接体和7-羟基-4-甲基香豆素（HMC）负载。基于pH依赖的动力学研究，HMC有效载荷在稍高的pH下（pH 5.5）表现出更快的裂解速度，表明较早的释放-可能在早期内体中比在溶酶体中更多。我们的研究结果表明，连接体和有效载荷结构的细微变化可以改变细胞内释放动力学，从而改善对细胞释放位点的控制，这对于优化前列腺癌细胞的靶向治疗和成像策略至关重要。

引用次数: 0

Evaluation of the efflux inhibitory potential of aminopyrazole derivative to restore azole sensitivity in Candida albicans 氨基吡唑衍生物对白色念珠菌恢复唑敏感性的外排抑制电位评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-30 DOI: 10.1016/j.bmcl.2025.130529

Vineetha K. Unnikrishnan , Niranjana sri Sundaramoorthy , Ramaravinth Manivannan , Markabandhu Shanthi , Divya Prakash Gnanadhas , Soundarya Alexander , Venkatasubramanian Ulaganathan , Ramesh Subburethinam , Saisubramanian Nagarajan

Candida albicans is an opportunistic fungus that causes infections in people with weakened immune system. Candida has the propensity to gain drug resistance by mutation, and its ability to extrude antifungals through drug transporters. Efflux pump inhibitors increase the intracellular drug concentration and restore drug sensitivity in resistant strains. We synthesized and screened 10 azole heterocyclic derivatives (pyrazole-5-amine and 2H-indazole) against Mdr1p/Cdr1p overexpressing and knock-out strains of Candida albicans. Among the derivatives screened, sulfenylated pyrazole-5-amine (designated as 4a) displayed strong efflux inhibitory potential and caused a 64-fold reduction in the fluconazole MIC. Compound 4a inhibited the Mdr1p pump, as MIC reversal was not observed in the Mdr1p knock-out strain. 4a exhibited synergy with fluconazole only against Mdr1p harboring strains, as discerned by the Checkerboard assay. Combining 4a with fluconazole restricted microbial growth and reduced cell counts by 4 log fold relative to treatment with fluconazole in a time-kill assay. Infection of RAW macrophages followed by treatment with a combination of sulfenylated aminopyrazole & fluconazole resulted in a significant 2 log reduction in intracellular cell counts relative to treatment with fluconazole. 4a also inhibited biofilm formation and yeast to hyphal shift in Candida, thereby reducing virulence. Combining EPIs with antifungal drugs has the potential to improve the treatment of C. albicans infections and reduce the risk of drug resistance. However, further research is needed to determine the safety and efficacy of these compounds in humans.

白色念珠菌是一种机会性真菌，在免疫系统较弱的人群中引起感染。念珠菌具有通过突变获得耐药性的倾向，并且具有通过药物转运体挤出抗真菌药物的能力。外排泵抑制剂增加耐药菌株的细胞内药物浓度并恢复药物敏感性。为了验证这一点，我们合成并筛选了10种抗Mdr1p/Cdr1p过表达和敲除菌株的唑类杂环衍生物（pyrazole-5-amine和2H-indazole）。在筛选的衍生物中，磺化吡唑-5-胺（指定为4a）显示出强大的外排抑制潜力，并导致氟康唑MIC降低64倍。化合物4a抑制Mdr1p泵，因为在Mdr1p敲除菌株中未观察到MIC逆转。通过棋盘试验发现，4a与氟康唑仅对Mdr1p携带菌株具有协同作用。在时间杀伤试验中，4a与氟康唑联合使用限制了微生物的生长，并使细胞计数比氟康唑治疗减少了4倍。与氟康唑治疗相比，磺化氨基吡唑和氟康唑联合治疗后，RAW巨噬细胞感染导致细胞内细胞计数显著减少2倍。4a还能抑制念珠菌生物膜的形成和酵母向菌丝的转移，从而降低毒力。EPIs联合抗真菌药物有可能改善白色念珠菌感染的治疗，并降低耐药性的风险。然而，需要进一步的研究来确定这些化合物在人体中的安全性和有效性。

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引用次数: 0

Discovery of novel 4-aminobenzamide derivatives as small molecule CBX2 inhibitors 新型4-氨基苯甲酰胺衍生物小分子CBX2抑制剂的发现。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-30 DOI: 10.1016/j.bmcl.2025.130526

