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

Radiolabeled probes for tumor hypoxia imaging. 放射性标记探针用于肿瘤缺氧成像。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-28 DOI: 10.1016/j.bmcl.2026.130565

Shuo Li, Taiwei Chu

The hypoxic microenvironment within tumors serves as a pivotal factor that propels malignant progression and fosters resistance to both radiotherapy and chemotherapy. Therefore, non-invasive hypoxia imaging using radionuclides is crucial for establishing personalized treatment plans. This review summarizes research progress on various radiolabeled hypoxia imaging probes. It focuses on bioreductive nitroimidazole derivatives, metal complexes, novel molecules targeting hypoxia-induced proteins (such as CA IX), and dual-targeting probes. The review elucidates the relationship between probe structural design and in vivo imaging performance. The development of probes has transitioned from an initial emphasis on high lipophilicity and uptake (e.g., [¹⁸F]FMISO) to a novel phase centered on hydrophilic modifications, including glycosylation and PEGylation. These modifications optimize pharmacokinetics and improve the signal-to-noise ratio. This review details the impact of various strategies on probe uptake in tumor and non-target tissues. These strategies encompass the nitroimidazole positional isomer effect, particularly highlighting the benefits of the 2-position, along with multivalent implementations. They also include the precise regulation of linker types and lengths, the selection of radionuclide chelators, and molecular charge adjustment. Furthermore, a comparative analysis elucidates the pivotal function of "fine-tuning the redox potential" in augmenting specificity. Modifying probes by incorporating electron-donating groups moderately decreases their reduction potential. This strategy effectively reduces non-specific background signals and achieves an optimal redox potential window. Finally, this review provides a concise summary of the existing challenges associated with hypoxia-targeting probes and puts forth innovative concepts for their future development. Ideal probe design should aim for the precise synergy of "appropriate pharmacokinetics", "optimal redox potential", and dual-targeting or multi-targeting strategies. These methodologies furnish a theoretical foundation and design concepts for the forthcoming generation of tumor hypoxia imaging agents.

肿瘤内的缺氧微环境是推动恶性进展和促进放疗和化疗耐药的关键因素。因此，使用放射性核素进行无创缺氧成像对于制定个性化治疗计划至关重要。本文综述了各种放射性标记缺氧成像探针的研究进展。它专注于生物还原硝基咪唑衍生物，金属配合物，靶向缺氧诱导蛋白的新分子（如CA IX）和双靶向探针。本文综述了探针结构设计与体内成像性能之间的关系。探针的发展已经从最初强调高亲脂性和摄取（例如[18F]FMISO）转变为以亲水修饰为中心的新阶段，包括糖基化和聚乙二醇化。这些改进优化了药代动力学，提高了信噪比。这篇综述详细介绍了各种策略对肿瘤和非靶组织中探针摄取的影响。这些策略包括硝基咪唑位置异构体效应，特别强调2位的好处，以及多价实施。它们还包括连接体类型和长度的精确调节，放射性核素螯合剂的选择和分子电荷调节。此外，一项比较分析阐明了“微调氧化还原电位”在增强特异性中的关键作用。通过加入给电子基团修饰探针适度地降低了它们的还原电位。该策略有效地减少了非特异性背景信号，实现了最佳氧化还原电位窗口。最后，本文简要总结了低氧靶向探针存在的问题，并对其未来的发展提出了创新的概念。理想的探针设计应以“适当的药代动力学”、“最佳氧化还原电位”和双靶向或多靶向策略的精确协同为目标。这些方法为下一代肿瘤缺氧显像剂提供了理论基础和设计概念。

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引用次数: 0

Discovery and antibacterial activity of kibdelomycin A-1 and A-2 from repeat batch fermentation of Kibdelosporangium banguiesne 基布洛霉素A-1和A-2的发现及其抑菌活性

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-27 DOI: 10.1016/j.bmcl.2026.130564

Jonah Fine , John B. Perkins , Vincent Gullo , Ryan D. Cohen , Jun Lu , Sheo B. Singh

Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by Kibdelosporangium banguiense CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for E. coli are comparable to kibdelomycin, whereas for S. aureus the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.

