Bioorganic & Medicinal Chemistry最新文献_第2页

Targeting epithelial-mesenchymal transition and apoptosis: novel histone methyltransferase inhibitors for colon cancer suppression 靶向上皮-间质转化和细胞凋亡：新型组蛋白甲基转移酶抑制剂抑制结肠癌

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-16 DOI: 10.1016/j.bmc.2026.118570

Hsueh-Yun Lee , Chia-Hsuan Chang , Yi-Ting Liu , Deepa Rohidas Landge , Tzu-Ying Chen , Er-Chieh Cho

Colon cancer is one of the major causes of cancer-related death worldwide and is considered a consequence of the accumulation of genetic and epigenetic changes in normal cells. Among epigenetic modifications, the critical involvement of histone methyltransferase (HMT) in epigenetic alterations and tumorigenesis has been widely reported. Targeting HMTs as an anti-cancer strategy has attracted considerable attention; however, limited HMT inhibitors have achieved success in the field of clinical oncology.

In this study, we aimed to design and synthesize small molecular compounds as potential HMT inhibitors for cancer therapy, and to investigate their biological impacts on cancer cell lines. We examined the anti-proliferative effect of potential HMT inhibitors in multiple cancer cell lines. Among all candidates, two 1-benzylpiperidin-4-amine derivatives, DHT-07343 and DHT-07171, exhibited the most significant anti-cancer potential, especially in colon cancer cells. These two compounds could suppress methyltransferase activity, likely via regulating nuclear receptor-binding SET domain protein 1 (NSD1) and NSD2. In addition, these two compounds were able to inhibit cancer cell migration and regulate epithelial-mesenchymal transition (EMT) markers. Treatment of these two compounds led to apoptosis induction as well as cell cycle regulation. Finally, non-cancerous human cell lines and the zebrafish embryotoxicity model were utilized for the evaluation of the drug safety of DHT-07343 and DHT-07171.

In conclusion, our study demonstrated that DHT-07343 and DHT-07171 could be promising HMT inhibitors that exhibit anti-cancer activities by suppressing cell proliferation and migration, providing a potential strategy for colon cancer therapy.

结肠癌是全球癌症相关死亡的主要原因之一，被认为是正常细胞中遗传和表观遗传变化积累的结果。在表观遗传修饰中，组蛋白甲基转移酶（HMT）在表观遗传改变和肿瘤发生中的关键作用已被广泛报道。靶向hmt作为抗癌策略引起了广泛关注；然而，有限的HMT抑制剂在临床肿瘤学领域取得了成功。在本研究中，我们旨在设计和合成小分子化合物作为潜在的HMT抑制剂用于癌症治疗，并研究其对癌细胞系的生物学影响。我们研究了潜在的HMT抑制剂在多种癌细胞系中的抗增殖作用。在所有候选药物中，2个1-苄基哌啶-4-胺衍生物DHT-07343和DHT-07171表现出最显著的抗癌潜力，特别是在结肠癌细胞中。这两种化合物可能通过调节核受体结合SET结构域蛋白1 （NSD1）和NSD2抑制甲基转移酶活性。此外，这两种化合物能够抑制癌细胞迁移并调节上皮-间质转化（EMT）标志物。这两种化合物的处理导致细胞凋亡诱导和细胞周期调节。最后，采用非癌性人细胞系和斑马鱼胚胎毒性模型对DHT-07343和DHT-07171的用药安全性进行评价。总之，我们的研究表明DHT-07343和DHT-07171可能是有希望的HMT抑制剂，通过抑制细胞增殖和迁移来表现出抗癌活性，为结肠癌治疗提供了潜在的策略。

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引用次数: 0

Harnessing N-substituted benzotriazole scaffolds as potent methionine aminopeptidase inhibitors: from chemical design to cellular efficacy 利用n -取代苯并三唑支架作为有效的蛋氨酸氨基肽酶抑制剂：从化学设计到细胞功效

