Bioorganic & Medicinal Chemistry Letters最新文献

英文中文

Pyridine and Pyrimidine hybrids as privileged scaffolds in antimalarial drug discovery: A recent development 吡啶和嘧啶杂化物作为抗疟药物发现的特殊支架：最新进展。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129992

Lekkala Ravindar , Siti Aishah Hasbullah , K.P. Rakesh , Saki Raheem , Norzila Ismail , Lau Yee Ling , Nurul Izzaty Hassan

Malaria continues to pose a significant threat to global health, which is exacerbated by the emergence of drug-resistant strains, necessitating the urgent development of new therapeutic options. Due to their substantial bioactivity in treating malaria, pyridine and pyrimidine have become the focal point of drug research. Hybrids of pyridine and pyrimidine offer a novel and promising avenue for developing effective antimalarial agents. The ability of these hybrids to overcome drug resistance is tinted, offering a potential solution to this critical obstacle in the treatment of malaria. By targeting multiple pathways, these hybrid compounds reduce the likelihood of resistance development, providing a promising strategy for combating drug-resistant strains of malaria. The review focuses on the most recent developments in 2018 in the structural optimization of pyridine and pyrimidine hybrid compounds, highlighting modifications that have been shown to improve antimalarial activity. Structure-activity studies have elucidated the essential characteristics required for potency, selectivity, and pharmacokinetics. Molecular docking and virtual screening expedite the identification of novel compounds with enhanced activity profiles. This analysis could aid in developing the most effective pyridine and pyrimidine hybrids as antimalarial agents.

疟疾继续对全球健康构成重大威胁，而抗药性菌株的出现又加剧了这一威胁，因此迫切需要开发新的治疗方案。由于吡啶和嘧啶在治疗疟疾方面的巨大生物活性，它们已成为药物研究的焦点。吡啶和嘧啶的混合物为开发有效的抗疟药物提供了一个新颖而有前景的途径。这些杂交化合物具有克服耐药性的能力，为治疗疟疾的这一关键障碍提供了潜在的解决方案。通过靶向多种途径，这些杂交化合物降低了抗药性产生的可能性，为抗击耐药性疟疾菌株提供了一种前景广阔的策略。这篇综述重点介绍了 2018 年吡啶和嘧啶杂化化合物结构优化方面的最新进展，着重介绍了已被证明能提高抗疟活性的修饰。结构-活性研究阐明了药效、选择性和药代动力学所需的基本特征。分子对接和虚拟筛选加速了具有更强活性特征的新型化合物的鉴定。这种分析有助于开发出最有效的吡啶和嘧啶混合物作为抗疟药物。

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引用次数: 0

Biological evaluation of signal transducer and activator of transcription 3 (STAT3) targeting by phaeosphaeride A and its analogs 对 phaeosphaeride A 及其类似物靶向信号转导子和转录激活子 3 (STAT3) 的生物学评价。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.130004

Yuichiro Hirayama, Masahiro Matsunaga, Ayaka Fukao, Kenichi Kobayashi

The inhibitory activities of phaeosphaeride A (PPA), phaeosphaeride B, and four synthetic derivatives against phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cell proliferation in cervical (HeLa) and breast (MDA-MB-231) cancer cells were evaluated. PPA inhibited IL-6-induced STAT3 phosphorylation and cell proliferation at similar concentrations. The structure–activity relationship studies revealed that the enantiomer of PPA was the most potent of the evaluated phaeosphaerides in both inhibiting STAT3 phosphorylation and cell growth. PPA clearly inhibited the IL-6-activated STAT3 signaling pathway. However, the presence or absence of activation of the STAT3 signaling pathway in cells showed no relationship to the antiproliferative activity. Notably, the possible covalent bond-forming ability of PPA was critical for its biological activities.

