European Journal of Medicinal Chemistry Reports最新文献_第9页

Preparation and pharmacological characterization of the enantiomers of the anticancer agent R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea: Identification of the R-enantiomer as the active eutomer 抗癌剂R/ s - n- 3-氰苯- n '-（6-叔丁基羰基氨基-3,4-二氢-2,2-二甲基- 2h -1-苯并吡喃-4-基）尿素对映体的制备及药理特性：R-对映体为活性自聚体的鉴定

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-12-19 DOI: 10.1016/j.ejmcr.2024.100244

Michael Schnekenburger , Eric Goffin , Matthieu Schoumacher , Nikolay Tumanov , Ange Mouithys-Mickalad , Pascal de Tullio , Johan Wouters , Philippe Lebrun , Marc Diederich , Bernard Pirotte

R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea (BPDZ 711, 4) initially designed as a K_ATP channel opener, was found to exhibit diverse biological activities. The compound inhibited insulin release from rat pancreatic islets, indicating a potential effect on glucose metabolism. Oxygraphy measurements on chronic myeloid leukemia (CML) K-562 cells revealed an impact on cellular respiration. Additionally, the compound demonstrated inhibitory activity on histone deacetylase class III enzymes (sirtuins), linking metabolic and epigenetic regulation. This was corroborated by its effect on protein acetylation and modulation of the extracellular pH of treated CML cells. Alterations in CML cells' nuclear morphology and the release of high-mobility group box 1 (HMGB1) protein confirmed mechanisms related to cellular stress and immunogenic cell death. BPDZ 711 preserved the viability of peripheral blood mononuclear cells, thus demonstrating excellent differential toxicity.

Since BPDZ 711 is a racemate, the present study focused on the preparation of the two enantiomers and examined the possibility that each isomer could display a distinct pharmacological profile. Our data revealed that the R-enantiomer (5) of BPDZ 711 was consistently the most biologically active compound (eutomer), making it the reference compound for future drug discovery and development.

R/ s - n- 3-氰苯基- n '-（6-叔丁基羰基氨基-3,4-二氢-2,2-二甲基- 2h -1-苯并吡喃-4-基）尿素（BPDZ 71,4）最初被设计为KATP通道开启剂，具有多种生物活性。该化合物抑制胰岛素从大鼠胰岛释放，表明其对葡萄糖代谢的潜在影响。对慢性髓性白血病（CML） K-562细胞的氧描测量揭示了对细胞呼吸的影响。此外，该化合物还显示出对组蛋白去乙酰化酶III类酶（sirtuins）的抑制活性，这与代谢和表观遗传调控有关。这是证实了其作用的蛋白质乙酰化和调节细胞外pH处理CML细胞。CML细胞核形态的改变和高迁移率组盒1 （HMGB1）蛋白的释放证实了细胞应激和免疫原性细胞死亡的相关机制。BPDZ 711保留了外周血单个核细胞的活力，因此显示出优异的差异毒性。由于BPDZ 711是外消旋体，本研究主要关注两种对映体的制备，并研究了每种异构体可能表现出不同药理特征的可能性。我们的数据显示，BPDZ 711的r -对映体(5)一直是最具生物活性的化合物（eutomer），使其成为未来药物发现和开发的参考化合物。

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引用次数: 0

Photochemical internalization of mRNA using a photosensitizer and nucleic acid carriers 利用光敏剂和核酸载体的mRNA光化学内化

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-12-09 DOI: 10.1016/j.ejmcr.2024.100242

Hayaki Maemoto , Ryohei Suzaki , Kazunori Watanabe , Keiji Itaka , Takashi Ohtsuki