Yuichiro Kawamoto , Shohei Takase , Kumar Ashutosh , Hiroki Maruo , Yuki Maemoto , Kam Y.J. Zhang , Hisanaka Ito , Akihiro Ito

CBX2 protein plays an important role in methyl-lysine recognition involved in epigenetic regulation. In contrast to CBX7 modulators, there are few reported CBX2 inhibitors, most of which are peptidergic molecules. This fact encouraged us to search non-peptidic small molecule CBX2 inhibitors with sufficient cell permeability by in silico screening followed by synthetic evolution. In virtual screening, we identified a 4-aminobenzamide scaffold with high in silico score and Nano BRET activities. Based on several in silico hit compounds, we synthesized a series of 4-aminobenzamide derivatives and tested their Nano BRET activities. Among them, compound 37 showed moderate CBX2 inhibitory activity with an IC₅₀ value of 9.6 μM, a potential lead compound. This is a first small molecule CBX2 inhibitor identified as a result of SAR studies and lead optimization by medicinal chemistry.

CBX2蛋白在参与表观遗传调控的甲基赖氨酸识别中起重要作用。与CBX7调节剂相比，CBX2抑制剂的报道很少，其中大多数是肽能分子。这一事实鼓励我们通过硅筛选和合成进化来寻找具有足够细胞渗透性的非肽类小分子CBX2抑制剂。在虚拟筛选中，我们确定了具有高硅评分和纳米BRET活性的4-氨基苯酰胺支架。在几种硅基化合物的基础上，我们合成了一系列的4-氨基苯甲酰胺衍生物，并测试了它们的纳米BRET活性。其中化合物37表现出中等的CBX2抑制活性，IC50值为9.6 μM，是潜在的先导化合物。这是首个小分子CBX2抑制剂，是通过SAR研究和药物化学先导优化的结果。

引用次数: 0

Correlation between tight binding of inhibitors and their target selectivity toward the non-native state in the DYRK family of kinases 在DYRK激酶家族中，抑制剂的紧密结合与它们对非天然状态的靶向选择性之间的关系。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-27 DOI: 10.1016/j.bmcl.2025.130527

Natsumi Yamada , Sora Suzuki , Nanae Fukahori , Yoshiyuki Yamaoka , Yuta Komiyama , Ninako Kimura , Koji Umezawa , Isao Kii

A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the non-native state autophosphorylates intramolecularly, whereas the folded conformation of DYRK1A in the native state no longer catalyzes this reaction. We identified FINDY, a small molecule that selectively inhibits the DYRK1A folding intermediate but not its fully folded conformation. These findings indicated the presence of a unique binding site that is exposed only in the folding intermediate. In the previous study, we developed a facile method for screening of inhibitors that target the folding intermediate in the non-native state using recombinant folded proteins in the native state. We found that FINDY and its derivatives target both DYRK1A and DYRK1B in their non-native states. In this study, we examined the potency of these inhibitors on DYRK2, another member of the DYRK family. FINDY inhibited DYRK2 in the non-native state slightly greater than that in the native state. Although RD0448, a FINDY derivative, selectively targets DYRK1A/1B in their non-native states, RD0448 exhibited no selectivity between the native and non-native states of DYRK2, indicating that the RD0448-binding site is hidden in the native state of DYRK1A/1B but is exposed in the native state of DYRK2. Furthermore, RD0448 bound tightly to DYRK1A/1B, whereas RD0448 showed weak affinity for DYRK2 and rapidly dissociated from the binding complex. These results suggest a correlation between the tight binding of the inhibitors and their target selectivity toward the non-native state in DYRK family kinases.

双特异性酪氨酸磷酸化调节激酶1A （DYRK1A）在非天然状态下的折叠中间体在分子内自磷酸化，而在天然状态下的DYRK1A的折叠构象不再催化该反应。我们发现了FINDY，一种选择性抑制DYRK1A折叠中间体但不抑制其完全折叠构象的小分子。这些发现表明存在一个独特的结合位点，仅暴露在折叠中间体中。在之前的研究中，我们开发了一种简单的方法来筛选靶向非天然状态折叠中间体的抑制剂，使用天然状态的重组折叠蛋白。我们发现FINDY及其衍生物在非天然状态下靶向DYRK1A和DYRK1B。在这项研究中，我们检测了这些抑制剂对DYRK2 （DYRK家族的另一个成员）的效力。FINDY在非天然状态下对DYRK2的抑制作用略大于天然状态。虽然FINDY衍生物RD0448选择性靶向DYRK1A/1B的非天然状态，但RD0448在DYRK2的天然状态和非天然状态之间没有选择性，这表明RD0448的结合位点隐藏在DYRK1A/1B的天然状态中，而暴露在DYRK2的天然状态中。此外，RD0448与DYRK1A/1B结合紧密，而RD0448对DYRK2的亲和力较弱，并且与结合复合物迅速分离。这些结果表明，抑制剂的紧密结合与它们对DYRK家族激酶非天然状态的靶向选择性之间存在相关性。