评估了 phaeosphaeride A（PPA）、phaeosphaeride B 和四种合成衍生物对宫颈癌细胞（HeLa）和乳腺癌细胞（MDA-MB-231）中信号转导和转录激活因子 3（STAT3）磷酸化和细胞增殖的抑制活性。在相似浓度下，PPA 可抑制 IL-6 诱导的 STAT3 磷酸化和细胞增殖。结构-活性关系研究表明，PPA 的对映体在抑制 STAT3 磷酸化和细胞生长方面是所评估的 phaeosphaerides 中最有效的。PPA 能明显抑制 IL-6 激活的 STAT3 信号通路。不过，细胞中 STAT3 信号通路的激活与否与抗增殖活性没有关系。值得注意的是，PPA 可能具有的共价键形成能力对其生物活性至关重要。

引用次数: 0

Evaluating delivery of peptide nucleic acids to Gram-negative bacteria using differently linked membrane-active peptides and their stapled analogs 评估使用不同连接的膜活性肽及其订书钉类似物向革兰氏阴性菌输送肽核酸的情况。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129993

Izabela Siekierska, Michał Burmistrz, Joanna Trylska

Antisense oligonucleotides have been developed as therapeutic compounds, with peptide nucleic acid (PNA) emerging as a promising nucleic acid mimic for antimicrobial applications. To be effective, PNAs must be internalized into bacterial cells, as they are not naturally absorbed. A strategy to improve PNA membrane penetration and cellular uptake involves covalently conjugating them to cell-penetrating peptides. However, these membrane-active peptides can exhibit cytotoxicity, and their efficiency as PNA carriers needs to be enhanced. Therefore, we explored new peptide–PNA conjugates and their linkers to understand how they affect PNA uptake into bacteria. We conjugated PNA to two peptides, anoplin and (KFF)₃K, along with their structurally stabilized hydrocarbon-stapled derivatives, and evaluated their transport into various bacterial strains. The PNA sequence targeted bacterial mRNA encoding the essential acyl carrier protein. As linkages, we used either a non-cleavable 8-amino-2,6-dioxaoctanoyl (ethylene glycol, eg1) linker or a reducible disulfide bridge. We found that the hydrocarbon-stapled peptides did not enhance PNA delivery, despite the strong inner- and outer-membrane-penetrating capabilities of the standalone peptides. Additionally, the disulfide bridge linkage, which is cleavable in the bacterial cytoplasm, decreased the antimicrobial activity of the peptide–PNA conjugates. Notably, we identified anoplin as a new potent PNA carrier peptide, with the anoplin–eg1–PNA conjugate demonstrating antibacterial activity against E. coli and S. Typhimurium strains in the 2–4 µM range.

反义寡核苷酸已被开发为治疗化合物，而肽核酸（PNA）则是一种很有前途的抗菌核酸模拟物。由于肽核酸不会被自然吸收，因此必须内化到细菌细胞中才能有效。改善 PNA 膜穿透性和细胞吸收的一种策略是将其与细胞穿透肽共价共轭。然而，这些膜活性肽会表现出细胞毒性，因此需要提高它们作为 PNA 载体的效率。因此，我们探索了新的多肽-PNA 共轭物及其连接体，以了解它们如何影响细菌对 PNA 的吸收。我们将 PNA 与两种肽（anoplin 和 (KFF)3K）及其结构稳定的碳氢化合物叠层衍生物共轭，并评估了它们在不同细菌菌株中的转运情况。PNA 序列以编码必需酰基载体蛋白的细菌 mRNA 为目标。作为连接，我们使用了不可裂解的 8-氨基-2,6-二氧杂辛酰（乙二醇，eg1）连接体或可还原的二硫桥。我们发现，尽管独立肽具有很强的内膜和外膜穿透能力，但碳氢化合物叠层肽并不能增强 PNA 的输送。此外，二硫桥连接（可在细菌细胞质中裂解）降低了肽-PNA 共轭物的抗菌活性。值得注意的是，我们发现anoplin是一种新的强效PNA载体肽，anoplin-eg1-PNA共轭物对大肠杆菌和鼠伤寒杆菌的抗菌活性在2-4 µM范围内。

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引用次数: 0

Synthesis of K+ channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice K+ 通道放射性配体[18F]5-甲基-3-氟-4-氨基吡啶的合成和小鼠 PET 成像。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129991

