European Journal of Medicinal Chemistry最新文献_第10页

Andrographolide: A promising therapeutic agent against organ fibrosis 穿心莲内酯：一种很有前景的器官纤维化治疗剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-20 DOI: 10.1016/j.ejmech.2024.116992

Wei Dai , Jiabin Wu , Ke Li , Yingying Xu , Wenhong Wang , Weihua Xiao

Fibrosis is the terminal pathology of chronic illness in many organs, marked by excessive accumulation of extracellular matrix proteins. These changes influence organ function, ultimately resulting in organ failure. Although significant progress has been achieved in comprehending the molecular pathways responsible for fibrosis in the last decades, effective and approved clinical therapies for the condition are still lacking. Andrographolide is a diterpenoid isolated and purified mainly from the aboveground parts of the Andrographis paniculata plant, which possesses good effects of purging heat, detoxifying, antibacterial and anti-inflammatory. In-depth research has gradually confirmed the anticancer, antioxidant, antiviral and other effects of Andro so that it can play a preventive and therapeutic role in various diseases. Over the past few years, an increasing number of research findings have indicated that Andro exerts antifibrotic effects in various organs by acting on transforming growth factor-β/small mother against decapentaplegic protein, mitogen-activated protein kinases, nuclear factor-E2-related factor 2, nuclear factor kappa-B and other signalling molecules to inhibit inflammation, oxidative stress, epithelial-mesenchymal transition, fibroblast activation and collagen buildup. This review presents a compilation of findings regarding the antifibrotic impact of Andro in tissue and cell models in vitro and in vivo. Emphasis is placed on the potential therapeutic benefits of Andro in diseases related to organ fibrosis. Existing studies and cutting-edge technologies on Andro pharmacokinetics, toxicity and bioavailability are briefly discussed to provide evidence for accelerating its clinical conversion and adoption.

纤维化是许多器官慢性病的终末病理，其特征是细胞外基质蛋白过度积累。这些变化会影响器官功能，最终导致器官衰竭。尽管在过去几十年中，人们在理解导致纤维化的分子途径方面取得了重大进展，但仍然缺乏有效的、已获批准的临床疗法。穿心莲内酯是一种二萜类化合物，主要从穿心莲的地上部分分离纯化而来，具有清热、解毒、抗菌、消炎等功效。深入的研究逐渐证实了穿心莲的抗癌、抗氧化、抗病毒等功效，从而对多种疾病起到预防和治疗作用。在过去几年中，越来越多的研究结果表明，安络血通过作用于转化生长因子-β/小母抗截瘫蛋白、丝裂原活化蛋白激酶、核因子-E2相关因子2、核因子卡巴-B和其他信号分子，抑制炎症、氧化应激、上皮-间质转化、成纤维细胞活化和胶原堆积，从而在各种器官中发挥抗纤维化作用。本综述汇编了有关 Andro 在体外和体内组织和细胞模型中抗纤维化影响的研究结果。重点是 Andro 对器官纤维化相关疾病的潜在治疗效果。简要讨论了有关 Andro 药代动力学、毒性和生物利用度的现有研究和前沿技术，为加速其临床转化和采用提供证据。

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引用次数: 0

Design, synthesis, in vitro and in vivo trypanosomaticidal efficacy of novel 5-nitroindolylazines 新型硝基吲哚嗪类化合物的设计、合成、体外和体内杀锥虫功效

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-19 DOI: 10.1016/j.ejmech.2024.116979

David D. N'Da , Janine Aucamp , Helena D. Janse van Rensburg , Keisuke Suganuma

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (S_N), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC₅₀: 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC₅₀: 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense, the causative agent of nagana, which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research.