Kibdelomycin和Kibdelomycin A是由kibdelsporangium banguiense CA-240109生物合成的抗生素。基布霉素具有广谱活性，对耐药革兰氏阳性菌具有显著活性。这些化合物通过独特的u型多接触结合机制抑制DNA GyrB和ParE，并且不会与现有抗生素产生交叉抗性。为了研究结构-活性关系，采用了各种方法来识别新的同源物，包括重复分批发酵的实施。本研究介绍了通过重复分批发酵生产的基布霉素A的两个单去氯同源物的发现、分离、结构鉴定和抗菌评价。新发现的化合物对金黄色葡萄球菌和大肠杆菌的生长有抑制作用，最低抑制浓度（MIC）在16 ~ 64 μg/mL之间。大肠杆菌的MIC值与基伯德霉素相当，而金黄色葡萄球菌的MIC值比基伯德霉素低64倍。人工智能辅助的DNA回转酶B对接研究为同系物的不同活性提供了合理的支持。

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引用次数: 0

Combined antitumor efficacy of a new tanshinone IIA analog and irinotecan with alleviating gastrointestinal side effect 新型丹参酮IIA类似物与伊立替康联合抗肿瘤及减轻胃肠道副作用的疗效观察。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-27 DOI: 10.1016/j.bmcl.2026.130563

Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li

1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-b]furan-7,10,11(6H)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated in vitro. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both in vitro and in vivo. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed in vivo. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.

新合成的丹参酮IIA类似物1,6,6-三甲基-2-（（4-甲基哌嗪-1-酰基）甲基）phenanthrol[1,2-b]furan-7,10,11(6H)-trione （TA401）是为了增强CPT-11联合治疗的抗肿瘤作用，减轻其胃肠道副作用。综合评价TA401和CPT-11对HT29和HCT116结直肠癌细胞的体外联合细胞毒性。我们还检测了经典的凋亡通路，包括Bax、BCL-2、caspase 3、ERK和AKT的磷酸化水平，以阐明体外和体内协同凋亡的分子机制。在固定比例（TA401:CPT-11: 1:20）下，观察到TA401和CPT-11协同抑制结直肠癌细胞增殖。联合处理诱导的细胞凋亡是通过激活经典凋亡通路和降低TOP I的表达而触发的，这在体内得到了进一步的证实。此外，TA401在联合治疗中减少了CPT-11的腹泻副作用。TA401可有效促进CPT-11的抗肿瘤作用，且副作用减轻，可能成为与CPT-11联合治疗结直肠癌的潜在候选药物。

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引用次数: 0

Discovery of furo[2,3-b]isoquinoline derivatives as novel Pks13 inhibitors with reduced hERG inhibition 呋喃[2,3-b]异喹啉衍生物作为hERG抑制作用降低的新型Pks13抑制剂的发现

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-26 DOI: 10.1016/j.bmcl.2026.130561

Jiangfeng Tian , Renyu Zhang , Zhiyang Xing , Yuanyuan Liu , Weijie Lin , Xupeng Huang , Zihe Rao , Wei Peng , Yuying Fang

Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as TAM16 have demonstrated significant efficacy in vitro and in vivo, their development was discontinued due to concerns about hERG inhibition. Herein, we designed and synthesized a series of novel furo[2,3-b]isoquinoline derivatives using ring fusion and basicity-reduction strategies. Through SAR studies, compound B23 was identified as a potent Pks13 inhibitor (IC₅₀ = 1.12 μM) with significantly reduced hERG inhibition (IC₅₀ > 10 μM). The markedly improved hERG selectivity not only validates our structural strategy for mitigating cardiotoxicity risks, but also provides a solid foundation for further development of Pks13-TE inhibitors that combine potent anti-TB activity with an improved safety profile.