mRNA has great potential for therapeutic applications because it can encode a variety of proteins and antigens, in addition to advantages over DNA in terms of gene expression without genomic integration, nuclear localization, or transcription. However, therapeutic applications of mRNA require safe and effective delivery into target cells. Therefore, we aimed to investigate photochemical internalization (PCI) as a promising strategy for delivering mRNA to target cells. In this strategy, mRNA is taken up into cells by endocytosis, accumulates in endosomes, and is released in a light-dependent manner from the endosomes using an endosome-accumulating photosensitizer, aluminum phthalocyanine disulfonate (AlPcS_2a), in combination with nucleic acid carrier molecules. We compared the efficacy of various nucleic acid carriers, including branched polyethyleneimine (bPEI) and poly{N'-[N-(2-aminoethyl)-2-aminoethyl] aspartamide} (PAsp(DET)) under the same conditions for PCI-based mRNA delivery. Our results indicated that bPEI and PAsp(DET) at low N/P ratios exhibited efficient light-enhancement of mRNA expression by PCI with AlPcS_2a. Notably, bPEI exhibited the highest light-dependent mRNA delivery among the carriers evaluated (including cationic polymers, cationic peptides, and lipids), whereas PAsp(DET) showed promise for clinical use because of its lower toxicity compared with bPEI. This PCI strategy allows effective cytosolic mRNA delivery at low N/P ratios, thereby reducing cationic carrier molecule-induced cytotoxicity. This method allows spatiotemporal control of protein expression and holds potential for novel light-dependent mRNA therapies. Overall, this study provided valuable insights into optimizing mRNA delivery systems for therapeutic applications.

mRNA具有巨大的治疗应用潜力，因为它可以编码多种蛋白质和抗原，并且在基因表达方面优于DNA，无需基因组整合，核定位或转录。然而，mRNA的治疗应用需要安全有效地递送到靶细胞中。因此，我们旨在研究光化学内化（PCI）作为将mRNA传递到靶细胞的一种有前途的策略。在这种策略中，mRNA通过内吞作用进入细胞，在核内体中积累，并使用核内体积累光敏剂酞菁二磺酸铝（AlPcS2a）与核酸载体分子结合，以依赖光的方式从核内体中释放出来。我们比较了不同核酸载体，包括支链聚乙烯亚胺（bPEI）和聚{N'-[N-（2-氨基乙基）-2-氨基乙基]阿斯巴胺}（PAsp(DET)）在相同条件下基于pci的mRNA递送的效果。我们的研究结果表明，低N/P比下的bPEI和PAsp（DET）在PCI与AlPcS2a的作用下表现出有效的光增强mRNA表达。值得注意的是，在被评估的载体（包括阳离子聚合物、阳离子肽和脂质）中，bPEI表现出最高的光依赖性mRNA递送，而PAsp（DET）因其与bPEI相比毒性较低而具有临床应用前景。这种PCI策略允许在低N/P比下有效的细胞质mRNA递送，从而降低阳离子载体分子诱导的细胞毒性。这种方法允许对蛋白质表达进行时空控制，并具有新型光依赖性mRNA治疗的潜力。总的来说，这项研究为优化治疗应用的mRNA传递系统提供了有价值的见解。

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引用次数: 0

Synthesis and in vitro/in silico evaluation of the antimalarial activity of potential amino-quinoline derivatives 潜在氨基喹啉衍生物的合成及其抗疟疾活性的体外/硅评价

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-12-02 DOI: 10.1016/j.ejmcr.2024.100241

Moussa Touré , Abdoulaye Gassama , Oumar Sambou , Christian Cavé , Sandrine Cojean

In this study, a series of N-arylamino-7-chloroquinolines were synthesized via an alkylation reaction involving aniline derivatives (2) and 4,7-dichloroquinoline (1). Additionally, the synthesis of a library of N-aryl-N-benzylamino-7-chloroquinoline analogues, modified on the aniline nitrogen, has also reported. A structure-activity relationship (SAR) study was conducted to evaluate the biological efficacy and safety of these derivatives against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfW2) Plasmodium falciparum strains. Compounds 5i and 5c showed promising efficacy against the Pf3D7 strain with IC₅₀ values of 0.25 μM and 0.54 μM, respectively, while compound 5l demonstrated significant activity against the PfW2 strain with an IC₅₀ of 5.82 μM. The cytotoxicity of these compounds was also evaluated on HUVEC cell lines. Additionally, their pharmacological and pharmacokinetic (ADME) properties were studied to predict their fate and identify promising candidates for further clinical studies.

