Bioorganic & Medicinal Chemistry Letters最新文献_第4页

Synthesis and biological activity evaluation of aromatic bisselenocyanate compounds 芳香族双硒氰酸酯化合物的合成及生物活性评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-02 DOI: 10.1016/j.bmcl.2025.130533

Chunrui Cai , Wenhao Tian , Meizhen Wei, Taichen Yang, Qiang Hu, Yanmin Huang, Zhiping Liu, Jianguo Cui

Motivated by the significant physiological activities of selenocyanate pharmacophores in biomedicine and the relative scarcity of research on diselenocyanates, this study designed and synthesized a series of novel aromatic diselenocyanate derivatives (including aniline-type 3a-3f, phenol-type 6a-6f, and biphenyl-type 8) using aniline and phenol as parent structures through aromatic ring electrophilic substitution and amide bond/ether bond bridging strategies, and systematically evaluated their biological activities. The results demonstrated that multiple compounds exhibited significant inhibitory activity against specific cancer cell lines. Among them, compound 3f showed an IC₅₀ value of 2.93 μmol/L against breast cancer MCF-7 cells, while compound 6c displayed superior IC₅₀ values compared to Cisplatin against SK-OV-3, HepG-2, and MCF-7 cells. The compounds also demonstrated excellent activity against drug-resistant bacteria MRSA/VRE (3f exhibited an MIC of 2 μg mL⁻¹ against MRSA, outperforming Vancomycin) and agricultural crop pathogens (citrus canker, rice bacterial leaf streak/leaf blight pathogens). Notably, compound 8 achieved sub-microgram EC₅₀ values against these phytopathogens. Structure-activity relationship analysis revealed that aniline derivatives showed better activity against breast cancer, while phenol derivatives exhibited stronger inhibition against ovarian cancer and phytopathogens. Molecular-docking studies corroborate enhanced binding stability of optimized compounds to validated biological targets. Collectively, these findings provide both mechanistic insight and lead candidates for novel antineoplastic agents and low-toxicity agricultural antimicrobials.

基于硒酸盐药效团在生物医学中的重要生理活性和二烯氰酸酯研究的相对缺乏，本研究以苯胺和苯酚为亲本结构，通过芳香环亲电取代和酰胺键/醚键桥接策略，设计合成了一系列新型芳香二烯氰酸酯衍生物（包括苯胺型3a-3f、酚型6a-6f和联苯型8）。系统地评估它们的生物活性。结果表明，多种化合物对特定癌细胞具有显著的抑制活性。其中，化合物3f对乳腺癌MCF-7细胞的IC50值为2.93 μmol/L，而化合物6c对SK-OV-3、HepG-2和MCF-7细胞的IC50值优于顺铂。该化合物对耐药细菌MRSA/VRE （3f对MRSA的MIC为2 μg mL-1，优于万古霉素）和农作物病原体（柑橘溃疡病、水稻细菌性叶斑病/叶枯病病原体）也表现出良好的活性。值得注意的是，化合物8对这些植物病原体的EC50值达到亚微克。构效关系分析显示，苯胺类衍生物对乳腺癌的抑制作用较好，而苯酚类衍生物对卵巢癌和植物病原体的抑制作用较强。分子对接研究证实了优化后的化合物与已验证的生物靶点的结合稳定性增强。总的来说，这些发现为新型抗肿瘤药物和低毒农业抗菌剂提供了机制见解和主要候选药物。

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引用次数: 0

Design, synthesis and biological evaluation of macrocyclic NTRK heterobifunctional degraders 大环NTRK异双功能降解剂的设计、合成及生物学评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-01 DOI: 10.1016/j.bmcl.2025.130516

Corey Anderson, Jennifer Han-Chun Tsai, Oscar Ingham, Richard W. Deibler, Bridget Kreger, Prasoon Chaturvedi, Ka Ying Sharon Hung, Christopher G. Nasveschuk, James A. Henderson, Mathew E. Sowa

Aberrant NTRK gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecule NTRK inhibitors targeting the NTRK ATP site have shown success in the clinic resulting in two approved drugs. Unfortunately, resistance mutations have created the need for additional therapies. In this study, we detail the design, synthesis, and evaluation of novel NTRK BiDAC™ degraders containing a macrocyclic, mutant active, NTRK targeting ligand.

异常的NTRK基因融合导致组成性激活的NTRK蛋白是一系列成人和儿童肿瘤的关键驱动因素。靶向NTRK ATP位点的小分子NTRK抑制剂已经在临床中显示出成功，导致两种药物获得批准。不幸的是，耐药突变产生了对额外治疗的需求。在这项研究中，我们详细介绍了新型NTRK BiDAC™降解剂的设计、合成和评价，这些降解剂含有大环、突变活性、NTRK靶向配体。

引用次数: 0

Synthesis of theaflavin-3′-gallate oxidation products and their impact on α-amylase activity 茶黄素-3′-没食子酸酯氧化产物的合成及其对α-淀粉酶活性的影响。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-01 DOI: 10.1016/j.bmcl.2025.130532

Jiale An , Keyu Zhao , Yangping Ding

This study optimized the oxidation of theaflavin-3′-gallate (TF-3′-G), yielding two isolated products: theadibenzotropolone_(TF-3_′_-G+EC) and theanaphthoquinone-3-gallate (TNQ-3-G). All compounds exhibited significant α-amylase inhibitory activity, with potency descending in the order: theadibenzotropolone_(TF-3_′_-G+EC)>TNQ-3-G>TF-3′-G ≈ acarbose. IC₅₀ analysis revealed that TNQ-3-G and theadibenzotropolone_(TF-3_′_-G+EC) were over 2-fold and 5-fold more potent than acarbose, respectively. These findings provide a foundation for developing efficient and low-toxicity α-amylase inhibitors.

本研究优化了茶黄素-3′-没食子酸酯（TF-3′-G）的氧化过程，得到了两个分离产物：二苯并唑波酮（TF-3′-G+EC）和茶醌-3-没食子酸酯（TNQ-3-G）。所有化合物均表现出显著的α-淀粉酶抑制活性，效价顺序为：二苯并唑波酮（TF-3′-G+EC）>TNQ-3-G>TF-3′-G ≈ 阿卡波糖。IC50分析显示，TNQ-3-G和二苯并唑波酮（TF-3′-G+EC）的效力分别是阿卡波糖的2倍和5倍以上。这些发现为开发高效、低毒的α-淀粉酶抑制剂提供了基础。

引用次数: 0

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