Pks13是一种有希望的结核病治疗靶点，为抗结核药物的开发提供了新的途径。尽管TAM16等苯并呋喃衍生物在体内和体外都显示出显著的疗效，但由于对hERG抑制的担忧，它们的开发已停止。在此，我们设计并合成了一系列新的呋喃[2,3-b]异喹啉衍生物，采用环融合和碱度降低策略。通过SAR研究，化合物B23被鉴定为有效的Pks13抑制剂（IC50 = 1.12 μM），显著降低了hERG抑制作用（IC50 > 10 μM）。显著提高的hERG选择性不仅验证了我们减轻心脏毒性风险的结构策略，而且为进一步开发结合有效抗结核活性和改进安全性的Pks13-TE抑制剂提供了坚实的基础。

引用次数: 0

Novel anticancer paeonol derivatives possessing a nitric oxide donor moiety as TrxR inhibitors: design, synthesis, biological evaluation 具有一氧化氮供体片段的新型抗癌丹皮酚衍生物作为TrxR抑制剂：设计、合成和生物学评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-23 DOI: 10.1016/j.bmcl.2026.130555

Ce Shi , Weisen Zhong , Guowei Qiang , Panjunjie Ying , Junyu Guo , Yameng Si , Jie Mou

The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC₅₀ = 0.26 ± 0.17 μM in vitro; IC₅₀ = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.

肿瘤微环境（tumor microenvironment， TME）在肿瘤进展和治疗反应中起关键作用。在TME中，由活性氧（ROS）和一氧化氮（NO）介导的氧化还原过程在调节细胞间和细胞内信号传导中起着关键作用。在这项研究中，我们假设将no释放片段偶联到丹皮酚衍生物上，并引入查尔酮结构来增强硫氧还蛋白还原酶（TrxR）的靶向性，将产生具有有效抗癌活性的化合物。据此，合成了一系列单取代和双取代的硝酸盐衍生物。采用CCK-8法测定合成的化合物对BGC823、HCT116、Hep G2和MCF-7细胞系的抑制活性。在丹皮酚查尔酮衍生物中，化合物11f在测试的癌细胞组中表现出显著的抗增殖活性。体外IC50 = 0.26 ± 0.17 μM，体内IC50 = 0.33 μM，具有较强的TrxR抑制活性。此外，化合物11f诱导MCF-7细胞s期阻滞并促进细胞凋亡。这些发现强调了由于NO和ROS的协同作用，丹皮酚查尔酮衍生物具有增强的抗癌潜力。

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引用次数: 0

Novel imidazolium salts bearing 2-oxindoles scaffold as potent acetylcholinesterase inhibitors for Alzheimer's disease: Design, synthesis, in vitro and in silico studies 新型含2-氧吲哚支架的咪唑盐作为阿尔茨海默病有效的乙酰胆碱酯酶抑制剂：设计、合成、体外和硅研究

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-22 DOI: 10.1016/j.bmcl.2026.130560

Le Quoc Tien , Hien Thi Thanh Phung , Huy-Hoang Do , Tiep N. Khac , Pham Thi Ngoc Minh , Vu Ngoc Hai Linh , Nguyen Quoc Thang , Shuai Wang , Phuong-Thao Tran

In this study, a series of thirty-five novel imidazolium salts bearing a 2-oxindoles were designed and synthesized as potent acetylcholinesterase (AChE) inhibitors for Alzheimer's disease. Structural diversity was introduced through substituent variation on both the oxindole and phenyl rings to investigate structure–activity relationships. All compounds were evaluated in vitro by the modified Ellman assay, revealing several highly potent inhibitors in the nanomolar to subnanomolar range. The most active compound, 32, exhibited an IC₅₀ of 0.17 nM, surpassing galantamine and donepezil. Enzyme kinetic study indicated that all compounds act as mixed-type AChE inhibitors. Machine learning–based binding affinity predictions (ΔG_ML = −10.30 to −8.18 kcal/mol) correlated well with experimental activity. Molecular docking against AChE (PDB ID: 4EY6 and 7E3H) revealed that compounds bearing electron-withdrawing substituents exhibited superior binding scores and favorable interactions with key catalytic residues and aromatic residues. Molecular dynamics (200 ns) simulations demonstrated that compound 32 maintained a highly stable conformation within the AChE active site, with consistent hydrogen bonding and low root-mean-square deviation (RMSD) fluctuations. In addition, MM-PBSA binding free energy analysis (ΔG_total = −33.42 kcal/mol) further confirmed its strong and stable interactions compared with galantamine (−17.82 kcal/mol) and donepezil (−21.20 kcal/mol). Furthermore, in silico ADME predictions suggested favorable oral absorption and potential blood-brain barrier permeability for compound 32, while maintaining an acceptable safety profile compared to galantamine and donepezil. These promising findings highlight the potential of oxindole–imidazolium hybrids as effective AChE inhibitors and warrant further investigation for the development of novel anti-Alzheimer agents.