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引用次数: 0

Development of the fluorescence polarization-based competition assay for the E3 ligase GID4 基于荧光偏振的E3连接酶GID4竞争测定方法的建立。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-27 DOI: 10.1016/j.bmcl.2025.130528

Meiling Zhang , Shijia Xiao , Kexin Yan , Jiyue Sun , Chen Xi , Yuhong Qin , Cheng Dong , Dongxing Chen

The proteolysis-targeting chimera (PROTAC) technology utilizes heterobifunctional molecules to induce targeted protein degradation through the ubiquitin-proteasome system. Structurally, PROTAC molecules consist of a target protein ligand and an E3 ligase ligand covalently linked by a suitable linker arm, forming the target protein-PROTAC-E3 ligase stable ternary complex and bringing the target protein in proximity to the E3 ligase for ubiquitination and subsequent proteasomal degradation. However, only a few E3 ligases have been used to generate effective PROTACs with limited small molecule E3 ligase ligands. Therefore, there is an urgent need to discover novel E3 ligase ligands to expand the toolbox for PROTACs. Unlike traditional E3 ligases such as ‌CRBN‌ and ‌VHL‌, GID4 E3 ligase recognizes substrates bearing N-terminal proline or other small residues through the Pro/N-degron pathway, and has already been successfully leveraged in ‌PROTAC technology. Here, we reported the development of a fluorescent probe YG11, with a K_d value of 8.1 ± 0.7 nM for GID4. With this probe, we established a robust fluorescence polarization (FP)-based competition assay for evaluation of GID4 ligands. The assay exhibited a high signal-to-noise ratio of over 20, 2.5 % DMSO tolerance, and a Z'-factor of 0.84, confirming its suitability and robustness for high-throughput screening. Thus, by enabling rapid identification of GID4 ligands, this FP competition assay promises to substantially advance PROTAC development initiatives.

proteolysis-targeting chimera （PROTAC）技术利用异功能分子通过泛素-蛋白酶体系统诱导靶向蛋白质降解。在结构上，PROTAC分子由靶蛋白配体和E3连接酶配体通过合适的连接臂共价连接组成，形成靶蛋白-PROTAC-E3连接酶稳定的三元复合物，使靶蛋白接近E3连接酶进行泛素化和随后的蛋白酶体降解。然而，只有少数E3连接酶被用来用有限的小分子E3连接酶配体生成有效的PROTACs。因此，迫切需要发现新的E3连接酶配体来扩充PROTACs的工具箱。与传统的E3连接酶如CRBN和VHL不同，GID4 E3连接酶通过Pro/N-degron途径识别含有n端脯氨酸或其他小残基的底物，并且已经成功地利用于PROTAC技术。在这里，我们报道了一种荧光探针YG11的开发，对GID4的Kd值为8.1 ± 0.7 nM。利用该探针，我们建立了一种基于荧光偏振（FP）的强效竞争检测方法，用于评估GID4配体，具有超过20,2.5 %的DMSO耐受性和0.84的高信噪比，证实了其高通量筛选的适用性和鲁棒性。因此，通过快速识别GID4配体，这种FP竞争分析有望大大推进PROTAC的开发计划。

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引用次数: 0

Design, synthesis, and antiviral activity evaluation of the bis-ester prodrug of N4-hydroxycytidine phosphate 磷酸n4 -羟基胞苷双酯前药的设计、合成及抗病毒活性评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-25 DOI: 10.1016/j.bmcl.2025.130525

Hao Sun , Xu Yan , Chunhuan Mo , Jia Chen , Yan Liu , Yaohui Liu , Xia Han , Jianqin Gao , Lehua Yin , Jinghua Xu , Yuan Chen , Xinhua He