利什曼病和锥虫病是热带和亚热带国家流行的致命病媒寄生虫病。目前还没有针对这两种疾病的预防疫苗，一旦确诊，只有少数几种临床上可获得的效果较差的药物可用于治疗这些疾病。尽管这些疾病是可以治愈的，但由于病原体出现了对多种药物产生抗药性的菌株，根除和消除这些疾病的工作受到了阻碍。因此，开发新的、有效的和可负担得起的药物变得越来越有必要。近几十年来，包括硝基芳香族化合物、内过氧化物等在内的几种分子支架被尝试用作生成低毒、有效的新型临床抗盘吸虫药物的构件，但至今仍未取得成功。为此，我们通过亲核取代（SN）、酰肼化和希夫碱缩合反应三步法合成了一系列硝基吲哚嗪衍生物，并针对各种利什曼原虫和锥虫物种和菌株进行了评估。研究发现了几种具有体外亚摩尔活性、对哺乳动物细胞无毒性的杀利什曼和杀锥虫药物。其中，硝基呋嗪 11（锝 IC50：0.08 ± 0.03 μM）和硝基噻吩嗪 13（锝 IC50：0.09 ± 0.01 μM）在体内对纳加纳锥虫（Trypanosoma congolense）进行了评估。然而，由于所有小鼠都在感染后 13 天内因高寄生虫血症而死亡，因此在治疗期间只观察到部分疗效。今后的研究将评估抗利什曼病和抗凝集素药物的转化潜力，并进一步确定其分子靶标。

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引用次数: 0

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors 一石二鸟：将哌嗪引入一系列核苷衍生物作为强效和选择性 PRMT5 抑制剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-19 DOI: 10.1016/j.ejmech.2024.116970

Huaxuan Li , Hong Yang , Li Liu , Jiahong Zheng , Qiongyu Shi , Bang Li , Xingcan Wang , Ying Zhang , Ruilin Zhou , Jian Zhang , Zhong-Zhu Chen , Chang-Yun Wang , Yuanxiang Wang , Xun Huang , Zhiqing Liu

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development.

蛋白精氨酸甲基转移酶 5（PRMT5）已成为治疗癌症的潜在靶点。人们一直在努力开发针对 S-腺苷蛋氨酸（SAM）口袋或底物结合口袋的强效、选择性 PRMT5 抑制剂。在这里，我们合理地设计了一系列与哌嗪结合的核苷衍生物，作为新型的 PRMT5 抑制剂，同时占据这两个口袋。具有代表性的化合物 36 表现出极强的 PRMT5 抑制活性，并且对其他甲基转移酶具有良好的选择性。进一步的细胞实验发现，化合物 36 能有效降低对称二甲基精氨酸（sDMA）的水平，并通过诱导细胞凋亡和细胞周期停滞来抑制 MOLM-13 细胞株的增殖。此外，化合物 36 比 JNJ64619178（9）具有更好的代谢稳定性和水溶性。同时，它在 MOLM-13 肿瘤异种移植模型中明显抑制了肿瘤的生长。这些结果清楚地表明，36 是一种高效且具有选择性的 PRMT5 抑制剂，值得进一步开发。

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引用次数: 0

Coumarin-Quinazolinone based photosensitizers: Mitochondria and endoplasmic reticulum targeting for enhanced phototherapy via different cell death pathways 香豆素-喹唑啉酮类光敏剂：通过不同的细胞死亡途径靶向线粒体和内质网以增强光疗效果

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-19 DOI: 10.1016/j.ejmech.2024.116990

Xuzi Zhao , Ting Wang , Fucheng Shang , Jiangyu Yan , Mingyan Jiang , Xiaoyan Zou , Guorui Li , Zhibin Song , Jing Huang

Organelle-targeted photosensitizers (PSs) offer valuable tools for improving photodynamic therapy (PDT), yet systematic studies on how different organelles influence phototherapeutic outcomes are limited. In particular, the connection between organelle targeting and various modes of programmed cell death remains unclear. In this study, we developed a series of PSs using the Coumarin-Quinazolinone (CQ) scaffold, each designed to target different organelles, including the mitochondria, endoplasmic reticulum (ER), lysosome, and nucleolus. Our results show that their PDT performance is highly dependent on their localization, with phototoxic index (PI) ranging from 2 to 245. Notably, the mitochondria-targeted CQ-Mito and ER-targeted CQ-ER exhibited profound phototherapeutic performances, with PI of 167 and 245 respectively. Our further study reveals that CQ-Mito causes cell death by both apoptosis and ferroptosis, while CQ-ER primarily triggers ferroptosis. This study not only provides new agents for PDT but also offers insights into how organelle targeting influences cell death mechanisms, which can shed light on the design of PSs for controlled cell death.