在本研究中，设计并合成了35种新型含2-吲哚咪唑盐，作为阿尔茨海默病的有效乙酰胆碱酯酶（AChE）抑制剂。通过氧吲哚环和苯基环上取代基的变化引入结构多样性，研究其构效关系。所有化合物都通过改进的Ellman法进行体外评估，揭示了几种在纳摩尔到亚纳摩尔范围内的高效抑制剂。活性最高的化合物32的IC50值为0.17 nM，超过了加兰他明和多奈哌齐。酶动力学研究表明，所有化合物均为混合型AChE抑制剂。基于机器学习的结合亲和预测（ΔGML = -10.30至-8.18 kcal/mol）与实验活动相关性良好。与AChE （PDB ID: 4EY6和7E3H）的分子对接表明，含有吸电子取代基的化合物与关键催化残基和芳香族残基的结合分数较高，相互作用良好。分子动力学（200 ns）模拟表明，化合物32在AChE活性位点内保持高度稳定的构象，具有一致的氢键和较低的均方根偏差（RMSD）波动。此外，MM-PBSA结合自由能分析（ΔGtotal = -33.42 kcal/mol）进一步证实了其与加兰他明（-17.82 kcal/mol）和多奈培齐（-21.20 kcal/mol）的强稳定相互作用。此外，计算机ADME预测表明，化合物32具有良好的口服吸收和潜在的血脑屏障通透性，同时与加兰他明和多奈哌齐相比，保持可接受的安全性。这些有希望的发现突出了吲哚-咪唑混合物作为有效乙酰胆碱酯酶抑制剂的潜力，并为开发新型抗阿尔茨海默病药物提供了进一步的研究。

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引用次数: 0

Organometallic gold(III) (C^S)-cyclometallated complexes as candidates to new drugs against chagas disease 有机金属金（III） (C^S)-环金属化配合物作为治疗恰加斯病新药的候选物

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-21 DOI: 10.1016/j.bmcl.2026.130559

Paula Pérez-Ramos , Rogelio Gomez-Escobedo , Benjamín Nogueda-Torres , Adriana Moreno-Rodriguez , Alejandro Llamedo , Humberto Rodríguez-Solla , Sara M. Soto , Gildardo Rivera , Raquel G. Soengas

Chagas disease or American trypanosomiasis remains a serious public health concern with unsatisfactory treatment outcomes. The serious problems with the efficacy and toxicity of the drugs currently used to treat Chagas disease, along with the emergence of resistant strains, have made the development of new chemotherapy strategies a priority. In this work, fourteen (C^S)-cyclometallated gold(III) complexes were evaluated as potential trypanocidal agents. All the tested compounds had better trypanocidal activity against trypomastigotes than the reference drugs, with five complexes presenting an SI above ten for both strains, and two complexes displaying a SI value >200 for the NINOA strain. Among them, complex 6b was identified as a highly selective agent against T. cruzi amastigotes of the NINOA strain. Furthermore, cytotoxicity to mouse macrophage cells is very low for this compound, resulting in a better selectivity index than that of reference drugs Bnz and Nfx. These results suggest the potential of (C^S)-cyclometallated gold (III) complexes as promising antiparasitic drug candidates.

恰加斯病或美洲锥虫病仍然是一个严重的公共卫生问题，治疗结果不令人满意。目前用于治疗恰加斯病的药物在疗效和毒性方面存在严重问题，加上耐药菌株的出现，使得开发新的化疗战略成为优先事项。在这项工作中，14个(C^S)-环金属化金（III）配合物被评价为潜在的锥虫剂。所有被测化合物对锥虫的杀虫活性均优于对照药物，其中5个配合物对两种菌株的SI值均大于10,2个配合物对NINOA菌株的SI值为200。其中，配合物6b被鉴定为对NINOA菌株克氏单轴绦虫具有高选择性的拮抗作用。此外，该化合物对小鼠巨噬细胞的细胞毒性很低，因此选择性指数优于对照药物Bnz和Nfx。这些结果表明(C^S)-环金属化金（III）配合物有潜力成为抗寄生虫药物的候选物。