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-06 DOI: 10.1016/j.bmc.2026.118553

Vivekananda Saha , Ajinur Hossain , Khairud Zaman Miraj , Nasim Sepay , Souvik Sarkar , Subarna Roy , Jungkyun Im , Goutam Biswas

Herein, we present the synthesis, characterization, and biological evaluation of twenty-five N-substituted benzotriazole derivatives as potential anticancer agents targeting methionine aminopeptidase (MAP) enzymes. The compounds were synthesized following a conventional procedure and characterized by spectroscopic techniques, including ¹H and ¹³C NMR, FT-IR, and LCMS, for structural endorsement. Molecular docking and dynamics simulations over 100 ns revealed strong binding affinities and stable complex formation between several N-substituted benzotriazole derivatives and MAP type-I, outperforming the reference anticancer drugs in key protein-ligand interactions. Additionally, the compound 4g showed the highest Mechanics Poisson-Boltzmann Surface Area (MMPBSA) energy of −12.53 ± 4.3 kcal/mol, with a major contribution from TYR-196 and TRP-353 amino acid residues. Pharmacokinetic profiling using ADMET tools showed that most compounds possessed favorable drug-like properties, suitable absorption, and low toxicity. Biological assays demonstrated significant cytotoxicity, with an IC₅₀ value of 34.8 μM for 4g. The relative apoptotic rates of HeLa cancer cell lines using selected derivatives against the control showed notable therapeutic outcomes for 4g, 6d, and 6f. In summary, this integrated approach highlights N-substituted benzotriazole scaffolds as promising modular precursors for the development of targeted anticancer therapies focused on metabolic enzyme inhibition.

在此，我们提出了25个n取代苯并三唑衍生物的合成、表征和生物学评价作为潜在的抗癌药物靶向甲硫氨酸氨基肽酶（MAP）酶。这些化合物是按照常规方法合成的，并通过1H和13C NMR、FT-IR和LCMS等光谱技术进行了结构表征。超过100 ns的分子对接和动力学模拟表明，几种n-取代苯并三唑衍生物与MAP - i型之间具有很强的结合亲和力和稳定的络合物形成，在关键的蛋白质-配体相互作用方面优于参考抗癌药物。此外，化合物4g的力学泊松-玻尔兹曼表面积（MMPBSA）能最高，为−12.53±4.3 kcal/mol，主要来自tyr1 -196和TRP-353氨基酸残基。利用ADMET工具进行药代动力学分析表明，大多数化合物具有良好的药物样特性、适宜的吸收和低毒性。生物实验显示出显著的细胞毒性，IC50值为34.8 μM。使用所选衍生物的HeLa癌细胞系相对于对照组的相对凋亡率在第4g、第6d和第6f显示出显著的治疗效果。总之，这种综合方法突出了n取代苯并三唑支架作为有前途的模块化前体，用于开发以代谢酶抑制为重点的靶向抗癌治疗。

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引用次数: 0

Design, synthesis and anti-tumor activities of pyridine-benzamide containing dithiocarbamate moiety as EZH2 inhibitors 含二硫代氨基甲酸酯部分吡啶-苯酰胺EZH2抑制剂的设计、合成及抗肿瘤活性研究

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2025-12-05 DOI: 10.1016/j.bmc.2025.118514