细胞器靶向光敏剂（PSs）为改善光动力疗法（PDT）提供了宝贵的工具，但有关不同细胞器如何影响光疗效果的系统研究却很有限。特别是，细胞器靶向与各种程序性细胞死亡模式之间的联系仍不清楚。在这项研究中，我们利用香豆素-喹唑啉酮（CQ）支架开发了一系列 PSs，每种 PSs 都针对不同的细胞器，包括线粒体、内质网（ER）、溶酶体和核仁。我们的研究结果表明，它们的光致透射性能高度依赖于它们的定位，光毒性指数（PI）从 2 到 245 不等。值得注意的是，线粒体靶向的 CQ-Mito 和 ER 靶向的 CQ-ER 表现出极强的光治疗性能，PI 分别为 167 和 245。我们的进一步研究发现，CQ-Mito 通过凋亡和铁凋亡两种方式导致细胞死亡，而 CQ-ER 则主要引发铁凋亡。这项研究不仅为光致猝死疗法提供了新的制剂，还深入揭示了细胞器靶向如何影响细胞死亡机制，从而为设计可控细胞死亡的 PSs 提供了启示。

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引用次数: 0

Development of membrane-targeting chalcone derivatives as antibacterial agents against multidrug-resistant bacteria 开发膜靶向查尔酮衍生物作为抗耐多药细菌的抗菌剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116969

Siyu Yang , Guoqing Miao , Xinyu Wang , Fen Zhou , Ziheng Yuan , Fuyao Wei , Lusha Ji , Xuekun Wang , Gaopan Dong , Yinhu Wang

The striking rise of infections caused by multidrug-resistant pathogens has evolved as a serious threat to public health worldwide. To develop new antibacterials to combat multidrug-resistant bacteria, a novel class of amphiphilic chalcone derivatives serving as antimicrobial peptidomimetics was designed and synthesized. Among them, the most promising compound 14b displayed broad-spectrum antimicrobial activity against both Gram-positive bacteria (MICs = 0.5–1 μg/mL) and Gram-negative bacteria (MICs = 1–32 μg/mL), low hemolytic activity, and good membrane selectivity. Moreover, compound 14b exhibited rapid bactericidal action, a low probability of developing resistance, high proteolytic stability, and strong capabilities of inhibiting and destroying bacterial biofilms. Further mechanism investigations revealed that compound 14b possessed strong membrane-disrupting abilities and could disintegrate the integrity of bacterial cell membranes by destroying transmembrane potential and enhancing membrane permeability, and causing the generation of intracellular ROS and the leakage of DNA and proteins, ultimately leading to bacterial death. More importantly, compound 14b also showed excellent in vivo therapeutic potency in a mouse septicemia model infected by both Gram-positive and Gram-negative bacteria, indicating its potential to be an antibacterial agent to confront bacterial infections.

耐多药病原体引起的感染显著增加，已成为对全球公共卫生的严重威胁。为了开发新的抗菌药物来对抗耐多药细菌，我们设计并合成了一类新型的两亲性查尔酮衍生物，作为抗菌肽拟分子。其中，最有前途的化合物 14b 对革兰氏阳性菌（MICs = 0.5-1 μg/mL）和革兰氏阴性菌（MICs = 1-32 μg/mL）均具有广谱抗菌活性，溶血活性低，膜选择性好。此外，化合物 14b 还具有杀菌作用迅速、产生耐药性的概率低、蛋白水解稳定性高、抑制和破坏细菌生物膜的能力强等特点。进一步的机理研究发现，化合物 14b 具有很强的膜破坏能力，可以通过破坏跨膜电位和提高膜通透性来瓦解细菌细胞膜的完整性，并导致细胞内 ROS 的产生以及 DNA 和蛋白质的泄漏，最终导致细菌死亡。更重要的是，化合物 14b 还在革兰氏阳性菌和革兰氏阴性菌感染的小鼠败血症模型中显示出卓越的体内疗效，这表明它有潜力成为一种抗菌剂来对抗细菌感染。