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引用次数: 0

Anti-tumor effect of ardicrenin against MG63 osteosarcoma cells 苦杏仁素对MG63骨肉瘤细胞的抗肿瘤作用。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-21 DOI: 10.1016/j.bmcl.2026.130558

Qingsu Cheng

Cancer remains one of the leading causes of mortality worldwide. As a result, bioactive compounds derived from herbal medicines have gained increasing attention in cancer research. Ardicrenin, extracted from Ardisia crenata, has been evaluated for its ability to suppress the growth of MG-63 cells. Remarkably, its inhibitory effect on MG-63 cell proliferation is comparable to that of Taxol. Unlike Taxol, which induces apoptosis by stabilizing microtubules, ardicrenin regulates cell proliferation and death through the integrin signaling pathway. These findings highlight ardicrenin as a promising candidate for anti-tumor drug development.

癌症仍然是全世界死亡的主要原因之一。因此，从草药中提取的生物活性化合物在癌症研究中受到越来越多的关注。Ardisia crenata中提取的Ardisia crenata苷已被评估其抑制MG-63细胞生长的能力。其对MG-63细胞增殖的抑制作用与紫杉醇相当。与通过稳定微管诱导细胞凋亡的紫杉醇不同，ardicrenin通过整合素信号通路调节细胞增殖和死亡。这些发现强调了苦苷素作为抗肿瘤药物开发的一个有前途的候选药物。

引用次数: 0

Design, synthesis and preliminary evaluation of mosquitoicidal activity of arecoline derivatives targeting muscarinic acetylcholine receptors 针对毒蕈碱乙酰胆碱受体的槟榔碱衍生物的设计、合成及杀蚊活性初步评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-20 DOI: 10.1016/j.bmcl.2026.130548

Hongyue Bu , Qi-Long Wu , Cun-Chen Wang , Qiaolu Guo , Shengqun Deng , Yiji Li , Shuojin Wang

To develop novel mosquito control agents, we designed and synthesized a series of derivatives based on the natural alkaloid arecoline as a lead compound, targeting muscarinic acetylcholine receptors (mAChRs). Using computer-aided drug design and docking techniques focused on mAChRs, we designed piperidine derivatives and screened for synthetically accessible candidates. The compounds were synthesized, structurally characterized, and evaluated for activity via a Fluo-4 calcium fluorescence assay using Chinese Hamster Ovary-K1 (CHO-K1) cells expressing the muscarinic acetylcholine receptor M1. Most compounds showed potent mAChRs agonist activity, with Half Maximal Effective Concentration (EC₅₀) values below 10 μM. In subsequent insecticidal activity tests, these piperidine derivatives exhibited strong larvicidal effects against Aedes aegypti. The Median Lethal Concentration (LC₅₀) values for compounds 1a, 2a, 3a, 4a, 13a, 22a, 2b, and 9b were 58.4, 29.6, 11.4, 21.7, 42.0, 61.7, 125.9, and 81.6 mg/L, respectively. Notably, compound 13a maintained high insecticidal activity even against pyrethroid-resistant mosquitoes, indicating a mode of action different from conventional neurotoxic insecticides. These results demonstrate that mAChR-targeting derivatives derived from betel alkaloids represent a promising strategy for developing new mosquito control agents and offer a novel approach to combating insecticide resistance.