Hui Lu, Yuling Xiang, Ping Gong

Based on the reported Enhancer of zeste homolog 2 (EZH2) inhibitors characterized by pyridone-benzamide components, a series of derivatives were designed and synthesized through structural optimization based on rational drug design principles. Compound N16 demonstrates significant inhibitory effects on EZH2 WT, with an IC₅₀ of 0.3 nM. Furthermore, compound N16 effectively inhibited the proliferation of Pfeiffer cells (IC₅₀ = 0.0074 ± 0.002 μM) and demonstrated greater efficacy compared to Tazemetostat. Compound N16 induced apoptosis in Pfeiffer cells and caused cell cycle arrest in the G1 phase. After treatment of Pfeiffer cells with N16 for 48 h at the indicated concentrations (1.85, 3.70, 7.40, 14.8 and 29.60 nM), the percentage of Pfeiffer cells in the G1 phase increased from 88.75 % (in the control group) to 85.2, 96.61, 92.04, 93.35 and 91.05 %, respectively. The author employed Western blotting analysis to examine the effect of compound N16 on H3K27 methylation. The results significantly showed that under high-concentration conditions, compound N16 obviously inhibited the trimethylation of lysine 27 on histone H3 (H3K27me3) in Pfeiffer cells. Our findings suggest that N16 is a promising EZH2 inhibitor, and further investigation is warranted to validate these findings and facilitate the subsequent development of N16.

以已报道的以吡啶酮-苯酰胺组分为特征的EZH2抑制剂为基础，根据合理的药物设计原则，通过结构优化，设计合成了一系列EZH2抑制剂衍生物。化合物N16对EZH2 WT有明显的抑制作用，IC50为0.3 nM。此外，化合物N16能有效抑制Pfeiffer细胞的增殖（IC50 = 0.0074±0.002 μM），且效果优于他泽美他汀。化合物N16诱导Pfeiffer细胞凋亡，使细胞周期阻滞在G1期。N16在指定浓度（1.85、3.70、7.40、14.8、29.60 nM）作用Pfeiffer细胞48 h后，Pfeiffer细胞处于G1期的比例分别从对照组的88.75%增加到85.2、96.61、92.04、93.35、91.05%。采用Western blotting方法检测化合物N16对H3K27甲基化的影响。结果显著表明，在高浓度条件下，化合物N16明显抑制Pfeiffer细胞中赖氨酸27对组蛋白H3 （H3K27me3）的三甲基化。我们的研究结果表明，N16是一种很有前景的EZH2抑制剂，需要进一步的研究来验证这些发现并促进N16的后续开发。

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引用次数: 0

Strategic approaches to the discovery of biologically active indole derivatives: a comprehensive review 发现生物活性吲哚衍生物的战略途径：全面回顾

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2025-12-25 DOI: 10.1016/j.bmc.2025.118541

Gui-Ping Gao , Quan-Ke Li , Jin-Cheng Ma , Zhi-Jun Zhang , Shao-Yong Zhang , Ying-Qian Liu

Indole, an aromatic heterocyclic compound formed by the fusion of a benzene ring with a pyrrole ring, is widely distributed in the secondary metabolites of plants, animals, and marine organisms. Owing to its unique physicochemical properties and high structural modifiability, indole derivatives can engage in specific interactions with various biological targets, demonstrating a broad spectrum of bioactivities including anticancer, anti-inflammatory, antiviral, and antibacterial effects. Consequently, indole holds an indispensable position in innovative drug discovery and development. This review provides a comprehensive summary of the primary strategies employed in the discovery of indole derivatives. These encompass structure optimization approaches inspired by natural products, such as structure simplification, diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), the “pseudo-natural product” (PNP) strategy, and bioinspired synthesis based on biosynthetic building blocks. Additionally, strategies like scaffold hopping, molecular hybridization, drug repurposing, and multicomponent reactions (MCRs) for constructing indole-based molecules are discussed. Particular emphasis is placed on target structure-based discovery strategies for indole derivatives, including ligand-based structure modification, molecular docking-assisted high-throughput virtual screening, and fragment-based drug design (FBDD). Furthermore, the application of emerging techniques such as phenotypic screening, DNA-encoded library (DEL) technology, and free energy perturbation (FEP) calculations in indole-based drug research and development is highlighted. This review aims to systematically organize the multi-dimensional R&D framework for indole derivatives, analyze the specific value of each strategy in addressing drug discovery challenges, and provide a theoretical foundation and methodological support for the rational design and development of novel indole-based drugs. It is anticipated that this work will further enhance the efficiency and innovation level in the development of this class of compounds.