Yang Sun, Karla M. Ramos-Torres, Kazue Takahashi, Amal Tiss, Lauren L. Zhang, Pedro Brugarolas

[¹⁸F]3-fluoro-4-aminopyridine ([¹⁸F]3F4AP) is the first positron emission tomography (PET) radioligand that targets voltage-gated potassium (K⁺) channels in the brain for imaging demyelination. [¹⁸F]3F4AP exhibits high brain penetration, favorable kinetics for PET imaging, and high sensitivity to demyelinating lesions. However, recent studies in awake human subjects indicate lower metabolic stability than in anesthetized animals, resulting in reduced brain uptake. Therefore, there is a need for novel radioligands for K⁺ channels with suitable pharmacological properties and enhanced metabolic stability. Recent in vitro studies demonstrate that 5-methyl-3-fluoro-4-aminopyridine (5Me3F4AP) exhibits comparable binding affinity to K⁺ channels, pK_a, logD, and membrane permeability as 3F4AP, and a slower enzymatic metabolic rate, suggesting its potential as a K⁺ channel PET tracer. In this study, we describe the radiochemical synthesis of [¹⁸F]5Me3F4AP using an isotope exchange method from the corresponding 3-fluoro-5-methyl-4-nitropyridine N-oxide, followed by a palladium on carbon mediated hydrogenation of the nitro and N-oxide groups. This method yielded [¹⁸F]5Me3F4AP with high purity and acceptable molar activity. PET/CT studies using naïve mice demonstrate that [¹⁸F]5Me3F4AP effectively crosses the blood–brain barrier and has comparable kinetics to [¹⁸F]3F4AP. These findings strongly suggest that [¹⁸F]5Me3F4AP is a promising candidate for neuroimaging applications and warrant further studies to investigate its sensitivity to lesions and in vivo metabolic stability.

[18F]3-氟-4-氨基吡啶（[18F]3F4AP）是第一种针对脑电压门控钾（K+）通道的正电子发射断层成像（PET）放射性配体，可用于脱髓鞘成像。[18F]3F4AP具有较高的脑穿透性，在 PET 成像中具有良好的动力学特性，对脱髓鞘病变具有较高的灵敏度。然而，最近在清醒人体中进行的研究表明，其代谢稳定性低于麻醉动物，导致脑摄取量降低。因此，需要具有合适药理特性和更高代谢稳定性的新型 K+ 通道放射性配体。最近的体外研究表明，5-甲基-3-氟-4-氨基吡啶（5Me3F4AP）与 K+ 通道的结合亲和力、pKa、logD 和膜通透性与 3F4AP 相当，而且酶代谢速率较慢，这表明它具有作为 K+ 通道 PET 示踪剂的潜力。在本研究中，我们介绍了用同位素交换法从相应的 3-氟-5-甲基-4-硝基吡啶 N-氧化物中合成 [18F]5Me3F4AP 的放射化学方法，然后用碳化钯介导硝基和 N-氧化基团的氢化反应。这种方法得到的 [18F]5Me3F4AP 具有高纯度和可接受的摩尔活性。利用天真小鼠进行的 PET/CT 研究表明，[18F]5Me3F4AP 能有效穿过血脑屏障，其动力学性能与 [18F]3F4AP 相当。这些研究结果有力地表明，[18F]5Me3F4AP 是一种很有希望应用于神经成像的候选物质，值得进一步研究其对病变的敏感性和体内代谢稳定性。

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引用次数: 0

Synchrotron Radiation: A Key Tool for Drug Discovery 同步辐射：药物发现的关键工具。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-13 DOI: 10.1016/j.bmcl.2024.129990

Fengcheng Li , Runze Liu , Wenjun Li , Mingyuan Xie , Song Qin

Synchrotron radiation is extensively utilized in the domains of materials science, physical chemistry, and life science, resulting from its high intensity, exceptional monochromaticity, superior collimation, and broad wave spectrum. This top-notch light source has also made significant contributions to the progress of biomedicine. The advancement of synchrotron radiation-based X-ray and protein crystallography technologies has created new prospects for drug discovery. These innovative techniques have opened up exciting avenues in the field. The investigation of protein crystal structures and the elucidation of the spatial configuration of biological macromolecules have revealed intricate details regarding the modes of protein binding. Furthermore, the screening of crystal polymorphs and ligands has laid the groundwork for rational drug modification and the improvement of drug physicochemical properties. As science and technology continue to advance, the techniques for analyzing structures using synchrotron radiation sources and the design of corresponding crystallographic beamline stations are undergoing continuous enhancement. These cutting-edge tools and facilities are expected to expedite the drug development process and rectify the current situation of a lack of targeted drugs.