Monophosphorylation is a key rate-limiting step for the efficacy of broad-spectrum nucleoside antiviral drugs, and designing phosphate prodrugs is an effective method to enhance antiviral efficacy. N4-hydroxycytidine (NHC) has a broad-spectrum antiviral effect. Based on the mechanism of action and metabolic inactivation characteristics of NHC, we designed a series of dual ester prodrugs targeting the N4-hydroxyl group and the 5′-phosphate of the ribose ring. Twenty-nine compounds were designed and synthesized. The cytotoxicity assay results showed low cytotoxicity (no significant toxicity at 160 μM). Using the Vesicular Stomatitis Virus expressing Green Fluorescent Protein (VSV-GFP) virus screen, it was found that all of them have antiviral activity. Compounds 2328 and 2322 showed better antiviral activity than molnupiravir. The EC₅₀s of 2328 against VSV, HMPV-A2, and RSV-A2 viruses were 2.19 μM, 35.6 μM, and 53.5 μM, respectively, and the EC₅₀s of 2322 against VSV, HMPV-A2, and RSV-A2 were 6.23 μM, 52.8 μM, and 28.2 μM, respectively. Structure-activity relationships indicate that the antiviral activity of compounds at the cellular level is closely linked to the structure of the prodrug's phosphate ester, whereas the ester group on the N4-hydroxyl is more tolerant of diverse functional groups.

单磷酸化是广谱核苷类抗病毒药物药效的关键限速步骤，设计磷酸原药是提高抗病毒药效的有效方法。n4 -羟基胞苷（NHC）具有广谱抗病毒作用。基于NHC的作用机制和代谢失活特点，我们设计了一系列针对NHC的n4 -羟基和核糖环的5′-磷酸的双酯前药。设计并合成了29个化合物。细胞毒性实验结果显示细胞毒性较低（160 μM无明显毒性）。通过表达绿色荧光蛋白的水疱性口炎病毒（VSV-GFP）病毒筛选，发现它们均具有抗病毒活性。化合物2328和2322的抗病毒活性优于molnupiravir。2328对VSV、HMPV-A2和RSV-A2病毒的ec50分别为2.19 μM、35.6 μM和53.5 μM， 2322对VSV、HMPV-A2和RSV-A2病毒的ec50分别为6.23 μM、52.8 μM和28.2 μM。构效关系表明，化合物在细胞水平上的抗病毒活性与前药的磷酸酯结构密切相关，而n4 -羟基上的酯基对多种官能团的耐受性更强。

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引用次数: 0

Cinnamoyl aryl hydrazones as potent leishmanicidal agents: design, synthesis, and structure–activity relationships 肉桂酰芳基腙作为有效的利什曼尼杀灭剂：设计、合成和构效关系。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-24 DOI: 10.1016/j.bmcl.2025.130523

Renan Augusto Gomes , Leonardo Luiz Gomes Ferreira , Witor Ribeiro Ferraz , Rodrigo Alves Heleno , Fernando Moura Gatti , Mariana Laureano de Souza , Cleydson Breno Rodrigues dos Santos , Adriano Defini Andricopulo , Gustavo Henrique Goulart Trossini

Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was synthesized and tested against Leishmania donovani and Trypanosoma cruzi. Four compounds showed promising antileishmanial activity (from 1.27 to 19.53 μM), with two analogues displaying superior potency compared to some current first-line treatments, such as sodium stibogluconate and paromomycin. Computational analyses revealed that activity is driven by specific electronic properties rather than steric factors, while a methyl group consistently reduced potency. The compounds demonstrated favorable predicted ADME properties and were not flagged as aggregators. This research identifies cinnamoyl aryl hydrazones as a promising scaffold for leishmanicidal drug discovery, providing a rational basis for future optimization efforts.

利什曼病和南美锥虫病等寄生虫病由于治疗选择有限和耐药性，对全球健康构成重大挑战。本研究合成了一系列新的肉桂酰芳基腙衍生物，并对其进行了抗多诺瓦利什曼原虫和克氏锥虫试验。四种化合物显示出有希望的抗利什曼原虫活性（从1.27到19.53 μM），其中两种类似物与目前一些一线治疗药物（如stibogluconate钠和paromomycin）相比表现出更强的效力。计算分析显示，活性是由特定的电子性质而不是空间因素驱动的，而甲基一直降低效力。这些化合物显示出良好的预测ADME特性，并且没有标记为聚合体。本研究确定了肉桂酰芳基腙是一种很有前途的利什曼尼药物发现支架，为未来的优化工作提供了合理的基础。