吲哚是苯环与吡咯环融合形成的芳香杂环化合物，广泛存在于植物、动物和海洋生物的次生代谢产物中。吲哚衍生物由于其独特的物理化学性质和高度的结构可修饰性，可以与各种生物靶点进行特异性相互作用，显示出广泛的生物活性，包括抗癌、抗炎、抗病毒和抗菌作用。因此，吲哚在创新药物的发现和开发中占有不可或缺的地位。这篇综述提供了在发现吲哚衍生物中采用的主要策略的全面总结。这些方法包括受天然产物启发的结构优化方法，如结构简化、面向多样性的合成（DOS）、面向生物学的合成（BIOS）、“伪天然产物”（PNP）策略和基于生物合成构建块的生物启发合成。此外，还讨论了诸如支架跳跃、分子杂交、药物重新利用和多组分反应（mcr）等用于构建吲哚基分子的策略。特别强调的是吲哚衍生物的基于目标结构的发现策略，包括基于配体的结构修饰、分子对接辅助的高通量虚拟筛选和基于片段的药物设计（FBDD）。此外，还重点介绍了表型筛选、dna编码文库（DEL）技术和自由能微扰（FEP）计算等新兴技术在吲哚类药物研究和开发中的应用。本文旨在系统梳理吲哚衍生物的多维研发框架，分析每种策略在应对药物发现挑战方面的具体价值，为新型吲哚类药物的合理设计和开发提供理论基础和方法支持。预计本工作将进一步提高该类化合物开发的效率和创新水平。

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引用次数: 0

Regio- and Diastereoselective Arylation of rosin acids: A practical strategy for bioactive compounds discovery 松香酸的区域和非对映选择性芳基化：发现生物活性化合物的实用策略

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-09 DOI: 10.1016/j.bmc.2026.118554

Farked S. Wahoodi , Antonio Fernández , Juan Sainz , Fernando Rodríguez-Serrano , Fernando J. Reyes-Zurita , Rachid Chahboun

A mild, sustainable, and cost-effective arylation of rosin-acids is reported. This new approach, based on a regio- and diastereoselective Friedel-crafts alkylation, enabled the synthesis of fourteen new resin acid derivatives. Selected compounds were screened for cytotoxic activity against three human tumor cell lines. Remarkably, quinone 14 exhibited significant activity: Against HL-60 cells (IC₅₀ = 5.94 μM) cell, and phenol 11f displayed selective cytotoxic activity against HT-29 cells (IC₅₀ = 8.90 μM) cells. Flow cytometry confirmed apoptosis as the primary mechanism of cell death, reaching 78% in HL-60 (14) and 72.6% in HT-29 (11 g), with minimal necrosis. Cell-cycle analysis showed S-phase arrest in HL-60 (14) and G₀/G₁ arrest in HT-29 (11f/11 g). Consistently, ΔΨm assays showed near-complete collapse in HL-60 (14) and significant depolarization in HT-29 (11 g). In addition, the anti-inflammatory activity of some synthesized compounds was assessed in LPS-stimulated RAW 264.7 macrophages. All tested compounds achieved 70–100% NO inhibition at subcytotoxic concentrations. Derivatives 13 and 14 showed the highest activity (IC_{50 NO} = 0.85 μM and 5.43 μM, respectively). Overall, this green arylation approach enables rapid access to 7-aryl methyl ester dehydroabietic acid libraries with significant cytotoxic and anti-inflammatory activities