同步辐射因其高强度、优异的单色性、卓越的准直性和宽广的波谱而被广泛应用于材料科学、物理化学和生命科学领域。这种顶级光源还为生物医学的进步做出了重大贡献。基于同步辐射的 X 射线和蛋白质晶体学技术的发展为药物发现开辟了新的前景。这些创新技术为该领域开辟了令人兴奋的道路。蛋白质晶体结构的研究和生物大分子空间构型的阐明揭示了蛋白质结合模式的复杂细节。此外，晶体多态性和配体的筛选也为药物的合理修饰和药物理化性质的改善奠定了基础。随着科学技术的不断进步，利用同步辐射源分析结构的技术和相应的晶体学光束线站的设计也在不断改进。这些前沿工具和设施有望加快药物开发进程，改善目前缺乏靶向药物的状况。

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引用次数: 0

Discovery of sulfone containing metallo-β-lactamase inhibitors with reduced bacterial cell efflux and histamine release issues 发现含砜金属-β-内酰胺酶抑制剂，可减少细菌细胞外流和组胺释放问题。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-11 DOI: 10.1016/j.bmcl.2024.129989

Frank Bennett , Yuhua Huang , Shuzhi Dong , Jinlong Jiang , David Hunter , Zhiqiang Zhao , Xin Gu , Jack D. Scott , Haiqun Tang , Dexi Yang , Li Xiao , Giovanna Scapin , Thierry Fischmann , Asra Mirza , Priya Dayananth , Ronald E. Painter , Artjohn Villafania , Charles G. Garlisi , Rumin Zhang , Todd W. Mayhood , Alexander Pasternak

The design, syntheses and antibacterial evaluation of sulfone analogues of previously disclosed metallo-β-lactamase inhibitors (MBLis) are described. The novel derivatives were overall more effective in gram-negative bacterial cell-based assays when combined with imipenem and relebactam. The major contributors to the improved anti-bacterial activity are enhanced enzyme-inhibitor interactions and reduced bacterial cell efflux monitored via an efflux assay involving isogenic Pseudomonas aeruginosa efflux + and efflux – tool strains.

本文介绍了先前公开的金属-β-内酰胺酶抑制剂（MBLis）的砜类似物的设计、合成和抗菌评估。新型衍生物与亚胺培南和雷巴坦联合使用时，在基于革兰氏阴性细菌细胞的试验中总体上更为有效。提高抗菌活性的主要原因是增强了酶抑制剂之间的相互作用，以及通过涉及 "外排+"和 "外排-"工具菌株的同源铜绿假单胞菌外排试验监测到的细菌细胞外排减少。

引用次数: 0

Diffusion of 1O2 along the PNA backbone diminishes the efficiency of photooxidation of PNA/DNA duplexes by biphenyl photosensitizer 1O2 沿 PNA 主干扩散会降低联苯光敏剂对 PNA/DNA 双链体的光氧化效率。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-11 DOI: 10.1016/j.bmcl.2024.129988

Yaoyao Du, Takashi Kanamori, Yuma Yaginuma, Nanai Yoshida, Shota Kaneko, Hideya Yuasa