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引用次数: 0

Trivalent oleanolic acid-glucose conjugates: Synthesis and efficacy against Influenza A virus 三价齐墩果酸-葡萄糖共轭物：合成与抗甲型流感病毒的功效

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116977

Ming Cai , Yuan Zhang , Jie Zhen , Fan Yang, Xia Ou, Jihong Zhang, Fei Yu

Influenza A virus (IAV) leads to significant morbidity and mortality due to the seasonal epidemics and spread. We have demonstrated that oleanolic acid (OA) C28 glucose conjugates and OA trimers are capable of effectively blocking the recognition and interaction between the influenza virus and host cells. In this study, a series of OA-glucose trimers were designed and synthesized through the CuAAC reaction. All trimers underwent screening for anti-IAV activities in vitro. Among these, compounds 13a and 13b showed inhibitory activity against the influenza virus, with IC₅₀ values of 0.68 μM and 0.47 μM, respectively, demonstrating greater potency than oseltamivir (IC₅₀ = 1.36 μM). Results from the time-of-addition experiment and hemagglutination inhibition assay suggest that these OA-glucose trimers may disrupt the recognition between the HA protein of IAV and sialic acid receptors on host cells, thus blocking viral entry. Furthermore, it was found that compound 13b effectively inhibits IAV infection in BALB/c mice. This study has elucidated the structure-activity relationships of OA trimers against the influenza virus and highlighted the utility of multivalent OA conjugates for enhancing ligand-target interactions in anti-influenza virus drug design, laying a groundwork for future research into the antiviral applications of these natural products.

甲型流感病毒（IAV）因季节性流行和传播而导致严重的发病率和死亡率。我们已经证明，齐墩果酸（OA）C28 葡萄糖共轭物和 OA 三聚体能够有效阻断流感病毒与宿主细胞之间的识别和相互作用。本研究通过 CuAAC 反应设计并合成了一系列 OA-葡萄糖三聚体。所有三聚体都进行了体外抗流感病毒活性筛选。其中，化合物 13a 和 13b 对流感病毒具有抑制活性，IC50 值分别为 0.68 μM 和 0.47 μM，显示出比奥司他韦（IC50 = 1.36 μM）更强的效力。添加时间实验和血凝抑制实验的结果表明，这些 OA-葡萄糖三聚体可能会破坏 IAV 的 HA 蛋白与宿主细胞上的唾液酸受体之间的识别，从而阻止病毒进入。此外，研究还发现化合物 13b 能有效抑制 IAV 在 BALB/c 小鼠体内的感染。这项研究阐明了 OA 三聚体抗流感病毒的结构-活性关系，突出了多价 OA 共轭物在抗流感病毒药物设计中增强配体-靶标相互作用的作用，为今后研究这些天然产物的抗病毒应用奠定了基础。

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引用次数: 0

Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors (2019–2023) 作为 HIV-1 非核苷逆转录酶抑制剂的二芳基嘧啶及相关类似物的研究进展（2019-2023 年）

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116973

Mu-Zi Nie , Shuang-Shuang Zhang , Shuang-Xi Gu , Jiao Long , Yuan-Yuan Zhu

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a vital cornerstone of highly active antiretroviral therapy (HAART) regimens, owing to their unique antiviral activity, low toxicity and high specificity. Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine and rilpivirine, have attracted extensive attention due to their high anti-HIV potency. However, rapid emergence of resistant mutations, suboptimal pharmacokinetics (PK), and toxicity remain significant challenges. Recent structural modifications of DAPY analogues have focused on improving resistance profiles, optimizing PK properties (such as half-life and bioavailability), diversifying core structures through scaffold hopping, refining side-chain structures to enhance activity and selectivity, and reducing toxicity and side effects. Moreover, developing new DAPY analogues with broad-spectrum antiviral activity has become a key research priority. This review provides a comprehensive overview of the evolution of DAPYs from 2019 to 2023, including scaffold hopping and structural modifications of the right wing, left wing, central pyrimidine core, and linker, affording valuable insights for the future development of effective HIV-1 inhibitors.