报道了一种温和、可持续、低成本的松香酸芳化反应。这种基于区域选择性和非对映选择性Friedel-crafts烷基化的新方法，使14种新的树脂酸衍生物得以合成。筛选了所选化合物对三种人肿瘤细胞系的细胞毒活性。值得注意的是，醌14表现出显著的活性：对HL-60细胞（IC₅₀= 5.94 μM）细胞，苯酚11f对HT-29细胞（IC₅₀= 8.90 μM）细胞表现出选择性的细胞毒性活性。流式细胞术证实细胞凋亡是细胞死亡的主要机制，HL-60（14）和HT-29 （11 g）的凋亡率分别为78%和72.6%，坏死较少。细胞周期分析显示HL-60的s期阻滞（14 g）和HT-29的G0/G1期阻滞（11 g /11 g）。一致地，ΔΨm实验显示HL-60（14）几乎完全崩溃，HT-29 （11 g）明显去极化。此外，我们在lps刺激的RAW 264.7巨噬细胞中评估了一些合成化合物的抗炎活性。所有测试的化合物在亚细胞毒性浓度下均达到70-100%的NO抑制。衍生物13和14的IC50 NO分别为0.85 μM和5.43 μM，活性最高。总的来说，这种绿色芳基化方法可以快速获得具有显著细胞毒性和抗炎活性的7-芳基甲酯脱氢枞酸文库

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引用次数: 0

Discovery and characterization of a high-affinity G-quadruplex binding peptide via mRNA display 通过mRNA展示发现并表征高亲和力g -四重体结合肽

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2025-12-27 DOI: 10.1016/j.bmc.2025.118543

Naka Kudo Ida , Yoshimasa Kawaguchi , Shiroh Futaki , Miki Imanishi

G-quadruplexes (G4s) are non-canonical secondary structures of nucleic acids that play crucial roles in gene expression, and their dysregulation has been implicated in various diseases. Therefore, development of G4-binding molecules, including peptides and proteins, is required to modulate G4-dependent biological processes for therapeutic purposes. In this study, a novel G4-binding peptide with high affinity for the G4 structure was developed using directed evolution based on mRNA display. The identified peptide, LP7, exhibited a preferential affinity for parallel G4 structures. Dimerization of LP7 significantly enhanced its binding to hTERC rG4 by approximately 70-fold, with a K_d of 7 nM. Analysis of the sequence-activity relationship revealed that both the basic and aromatic amino acid residues of the peptide are critical for its binding affinity to G4. Functional assays confirmed that LP7 inhibits reverse transcription in a G4-dependent manner by binding to the rG4 region. This study demonstrates the successful application of the mRNA display platform for discovering novel G4-binding peptides. A detailed characterization of LP7 provides valuable insights into the molecular interactions that govern G4 recognition. These findings highlight the potential of G4-binding peptides as tools for targeting and regulating G4-mediated gene functions, offering a promising avenue for the development of G4-dependent therapeutic strategies in the future.

g -四联体（G4s）是核酸的非规范二级结构，在基因表达中起着至关重要的作用，其失调与多种疾病有关。因此，需要开发g4结合分子，包括肽和蛋白质，来调节g4依赖的生物过程以达到治疗目的。本研究采用基于mRNA展示的定向进化方法，开发了一种与G4结构具有高亲和力的新型G4结合肽。所鉴定的肽LP7对平行G4结构表现出优先亲和力。LP7的二聚化使其与hTERC rG4的结合增强了约70倍，Kd为7 nM。序列-活性关系分析表明，该肽的碱性和芳香氨基酸残基对其与G4的结合亲和力至关重要。功能分析证实，LP7通过与rG4区域结合，以g4依赖的方式抑制逆转录。本研究证明了mRNA展示平台在发现新的g4结合肽方面的成功应用。LP7的详细表征为控制G4识别的分子相互作用提供了有价值的见解。这些发现突出了g4结合肽作为靶向和调节g4介导的基因功能的工具的潜力，为未来开发依赖g4的治疗策略提供了一条有希望的途径。