Nitrobiphenyl photosensitizer (NBP)-peptide nucleic acids (PNA) conjugates were synthesized to develop a tool for photo-knockdown of target DNAs. The presence of NBP hardly hindered duplex formation with the complementary single strand DNA as demonstrated by the comparison of T_m values and CD spectra with those for standard PNA/DNA duplexes. However, the photooxidation of guanines in NBP-PNA/DNAs was significantly less effective than those of corresponding NBP-DNA/DNA. Production of singlet oxygen (¹O₂) during the photooxidation was confirmed by consumption of furfuryl alcohol, a ¹O₂ detector. The poor photooxidation efficiency was ameliorated with ¹O₂ generated from an externally added NBP derivative. It was found that, when complexed with the sticky end of a double strand DNA, NBP-PNA was able to photooxidize G in the DNA/DNA duplex region, whereas G in the PNA/DNA duplex region was considerably unreactive. These results suggest that ¹O₂ produced from NBP-PNA tends to quench during diffusion along the PNA/DNA backbone, whereas quenching is less likely during diffusion along DNA/DNA region.

我们合成了硝基联苯光敏剂（NBP）-肽核酸（PNA）共轭物，以开发一种光敲除目标 DNA 的工具。与标准 PNA/DNA 双链的 Tm 值和 CD 光谱相比，NBP 的存在几乎不妨碍与互补单链 DNA 形成双链。然而，NBP-PNA/DNA 中鸟嘌呤的光氧化作用明显不如相应的 NBP-DNA/DNA 的光氧化作用。光氧化过程中产生的单线态氧（1O2）通过消耗 1O2 检测器糠醇得到了证实。外部添加的 NBP 衍生物产生的 1O2 改善了光氧化效率低下的问题。研究发现，当 NBP-PNA 与双链 DNA 的粘性末端复合时，NBP-PNA 能够光氧化 DNA/DNA 双链区中的 G，而 PNA/DNA 双链区中的 G 则明显没有反应。这些结果表明，NBP-PNA 产生的 1O2 在沿 PNA/DNA 主干扩散时趋于淬灭，而在沿 DNA/DNA 区域扩散时则不太可能淬灭。

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引用次数: 0

Design, synthesis and biological evaluation of sulfonylurea derivatives as NLRP3 inflammasome inhibitors 作为 NLRP3 炎症小体抑制剂的磺酰脲衍生物的设计、合成和生物学评价。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129987

Haonan Feng , Donglai Li , Fuli Zhu , Caihong Jiang , Mengjun Su , Yichao Kong , Yonghao Zheng , Yaxia Yuan , Weiwei Huang , Xiabin Chen , Lei Ma

The NLRP3 inflammasome has been extensively studied in recent years and its aberrant activation can exacerbate inflammatory responses, contributing to various diseases. MCC950, a sulfonylurea drug, is a potent selective inhibitor of the NLRP3 inflammasome. However, its clinical development was halted due to hepatotoxicity, and studies have indicated significant reduction in activity among its metabolites. Building upon MCC950, we referenced substitution sites of NP3-146 for structural modifications aimed at addressing potential metabolism-related issues. Consequently, we synthesized a series of sulfonylurea derivatives. Ultimately, the optimized compound C4 exhibited a remarkable 80.39 % inhibition of IL-1β at 2 μM, with an IC₅₀ value of 0.805 μM. In conclusion, compound C4 shows potential as a lead compound and warrants further development as an anti-inflammatory NLRP3 inhibitor.

近年来，人们对 NLRP3 炎症小体进行了广泛研究，它的异常激活会加剧炎症反应，导致各种疾病。磺脲类药物 MCC950 是一种强效的 NLRP3 炎性体选择性抑制剂。然而，该药物的临床开发因肝毒性而停止，研究表明其代谢产物的活性显著降低。在 MCC950 的基础上，我们参考 NP3-146 的替代位点进行结构修饰，旨在解决潜在的代谢相关问题。因此，我们合成了一系列磺酰脲类衍生物。最终，优化后的化合物 C4 在 2 μM 的浓度下对 IL-1β 的抑制率高达 80.39%，IC50 值为 0.805 μM。总之，化合物 C4 显示出作为先导化合物的潜力，值得作为抗炎 NLRP3 抑制剂进一步开发。

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引用次数: 0

Design and optimization of novel Tetrahydro-β-carboline-based HDAC inhibitors with potent activities against tumor cell growth and metastasis 设计和优化新型四氢-β-咔啉基 HDAC 抑制剂，使其具有抑制肿瘤细胞生长和转移的强效活性