非核苷类逆转录酶抑制剂（NNRTIs）因其独特的抗病毒活性、低毒性和高特异性，已成为高效抗逆转录病毒疗法（HAART）的重要基石。作为第二代 NNRTIs，以依曲韦林和利匹韦林为代表的二乙基嘧啶类（DAPYs）因其高抗病毒效力而受到广泛关注。然而，耐药性突变的快速出现、药代动力学（PK）不理想以及毒性仍然是重大挑战。最近对 DAPY 类似物进行的结构改造主要集中在改善耐药性特征、优化 PK 性能（如半衰期和生物利用度）、通过支架跳跃实现核心结构多样化、改进侧链结构以提高活性和选择性，以及降低毒性和副作用。此外，开发具有广谱抗病毒活性的新型 DAPY 类似物已成为研究的重中之重。本综述全面概述了2019年至2023年DAPY的演变，包括右翼、左翼、中央嘧啶核心和连接体的支架跳跃和结构修饰，为未来开发有效的HIV-1抑制剂提供了宝贵的见解。

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引用次数: 0

Discovery of quinazoline-benzothiazole derivatives as novel potent protease-activated receptor 4 antagonists with improved pharmacokinetics and low bleeding liability 发现喹唑啉-苯并噻唑衍生物作为新型强效蛋白酶激活受体 4 拮抗剂，改善药代动力学，降低出血风险

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116980

Shanshan Li , Shangde Liu , Duo Yuan , Renjie Liu , Lifang Hu , Xiong Zhu

Protease-activated receptor 4 (PAR4) plays a critical role in the development of pathological thrombosis, and targeting PAR4 is considered a promising strategy for improving antiplatelet therapies. Here, we reported the design of a series of quinazoline-benzothiazole-based PAR4 antagonists using a scaffold-hopping strategy. Systematic structure-activity relationship exploration leads to the discovery of compounds 20f and 20g, which displayed optimal activity (h. PAR4-AP PRP IC₅₀ = 6.39 nM and 3.45 nM, respectively) on human platelets and high selectivity for PAR4. Both of them also showed excellent metabolic stability in human liver microsomes (compound 20f, T_1/2 = 249.83 min, compound 20g, T_1/2 = 282.60 min) and favourable PK profiles in rats (compound 20f, T_1/2 = 5.16 h, F = 50.5 %, compound 20g, T_1/2 = 7.05 h, F = 27.3 %). More importantly, neither compound prolonged the bleeding time in the mouse tail-cutting model (10 mg/kg, p.o.). These results suggest that these compounds have great potential for use in antiplatelet therapies.

蛋白酶活化受体 4（PAR4）在病理性血栓形成中起着关键作用，靶向 PAR4 被认为是改进抗血小板疗法的一种有前途的策略。在此，我们报告了利用支架跳转策略设计的一系列基于喹唑啉-苯并噻唑的 PAR4 拮抗剂。通过系统的结构-活性关系探索，我们发现了化合物 20f 和 20g，它们在人血小板上显示出最佳活性（h. PAR4-AP PRP IC50 = 6.39 nM 和 3.45 nM），并且对 PAR4 具有高选择性。这两种化合物在人肝脏微粒体中也表现出极佳的代谢稳定性（化合物 20f，T1/2 = 249.83 分钟；化合物 20g，T1/2 = 282.60 分钟），在大鼠体内的 PK 曲线也很理想（化合物 20f，T1/2 = 5.16 小时，F = 50.5%；化合物 20g，T1/2 = 7.05 小时，F = 27.3%）。更重要的是，这两种化合物都不会延长小鼠切尾模型（10 毫克/千克，口服）的出血时间。这些结果表明，这些化合物在抗血小板疗法中具有很大的应用潜力。