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引用次数: 0

Thiazolidinedione-based dual inhibitors of α-amylase and aldose reductase: Design, in vitro evaluation, and in vivo hypoglycemic activity 以噻唑烷二酮为基础的α-淀粉酶和醛糖还原酶双重抑制剂：设计、体外评价和体内降糖活性。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-16 DOI: 10.1016/j.bmc.2026.118569

Mohammad M. Al-Sanea , Mohamed R. Elnagar , Ahmed A.B. Mohamed , Hamed W. El-Shafey , Lamiaa O. El-Halaby , Samar S. Tawfik , Susi Zara , Marwa Balaha , Abdullah A. Elgazar , Syed N.A. Bukhari , Abdelrahman Hamdi

This study reports the design, synthesis, and biological evaluation of thiazolidinedione (TZD) derivatives as dual inhibitors of α-amylase (α-AMY) and aldose reductase (AR) for potential use in the management of diabetes mellitus. Using a structure-based design strategy, the epalrestat scaffold was modified by introducing a TZD core with either an N-ethyl urea or N-acetamide linker and various benzylidene substituents. Two series of compounds (8a–g and 9a–g) were synthesized and characterized. In vitro assays showed that several derivatives exhibited dual inhibitory activity. Compound 9a, containing an N-acetamide linker and a 4-fluorobenzylidene group, inhibited AR (IC₅₀ = 117.6 nM) and α-AMY (IC₅₀ = 2.2 μM), with lower IC₅₀ values than epalrestat (127 nM) and acarbose (15 μM), respectively. Structure–activity relationship analysis indicated that the N-acetamide linker favored AR inhibition, whereas the N-ethyl urea linker was more favorable for α-AMY inhibition. Kinetic studies showed that 9a inhibits AR non-competitively and α-AMY via a mixed-type mechanism. Molecular docking suggested that 9a binds to an allosteric site in AR and the catalytic pocket of α-AMY. In a streptozotocin-induced diabetic mouse model, 9a reduced blood glucose levels by 68.4% at a dose of 50 mg/kg. These results suggest that 9a could serve as a starting point for further development of multi-target antidiabetic agents.

本研究报道了噻唑烷二酮（TZD）衍生物作为α-淀粉酶（α-AMY）和醛糖还原酶（AR）的双重抑制剂在糖尿病治疗中的潜在应用的设计、合成和生物学评价。采用基于结构的设计策略，通过引入带有n -乙基尿素或n -乙酰胺连接剂和各种苄基取代基的TZD核心来修饰依帕司他支架。合成了8a-g和9a-g两个系列化合物并对其进行了表征。体外实验表明，几种衍生物具有双重抑制活性。化合物9a含有n -乙酰胺连接剂和4-氟乙基，抑制AR （IC₅₀= 117.6 nM）和α-AMY (IC₅₀= 2.2 μM)， IC₅₀值分别低于依帕司他（127 nM）和阿卡波糖（15 μM）。构效关系分析表明，n -乙酰胺连接物更有利于抑制AR，而n -乙基尿素连接物更有利于抑制α-AMY。动力学研究表明，9a通过混合型机制抑制AR和α-AMY。分子对接表明，9a结合了AR中的一个变构位点和α-AMY的催化袋。在链脲佐菌素诱导的糖尿病小鼠模型中，9a在50mg /kg剂量下使血糖水平降低68.4%。这些结果表明，9a可以作为进一步开发多靶点降糖药的起点。

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引用次数: 0

Synthesis and evaluation of 5-phenoxylmethyl-1,3,4-oxadiazol-2-ones/oxadiazole-2-thiones as potent urease inhibitors 高效脲酶抑制剂5-苯氧基甲基-1,3,4-恶二唑-2-酮/恶二唑-2-硫酮的合成与评价。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-17 DOI: 10.1016/j.bmc.2026.118567

Meng-Jing Xiao , Yi-Ning Wang , Liang-Chao Yuan , Yao Zeng , Zi-Wei Wu , Yun-Qi Zhang , Zhu-Ping Xiao , Hai-Liang Zhu