本研究以苯胺衍生物(2)和4,7-二氯喹啉(1)为原料，通过烷基化反应合成了一系列n -芳基- n -苄基氨基-7-氯喹啉类似物。此外，在苯胺氮上修饰的n -芳基- n -苄基氨基-7-氯喹啉类似物库也有报道。通过构效关系（SAR）研究评价了这些衍生物对氯喹敏感（Pf3D7）和耐氯喹（PfW2）恶性疟原虫的生物有效性和安全性。化合物5i和5c对Pf3D7菌株的IC50值分别为0.25 μM和0.54 μM，化合物5l对PfW2菌株的IC50值为5.82 μM，具有较好的抑制作用。在HUVEC细胞株上评价了这些化合物的细胞毒性。此外，研究了它们的药理学和药代动力学（ADME）特性，以预测它们的命运，并确定有希望进行进一步临床研究的候选药物。

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引用次数: 0

Corrigendum to “The pyrazolo[4,3-c]pyrazole core as a novel and versatile scaffold for developing dual DYRK1A-CLK1 inhibitors targeting key processes of Alzheimer's disease pathology” [Europ. J. Med. Chem. Rep. 12 (2024) 100193] “pyrazolo[4,3-c]吡唑核心作为一种新型的多功能支架，用于开发针对阿尔茨海默病病理关键过程的双DYRK1A-CLK1抑制剂”的更正[欧洲]。医学化学。众议员12 (2024)100193]

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-12-01 DOI: 10.1016/j.ejmcr.2024.100222

Vaia-Argyro Bakalakou , Barbara Mavroidi , Amalia D. Kalampaliki , Béatrice Josselin , Stéphane Bach , Alexios-Leandros Skaltsounis , Panagiotis Marakos , Nicole Pouli , Maria Pelecanou , Vassilios Myrianthopoulos , Sandrine Ruchaud , Ioannis K. Kostakis

引用次数: 0

Novel synthesized seleno-glycoconjugates as cosmeceutical ingredients: Antioxidant activity and in vitro skin permeation 作为药妆成分的新型合成硒糖共轭物：抗氧化活性和体外皮肤渗透性

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-11-12 DOI: 10.1016/j.ejmcr.2024.100240

Giovanna Cimmino , Mauro De Nisco , Cristina Alonso , Claudia Gravina , Vincenzo Piscopo , Reinier Lemos , Luisa Coderch , Simona Piccolella , Severina Pacifico , Silvana Pedatella

Following recent successful results in the search for innovative semi-synthetic cosmeceutical Se-glycoconjugates, the work reported herein explores the development and evaluation of second-generation selenosugar-linked hydroxycinnamic acids as new potential cosmeceutical ingredients. Utilizing a Pummerer-like rearrangement for C1-acetylation, these novel compounds were synthesized and characterized using NMR spectroscopy and HRMS, confirming their structures and purity. The biological evaluation focused on their radical scavenging preliminary screening, and cytotoxic and antioxidant activities in human immortalized keratinocytes, revealing significant potential for use in skin care formulations aimed at counteracting oxidative stress and promoting skin health. Cellular uptake studies conducted on HaCaT keratinocytes using UHPLC-QqTOF-MS metabolomics demonstrated effective internalization of these compounds, which is crucial for their efficacy as topical agents. Furthermore, percutaneous absorption tests using the Franz diffusion cell method and subsequent HPLC-DAD analysis provided insights into the compound skin permeation capabilities, a critical factor for their practical application in cosmeceuticals.

继最近在寻找创新型半合成药用硒糖共轭物方面取得成功结果之后，本文所报告的研究工作探索了作为新的潜在药用化妆品成分的第二代硒糖连接羟基肉桂酸的开发和评估。这些新型化合物是利用类似于普默的重排法进行 C1-乙酰化合成的，并利用核磁共振光谱和 HRMS 对其进行了表征，确认了它们的结构和纯度。生物评估的重点是它们的自由基清除初步筛选，以及在人类永生化角质细胞中的细胞毒性和抗氧化活性，揭示了它们在旨在对抗氧化应激和促进皮肤健康的护肤配方中的巨大应用潜力。利用超高效液相色谱-QqTOF-MS 代谢组学对 HaCaT 角质细胞进行的细胞吸收研究表明，这些化合物能有效内化，这对它们作为外用制剂的功效至关重要。此外，利用弗朗兹扩散细胞法进行的经皮吸收测试以及随后的 HPLC-DAD 分析，让我们深入了解了这些化合物的皮肤渗透能力，这对它们在药用化妆品中的实际应用至关重要。