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129986

Shule Fan , Zeyi Wan , Yuhua Qu , Wenxia Lu, Xiangzhi Li, Feifei Yang, Hua Zhang

Histone deacetylases (HDACs) are validated drug targets for various therapeutic applications. A series of Tetrahydro-β-carboline-based hydroxamate derivatives, designed as HDAC inhibitors (HDACis), were synthesized. Compound 11g exhibited strong inhibitory activity against HDAC1 and the A549 cancer cell line. Additionally, this compound increased the levels of acetylated histone H3 and H4. Notably, 11g effectively arrested A549 cells in the G2/M phase and also increased ROS production and DNA damage, thereby inducing apoptosis. Further molecular docking experiments illustrated the potential interactions between compound 11g and HDAC1. These findings suggested that the novel Tetrahydro-β-carboline-based HDACis could serve as a promising framework for further optimization as anticancer agents.

组蛋白去乙酰化酶（HDACs）是各种治疗应用的有效药物靶点。研究人员合成了一系列四氢-β-咔啉基羟酰胺衍生物，并将其设计为 HDAC 抑制剂（HDACis）。化合物 11g 对 HDAC1 和 A549 癌细胞株具有很强的抑制活性。此外，该化合物还能提高乙酰化组蛋白 H3 和 H4 的水平。值得注意的是，11g 能有效地使 A549 细胞停滞在 G2/M 期，还能增加 ROS 生成和 DNA 损伤，从而诱导细胞凋亡。进一步的分子对接实验表明，化合物 11g 与 HDAC1 之间存在潜在的相互作用。这些研究结果表明，基于四氢-β-咔啉的新型 HDACis 可作为一种有前景的框架，进一步优化为抗癌药物。

引用次数: 0

Identification of 3-methyl-1-(3-methylpyridin-2-yl)-1H-pyrazol-5-ol as promising neuroprotective agent 鉴定 3-甲基-1-（3-甲基吡啶-2-基）-1H-吡唑-5-醇为有前途的神经保护剂。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2024-10-10 DOI: 10.1016/j.bmcl.2024.129983

Peng Zhu , Yulu Wu , Zhikang Du , Siyi Li , Jiaming Li , Xin Lu , Xueyang Jiang

Pyrazolol derivatives are gaining significant attention for their diverse pharmacological effects, such as analgesic, anti-inflammatory, antioxidant, and anticancer activities. In this study, 20 pyrazolol derivatives were designed and synthesized to develop an anti-ischemic stroke formulation with free radical scavenging activity. Most of these synthesized compounds demonstrated antioxidant capabilities in DPPH, ABTS radical scavenging, and ORAC_FL assays. The methyl-substituted compound Y12, in particular, showed exceptional antioxidant capacity. Additionally, these compounds showed excellent neurocytoprotective effects in the SH-SY5Y cell injury model subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Notably, Y12 exhibited significant metal chelating activity with Cu²⁺. In vivo studies confirmed that compound Y12 has neuroprotective effects and can significantly reduce the infarct area in a mouse model of focal cerebral ischemia induced by transient middle cerebral artery occlusion (tMCAO).

吡唑啉衍生物具有多种药理作用，如镇痛、抗炎、抗氧化和抗癌活性，因而备受关注。本研究设计并合成了 20 种吡唑啉衍生物，以开发具有清除自由基活性的抗缺血性中风制剂。这些合成的化合物大多在 DPPH、ABTS 自由基清除和 ORACFL 试验中表现出抗氧化能力。尤其是甲基取代化合物 Y12，显示出了卓越的抗氧化能力。此外，在氧-葡萄糖剥夺/复氧（OGD/R）的 SH-SY5Y 细胞损伤模型中，这些化合物显示出卓越的神经细胞保护作用。值得注意的是，Y12 与 Cu2+ 具有明显的金属螯合活性。体内研究证实，化合物 Y12 具有神经保护作用，在一过性大脑中动脉闭塞（tMCAO）诱导的小鼠局灶性脑缺血模型中，能显著缩小梗死面积。

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引用次数: 0

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