A serial of oxadiazol-2-ones/oxadiazole-2-thiones were designed, synthesized and evaluated as urease inhibitors. Out of these compounds, oxadiazole-2-thiones showed excellent inhibition against urease with twenty-two showing higher potency than the clinical used drug AHA. It is emphasized that 1,3,4-oxadiazole-2-thiones containing 3-propylphenoxy (d34) and 3-nitrophenoxy (d46) on the side chain were the two most active compounds. They were demonstrated having 230- and 360-fold higher potency than AHA and inhibiting urease with a mixed mechanism.

设计、合成了一系列的恶二唑-2-酮/恶二唑-2-硫酮作为脲酶抑制剂，并对其性能进行了评价。在这些化合物中，恶二唑-2-硫酮对脲酶表现出良好的抑制作用，其中22种化合物的效力高于临床使用的药物AHA。在侧链上含有3-丙基苯氧基（d34）和3-硝基苯氧基（d46）的1,3,4-恶二唑-2-硫酮是活性最高的两种化合物。它们被证明具有比AHA和抑制脲酶的混合机制高230倍和360倍的效力。

引用次数: 0

Discovery of the thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors 噻吩[2,3-b][1,4]噻嗪-2(3H)- 1型STING抑制剂的发现。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-16 DOI: 10.1016/j.bmc.2026.118571

Lu Han , Shumin Zang , Wenxin Li , Hangtian Yue , Xiaoqian Zhou , Jie Chen , Meiyu Geng , Wenhu Duan , Zuoquan Xie , Zhengsheng Zhan

The adaptor molecule STING is embedded in the endoplasmic reticulum (ER) membrane. In innate immunity, STING is a critical cascade in regulating the cytoplasmic DNA-recognizing signaling. Aberrant STING signaling facilitates the host body to secrete an intolerable level of inflammatory cytokines as well as interferons, causing interferonopathies including STING-associated infantile vasculopathy, familial chilblain lupus, and amyotrophic lateral sclerosis. Suppressing the disordered STING signaling has demonstrated to ameliorate the inflammatory impairments of interferonopathy diseases. In this article, we provide the discovery of thieno[2,3-b][1,4]thiazin-2(3H)-one STING inhibitors. Through the structure-activity relationship (SAR) exploration, we identified compound 11 h as an oral-available STING inhibitor possessing cellular mouse- or human-STING inhibiting IC₅₀ of 8.8 or 11.5 nM. Compound 11 h markedly hindered the cellular STING cascade in both murine- and human-derived cells. Furthermore, 11 h achieved robust in vivo activity opposing MAS-2-caused systemic inflammatory damage and cisplatin-caused renal inflammation and injury. Proposed binding model of 11 h-STING indicates that 11 h engages the transmembrane area of STING.

适配分子STING嵌入内质网（ER）膜中。在先天免疫中，STING是调控细胞质dna识别信号的关键级联。异常的STING信号使宿主机体分泌难以忍受的炎症细胞因子和干扰素，导致STING相关的婴儿血管病变、家族性冻疮狼疮和肌萎缩性侧索硬化症等干扰素病变。抑制紊乱的STING信号传导已被证明可以改善干扰素病变的炎症损伤。在这篇文章中，我们提供了thieno[2,3-b][1,4]thiazin-2(3H)-one STING抑制剂的发现。通过构效关系（SAR）探索，我们确定化合物11h是一种口服STING抑制剂，对小鼠或人细胞的STING抑制IC50分别为8.8或11.5 nM。化合物11h在小鼠和人源性细胞中均能明显抑制细胞STING级联反应。此外，11 h在体内具有抗mas -2引起的全身炎症损伤和顺铂引起的肾脏炎症和损伤的强大活性。提出的11h -STING结合模型表明，11h结合了STING的跨膜区域。