为了开发新型灭蚊剂，我们以天然生物碱槟油碱为先导化合物，设计并合成了一系列以毒蕈碱类乙酰胆碱受体（mAChRs）为靶点的衍生物。利用计算机辅助药物设计和以machr为重点的对接技术，我们设计了哌啶衍生物并筛选了可合成的候选药物。合成了这些化合物，对其进行了结构表征，并利用表达毒毒碱乙酰胆碱受体M1的中国仓鼠卵巢- k1 （CHO-K1）细胞进行了Fluo-4钙荧光测定。大多数化合物显示出有效的machr激动剂活性，一半最大有效浓度（EC₅0）值低于10 μM。在随后的杀虫活性试验中，这些哌啶衍生物对埃及伊蚊表现出较强的杀幼虫作用。化合物1a、2a、3a、4a、13a、22a、2b和9b的中位致死浓度（LC₅₀）值分别为58.4、29.6、11.4、21.7、42.0、61.7、125.9和81.6 mg/L。值得注意的是，化合物13a即使对拟除虫菊酯抗性蚊子也保持了很高的杀虫活性，表明其作用模式不同于传统的神经毒性杀虫剂。这些结果表明，从槟榔生物碱中提取的以machr为靶点的衍生物为开发新的蚊虫控制剂提供了一种有前景的策略，并为对抗杀虫剂抗性提供了一种新的途径。

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引用次数: 0

Nitric oxide and α-glucosidase inhibitors from Ludwigia adscendens: An integrated in vitro and in silico study 来自路德维希菌的一氧化氮和α-葡萄糖苷酶抑制剂：一项体外和计算机综合研究。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-01-20 DOI: 10.1016/j.bmcl.2026.130556

Thi Bich Hanh Dam , Truong Nhan Ngu , Phu Chi Hieu Truong , Hong Khuyen Thi Pham , Thi Thu Le Vu , Tien Lam Do , Hai Nam Vu , Phuong Dai Nguyen Nguyen , Thi Thuy Loan Le , Thi Thuy Do , Phi Hung Nguyen , Minh Quan Pham , Le Minh Hoang , Tien Khi Nguyen , Dao Cuong To

Ludwigia adscendens (Onagraceae) has been traditionally used for the treatment of inflammatory and metabolic disorders; however, the bioactive constituents responsible for these effects remain insufficiently characterized. In this study, twelve secondary metabolites (1−12), including triterpenoids, flavonoids, and phenolic acids, were isolated from L. adscendens and evaluated for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and α-glucosidase activity in vitro. Among the tested compounds, sulfuretin (8) exhibited the most potent NO inhibitory activity (IC₅₀ = 12.3 ± 0.56 μM), while uvaol (3) and ursolic aldehyde (4) showed strong α-glucosidase inhibition (IC₅₀ = 5.6 ± 0.7 and 4.2 ± 0.3 μM, respectively), surpassing acarbose. Molecular docking studies against inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and oligo-1,6-glucosidase supported the experimental findings, revealing favorable binding affinities and key interactions consistent with the observed structure–activity relationships. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis predicted acceptable drug-likeness and low acute toxicity for the active compounds. Collectively, these results identify sulfuretin as a promising dual anti-inflammatory and antidiabetic scaffold, while triterpenoid derivatives emerge as potent and selective α-glucosidase inhibitors, providing a rational basis for further medicinal chemistry optimization.

金缕参（onagracae）传统上用于治疗炎症和代谢紊乱；然而，造成这些影响的生物活性成分仍然没有得到充分的表征。本研究从L. adscendens中分离了12种次生代谢产物（1-12），包括三萜、黄酮类和酚酸，并在体外研究了它们对脂多糖（LPS）刺激的RAW264.7巨噬细胞一氧化氮（NO）产生和α-葡萄糖苷酶活性的抑制作用。在测试化合物,sulfuretin(8)表现出最有效的没有抑制活性(IC50 = 12.3 ±0.56  μM),而uvaol索醛含量(3)和(4)显示了强劲的α葡糖苷酶抑制(IC50 = 5.6 ±  0.7和4.2±0.3  μM,分别),超过了阿卡波糖。对诱导型一氧化氮合酶（iNOS）、环氧合酶-2 （COX-2）、白细胞介素-8 （IL-8）和寡聚-1,6-葡萄糖苷酶的分子对接研究支持了实验结果，揭示了良好的结合亲和力和与观察到的结构-活性关系一致的关键相互作用。计算机ADMET（吸收、分布、代谢、排泄和毒性）分析预测活性化合物具有可接受的药物相似性和低急性毒性。综上所述，这些结果确定了硫维素是一种有前景的抗炎和降糖双重支架，而三萜衍生物则是一种有效的选择性α-葡萄糖苷酶抑制剂，为进一步的药物化学优化提供了合理的基础。

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引用次数: 0