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引用次数: 0

Use of radiopharmaceuticals in the diagnosis of neurodegenerative diseases 使用放射性药物诊断神经退行性疾病

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-11-04 DOI: 10.1016/j.ejmcr.2024.100239

Anna Tempesta , Anna Tolomeo , Azzurra Stefanucci , Lorenza Marinaccio , Adriano Mollica

Neurodegenerative diseases are illnesses that affect the central nervous system (CNS) characterized by a series of symptoms such as dementia, motor disturbances, behavioural and psychological disorders, and cognitive impairments. The most common neurodegenerative disorders are Alzheimer's disease and Parkinson's disease, for which radiopharmaceuticals have been developed and approved for the purpose of PET investigation. Biomarkers are molecules that can be studied and used for diagnostic purposes, to monitor diseases, and to identify potential risk factors early.

神经退行性疾病是一种影响中枢神经系统（CNS）的疾病，以痴呆、运动障碍、行为和心理障碍以及认知障碍等一系列症状为特征。最常见的神经退行性疾病是阿尔茨海默病和帕金森病，针对这两种疾病开发的放射性药物已被批准用于 PET 研究。生物标记物是可以研究和用于诊断目的、监测疾病和早期识别潜在风险因素的分子。

引用次数: 0

Gold nanobiosensors and Machine Learning: Pioneering breakthroughs in precision breast cancer detection 金纳米生物传感器和机器学习：乳腺癌精准检测的开创性突破

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-10-30 DOI: 10.1016/j.ejmcr.2024.100238

Soheil Sadr , Ashkan Hajjafari , Abbas Rahdar , Sadanand Pandey , Parian Poorjafari Jafroodi , Narges Lotfalizadeh , Mahdi Soroushianfar , Shahla Salimpour Kavasebi , Zelal Kharaba , Sonia Fathi-karkan , Hassan Borji

Breast cancer is still one of the major health concerns of today's world. In light of such a scenario, regular improvement in the detection technique is crucial to meet better early diagnosis and treatment outcomes. This present work places much emphasis on gold nanobiosensors, which might be of utmost use in improving breast cancer diagnosis by the excellent sensitivity and specificity they offer for the identification of cancer-related biomarkers. These sensors take advantage of the unique optical and electric properties that gold nanoparticles have, enabling them to achieve an accurate molecular level of detection. Gold nanobiosensors have been significantly developed through innovations like signal amplification and surface functionalization, integrated with the use of advanced imaging techniques. Efforts have been done to enhance their biocompatibility, stability, and scalability for clinical applications. The integration of gold nanobiosensors with emerging technologies, including microfluidics and machine learning, opens new perspectives for personalized diagnostics and point-of-care testing in resource-constrained settings. However, further challenges lie ahead: to enhance manufacturing techniques, to conduct large-scale clinical trials, and to overcome limitations in regulations before widespread clinical applications. Continuous studies and technological advances indicate that gold nanobiosensors have the potential to significantly improve early diagnosis of breast cancer, reducing mortality rates and enhancing the care of patients.

乳腺癌仍然是当今世界的主要健康问题之一。有鉴于此，定期改进检测技术对于实现更好的早期诊断和治疗效果至关重要。本研究的重点是金纳米生物传感器，这种传感器具有极高的灵敏度和特异性，可用于识别与癌症相关的生物标志物，从而在改善乳腺癌诊断方面发挥重要作用。这些传感器利用金纳米粒子所具有的独特光学和电学特性，实现了精确的分子水平检测。通过信号放大和表面功能化等创新技术，并结合使用先进的成像技术，金纳米生物传感器得到了长足的发展。人们一直在努力提高它们的生物相容性、稳定性和临床应用的可扩展性。金纳米生物传感器与微流控技术和机器学习等新兴技术的结合，为资源有限环境下的个性化诊断和护理点检测开辟了新的前景。然而，未来还有更多的挑战：提高制造技术、开展大规模临床试验，以及在广泛临床应用之前克服法规限制。不断的研究和技术进步表明，金纳米生物传感器有可能显著改善乳腺癌的早期诊断，降低死亡率并加强对患者的护理。