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引用次数: 0

Bio-responsive self-assembled nanoparticles of fatty acid prodrugs of sulfapyridine for the management of Rheumatoid arthritis 磺胺吡啶脂肪酸前药的生物反应性自组装纳米颗粒治疗类风湿关节炎

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-04-01 Epub Date: 2026-01-25 DOI: 10.1016/j.bmc.2026.118577

Pooja Rani , Monica Gulati , Bhupinder Kapoor

Despite significant advancements in medical research, the treatment of rheumatoid arthritis (RA) is still challenging due to limitations associated with the conventional therapies, which include low tissue specificity, poor retention within inflamed joints, and systemic toxicity. Sulfapyridine (SP), a second-line drug for the management of RA, has low solubility and permeability, classifying is as a BCS class IV drug. To overcome these limitations, SP was chemically conjugated with fatty acid (FA) side chains to make amphiphilic prodrugs that formed nanostructures on self-assembly in aqueous milieu. Among the synthesized prodrugs, heptanoyl and oleoyl derivates i.e., SP-Hept and SP-Ole were selected as lead candidates for further pharmacological evaluation due to their favorable self-assembly behaviour and physicochemical properties. Both prodrugs spontaneously formed uniform sized spherical nanoparticles (NPs) with high colloidal stability, which was better maintained under refrigerated storage. In vitro cytotoxicity studies using L929 fibroblast cells demonstrated reduced toxicity for the prodrugs compared to the parent drug. Controlled and selective release of SP was confirmed via pH- and enzyme-responsive hydrolysis in chemical buffers, human plasma, synovial fluid, and simulated synovial fluid (SSF)., notably, SP-Hept showed greater sensitivity to acidic conditions and esterase activity, whereas SP-Ole was preferentially cleaved by collagenase. In a complete Freund's adjuvant (CFA)-induced rat arthritis models, treatment with these NPs significantly alleviated paw swelling and joint inflammation by downregulating inflammatory mediators. Histological and radiographic analyses confirmed preservation of joint architecture and cartilage integrity, while hematological and biochemical parameters were restored toward normal levels. Overall, these findings highlight the potential of SP-Hept and SP-Ole NPs as a precisely tunable, localized drug delivery platform for improved RA management.

尽管医学研究取得了重大进展，但类风湿关节炎（RA）的治疗仍然具有挑战性，这是由于传统疗法的局限性，包括低组织特异性、炎症关节内潴留不良和全身毒性。磺胺吡啶（Sulfapyridine， SP）是治疗类风湿性关节炎的二线药物，其溶解度和渗透性较低，属于BCS IV类药物。为了克服这些限制，SP与脂肪酸（FA）侧链化学偶联，制成两亲性前药，在水环境中通过自组装形成纳米结构。在合成的前体药物中，由于其良好的自组装行为和理化性质，选择庚烷基和油基衍生物SP-Hept和SP-Ole作为进一步药理评价的主要候选药物。两种前药均能自发形成粒径均匀的球形纳米颗粒（NPs），具有较高的胶体稳定性，在冷藏条件下能更好地保持胶体稳定性。使用L929成纤维细胞进行的体外细胞毒性研究表明，与母体药物相比，前药的毒性降低。通过化学缓冲液、人血浆、滑液和模拟滑液（SSF）的pH和酶响应水解，证实了SP的可控和选择性释放。值得注意的是，SP-Hept对酸性条件和酯酶活性表现出更大的敏感性，而SP-Ole优先被胶原酶裂解。在完全的弗氏佐剂（CFA）诱导的大鼠关节炎模型中，用这些NPs治疗通过下调炎症介质显著减轻足跖肿胀和关节炎症。组织学和放射学分析证实了关节结构和软骨完整性的保存，而血液学和生化参数恢复到正常水平。总的来说，这些发现突出了SP-Hept和SP-Ole np作为一种精确可调的局部给药平台的潜力，可以改善RA的管理。

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