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引用次数: 0

Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2 含萘-1-乙胺的 SARS-CoV-2 木瓜蛋白酶类小分子抑制剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116963

Kouki Shinohara , Takuya Kobayakawa , Kohei Tsuji , Yuki Takamatsu , Hiroaki Mitsuya , Hirokazu Tamamura

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M^pro) and a papain-like protease (PL^pro), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL^pro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL^pro showed that GRL-0048 noncovalently interacts with PL^pro, and there is a newly identified binding pocket in PL^pro. Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1, 2b, and 3h, that have more potent inhibitory activity than GRL-0048.

导致 2019 年冠状病毒病（COVID-19）的严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）尚未被根除。SARS-CoV-2 有两种蛋白酶，一种是主蛋白酶（Mpro），另一种是木瓜蛋白酶样蛋白酶（PLpro），它们共同处理两种已翻译的非结构性多聚蛋白 pp1a 和 pp1ab，生成功能性病毒蛋白。本研究以 GRL-0048 为先导，设计并合成了针对 SARS-CoV-2 PLpro 的有效抑制剂。GRL-0048与SARS-CoV-2 PLpro的对接模拟显示，GRL-0048与PLpro存在非共价相互作用，并且在PLpro中发现了一个新的结合口袋。接下来对 GRL-0048 进行了结构-活性关系研究，最终开发出了几种抑制剂，特别是化合物 1、2b 和 3h，它们比 GRL-0048 具有更强的抑制活性。

引用次数: 0

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects 作为神经保护性 NMDA 受体拮抗剂的地佐西平衍生物不会产生拟精神副作用

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.ejmech.2024.116981

Jan Konecny , Anna Misiachna , Marketa Chvojkova , Lenka Kleteckova , Marharyta Kolcheva , Martin Novak , Lukas Prchal , Marek Ladislav , Katarina Hemelikova , Jakub Netolicky , Martina Hrabinova , Tereza Kobrlova , Jana Zdarova Karasova , Jaroslav Pejchal , Jakub Fibigar , Zbynek Vecera , Tomas Kucera , Pavla Jendelova , Petra Zahumenska , Emily Langore , Martin Horak

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-d-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90 % for GluN1/GluN2A), while 3l showed moderate inhibition (∼50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

我们的目标是制备新型二苯并[a,d][7]茚衍生物，这种衍生物可作用于 N-甲基-D-天冬氨酸（NMDA）受体，具有潜在的神经保护作用。MK-801是一种强效开放通道阻断剂，以其拟精神副作用而闻名，我们的研究方法是通过引入一个具有取代基分子的七元环，对MK-801的托烷分子进行修饰，以减轻这些不良反应。我们的硅学分析表明，这些衍生物应具有较高的胃肠道吸收率，并能穿过血脑屏障（BBB）。我们在大鼠体内进行的药代动力学研究支持了这一结论，并证实了前导化合物 3l 和 6f 穿透 BBB 的能力。电生理实验表明，所有化合物都对两种主要的 NMDA 受体亚型（GluN1/GluN2A 和 GluN1/GluN2B）具有不同的抑制活性。在所选的抑制效力有意不同的化合物中，6f 表现出较高的相对抑制作用（对 GluN1/GluN2A 的抑制率为 90%∼），而 3l 则表现出中等程度的抑制作用（50%∼）。一项体内毒性研究确定，化合物 3l 和 6f 在 10 毫克/千克剂量下是安全的，没有不良反应。行为研究表明，这些化合物不会诱发大鼠过度运动，也不会损害对惊吓反应的前脉冲抑制。使用 NMDA 诱导的海马神经变性模型进行的神经保护试验表明，浓度为 30 μM 的化合物 3l 能显著减轻大鼠海马的损伤。这些结果表明，这些新型二苯并[a,d][7]茚衍生物是开发 NMDA 受体靶向疗法的有希望的候选化合物，其拟精神药物的副作用极小。

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