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引用次数: 0

A reagent-free, sequence-dependent in situ peptide self-cyclization strategy under physiological condition 生理条件下的无试剂、序列依赖性原位多肽自环化策略

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-10-24 DOI: 10.1016/j.ejmcr.2024.100236

Nibedita Ghosh , Lal Mohan Kundu

Cyclic peptides are an important class of bioactive molecules used as drugs as well as biomolecular probes. Peptide cyclization under the physiological environment, without added chemicals or reagents, would be a highly useful technique for in situ applications. A simple, highly efficient, and green procedure for side-chain to side-chain in situ peptide cyclization is established here at the physiological condition. The methodology further allows the release of small biologically active molecules through peptide self-cyclization. Bioactive molecules, as well as other organic leaving groups (having primary or secondary alcohol as a functional group), were conjugated to a short peptide RXE sequence (X = Pro/Ala/Gly). The peptides were designed to undergo cyclization under physiological conditions and release the covalently attached chemotherapeutic drug and nucleobases, in a controlled manner. In vitro studies were performed in detail, with optimized physiological parameters, to understand the kinetics as well as the mechanism of self-cyclization. The mechanism of action was investigated by HPLC and ESI-Mass spectrometry. The conformational change, due to cyclization of the peptides, was monitored by CD spectroscopy. The present concept of peptide self-cyclization leading to a bond cleavage could be a potential method of delivery of small, bioactive molecules such as chemotherapeutic drugs.

环肽是一类重要的生物活性分子，可用作药物和生物分子探针。在生理环境下进行肽环化，无需添加化学品或试剂，将是一种非常有用的原位应用技术。本文建立了一种简单、高效、绿色的生理条件下侧链与侧链原位肽环化程序。该方法还能通过肽自环化进一步释放生物活性小分子。生物活性分子以及其他有机离去基团（以伯醇或仲醇为官能团）被连接到短肽 RXE 序列（X = Pro/Ala/Gly）上。这些肽的设计目的是在生理条件下发生环化，并以可控的方式释放共价连接的化疗药物和核碱基。我们利用优化的生理参数进行了详细的体外研究，以了解自环化的动力学和机制。高效液相色谱法和 ESI-质谱法对其作用机制进行了研究。CD 光谱法监测了肽环化引起的构象变化。肽的自环化导致键的断裂，这一概念可能是一种潜在的生物活性小分子（如化疗药物）输送方法。

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引用次数: 0

Novel small molecule-based acetylcholinesterase (AChE) inhibitors: From biological perspective to recent developments 基于小分子的新型乙酰胆碱酯酶（AChE）抑制剂：从生物学角度看最新进展

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-10-24 DOI: 10.1016/j.ejmcr.2024.100237

Anjali Sobha , Anand Ganapathy , Sangeetha Mohan , Nithya Madhusoodanan , Alansheeja D. Babysulochana , Kumaran Alaganandan , Sasidhar B. Somappa

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that imposes a substantial socioeconomic burden globally. The increasing prevalence of AD, coupled with an incomplete understanding of its fundamental etiology and the absence of a definitive cure, has intensified research efforts in this area. Over the past decade, the cholinergic theory has garnered significant attention from researchers, particularly in the development of small molecule-based Acetylcholinesterase (AChE) inhibitors using molecular modelling and computer-aided drug discovery. In recent years, the focus has expanded to include multi-target-directed ligands (MTDLs), which address the multifaceted pathological mechanisms of AD. These ligands offer the potential to reduce amyloid-beta plaque accumulation, neurofibrillary tangle (NFT) formation, oxidative stress, and neuroinflammation, while also providing metal chelation properties and selective MAO-B inhibition. Despite the progress in small molecule-based AD therapeutics, issues related to toxicity and severe side effects have underscored the urgent need for novel drug development. This has spurred interest in the structural modification of existing drugs such as tacrine, donepezil, galantamine, and rivastigmine, as well as the synthesis of new molecules informed by structure-activity relationship (SAR) studies. In this review, we summarize and analyse recent advancements in small molecule-based AChE inhibitors, with a focus on various drug design strategies aimed at generating potent therapeutic candidates.