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引用次数: 0

Design and synthesis of Tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives as antiproliferative agents for prostate Cancer cells 四氢茚二酮[4,5-c] 4(3H)- 1衍生物抗前列腺癌细胞增殖的设计与合成。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-24 DOI: 10.1016/j.bmcl.2025.130515

Hui-Yu Chan , Pin-Shuo Huang , Pei-Fang Chiu , Tzung-Sheng Lin , Li-Jou Huang , Pi-Hui Liang , Jih-Hwa Guh , Mei-Hsiang Lin

Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives with pyridine congeners at C-1 position. Notably, 13c and 14c exhibited the GI₅₀ of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that 14c shares a similar binding mode with abiraterone at the CYP17A1 active site.

阿比特龙是一种CYP17A1抑制剂，已被FDA批准用于去势抵抗性前列腺癌。为了模拟阿比特龙的结构，我们设计并合成了9个在C-1位置具有吡啶同族物的四氢茚[4,5-c]铬-4(3H)- 1衍生物。值得注意的是，13c和14c对PC-3细胞的GI50为10 nM，而阿比特龙对PC-3细胞的GI50为21.4 μM。对接研究进一步发现，14c在CYP17A1活性位点与阿比特龙具有相似的结合模式。

引用次数: 0

Alternariol from the endophytic fungus Alternaria sp. S4 acts as a membrane-targeting bactericidal agent against Staphylococcus aureus 来自内生真菌Alternaria sp. S4的Alternariol是一种针对金黄色葡萄球菌的膜靶向杀菌剂。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-12-23 DOI: 10.1016/j.bmcl.2025.130513

Yanlin He , Yuwan Zhang , Wei Wang , Chaoyong Cui , Qianyun Hao , Hongguan Xie , Rui Yang

The endophytic fungus Alternaria sp. S4, derived from Ruta graveolens, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation, alternariol (1) and alternariol-5-O-methyl ether (2) were isolated from the ethyl acetate fraction of Alternaria sp. S4 and characterized spectroscopically. Compound 1 exhibited potent bactericidal activity against Staphylococcus aureus (MIC = 4 μg/mL, MBC = 16 μg/mL), whereas compound 2 was inactive. Time-growth assays confirmed concentration-dependent bacterial eradication, with 2× MIC of compound 1 achieving complete growth inhibition. Mechanistic investigations revealed that compound 1 targets the bacterial membrane, inducing depolarization, compromising permeability (evidenced by ion leakage and release of intracellular constituents), and causing ultrastructural damage visualized via SEM. Furthermore, compound 1 prevented biofilm formation via bacterial eradication and disrupted preformed biofilms. Checkerboard assays indicated additive effects when combined with conventional antibiotics. Notably, compound 1 displayed no hemolytic activity even at 1024 μg/mL, highlighting its membrane selectivity. This work identifies alternariol as a promising membrane-targeting bactericidal agent from an endophytic source, capable of preventing biofilm establishment, with potential for combinatorial therapy against S. aureus.

从芦笋中提取的内生真菌Alternaria sp. S4显示出显著的抗菌潜力，但其有效成分和作用方式尚不清楚。采用生物测定引导分离的方法，从Alternaria sp. S4的乙酸乙酯部位分离得到交替蒿醇(1)和交替蒿醇-5- o -甲基醚(2)，并对其进行了光谱表征。化合物1对金黄色葡萄球菌具有较强的杀菌活性（MIC = 4 μg/mL, MBC = 16 μg/mL），而化合物2对金黄色葡萄球菌无活性。时间生长试验证实了浓度依赖的细菌根除，化合物1的2倍MIC达到完全生长抑制。机制研究表明，化合物1靶向细菌膜，诱导去极化，损害渗透性（通过离子泄漏和细胞内成分释放证明），并通过扫描电镜观察造成超微结构损伤。此外，化合物1通过细菌根除阻止生物膜的形成，并破坏预先形成的生物膜。棋盘试验表明，当与常规抗生素联合使用时，会产生叠加效应。值得注意的是，化合物1即使在1024 μg/mL浓度下也没有溶血活性，表明其具有膜选择性。这项工作确定了交替蒿醇是一种有前途的内生膜靶向杀菌剂，能够阻止生物膜的形成，具有联合治疗金黄色葡萄球菌的潜力。

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引用次数: 0