阿尔茨海默病（AD）是一种慢性神经退行性疾病，给全球造成了巨大的社会经济负担。阿兹海默病的发病率越来越高，加上人们对其基本病因的了解还不全面，也没有确切的治疗方法，因此该领域的研究工作愈演愈烈。在过去十年中，胆碱能理论引起了研究人员的极大关注，特别是在利用分子建模和计算机辅助药物发现技术开发基于小分子的乙酰胆碱酯酶（AChE）抑制剂方面。近年来，研究重点已扩展到多靶点配体（MTDLs），这些配体可解决注意力缺失症的多方面病理机制。这些配体具有减少淀粉样蛋白-β斑块堆积、神经纤维缠结（NFT）形成、氧化应激和神经炎症的潜力，同时还具有金属螯合特性和选择性 MAO-B 抑制作用。尽管基于小分子的注意力缺失症疗法取得了进展，但与毒性和严重副作用相关的问题凸显了对新型药物开发的迫切需求。这激发了人们对他克林、多奈哌齐、加兰他敏和利伐斯的明等现有药物进行结构改造以及通过结构-活性关系（SAR）研究合成新分子的兴趣。在这篇综述中，我们总结并分析了基于小分子的 AChE 抑制剂的最新进展，重点介绍了旨在产生强效候选疗法的各种药物设计策略。

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引用次数: 0

Targeting Alzheimer's disease with novel dual-function 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives 用新型双功能 3,5-二芳基-4,5-二氢-1H-吡唑-1-硫代甲酰胺衍生物治疗阿尔茨海默病

European Journal of Medicinal Chemistry Reports

Pub Date : 2024-10-21 DOI: 10.1016/j.ejmcr.2024.100235

Aikaterini Katsogiannou , Danai Karta , Antonio Di Stefano , Sena Oner , Mehmet Enes Arslan , Adil Mardinoglu , Hasan Turkez , Stamatia Vassiliou , Ivana Cacciatore

In the field of medicinal chemistry, the versatility of the thiosemicarbazone scaffold makes it a promising platform for the development of next-generation pharmaceuticals. In this paper the thiosemicarbazone scaffold was explored to obtain novel series of derivatives: a) thiosemicarbazones 15–31, and 33 containing a linear thiosemicarbazone scaffold, b) 34–38 and 44–64 containing pyrazoline ring, and c) 39–43 containing the dihydropyrimidine cycle. Among these, compounds 21, 23, 26, 33–35, 37, 38, 44, 57, 61, and 62 demonstrated no significant cytotoxic effects on HDFa cells at concentrations up to 500 μg/mL. Importantly, compounds 21, 23, 26, 33, 34, 35, and 37 exhibited significant protective effects against neurotoxicity induced by beta-amyloid peptide (1-42) in differentiated SHSY-5Y cell cultures. Enzymatic assays targeting BACE1 and AChE revealed modest inhibitory activity in compounds 21, 23, and 34, 37, respectively. The identification of compounds with inhibitory effects and neuroprotective activity against beta-amyloid peptide (1-42) offers a platform for further optimization and refinement of these compounds to enhance their potency and selectivity.

在药物化学领域，硫代氨基脲支架的多功能性使其成为开发下一代药物的一个前景广阔的平台。本文通过对硫代氨基羰基支架的探索，获得了一系列新型衍生物：a) 含有线性硫代氨基羰基支架的硫代氨基羰基 15-31 和 33；b) 含有吡唑啉环的 34-38 和 44-64；c) 含有二氢嘧啶循环的 39-43。其中，化合物 21、23、26、33-35、37、38、44、57、61 和 62 在浓度高达 500 μg/mL 时对 HDFa 细胞没有明显的细胞毒性作用。重要的是，在分化的 SHSY-5Y 细胞培养物中，化合物 21、23、26、33、34、35 和 37 对 beta 淀粉样肽（1-42）诱导的神经毒性具有明显的保护作用。针对 BACE1 和 AChE 的酶测定显示，化合物 21、23 和 34、37 分别具有适度的抑制活性。对β-淀粉样肽（1-42）具有抑制作用和神经保护活性的化合物的鉴定为进一步优化和改进这些化合物以提高其效力和选择性提供了一个平台。

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引用次数: 0