Bioorganic & Medicinal Chemistry最新文献_第3页

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 : 2026-01-09 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

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 : 2026-01-06 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

Structure-activity relationship study of a new class of 2-amino-3,4-dihydroquinazolines as antitubercular agents 一类新型抗结核药物- 2-氨基-3,4-二氢喹唑啉的构效关系研究。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-05 DOI: 10.1016/j.bmc.2026.118549

Lena Trifonov, Helena I. Boshoff, Jose Santinni O. Roma, Yixuan Fan, He Eun Forbes, Clifton E. Barry III, Sangmi Oh

The discovery of novel chemical matter with antitubercular activity that could feed into the tuberculosis (TB) drug discovery pipeline addresses the need to develop novel drugs that inhibit growth of both drug sensitive and drug resistant strains of Mycobacterium tuberculosis (Mtb). Whole cell-based screening yielded a 2-amino-3,4-dihydroquinazoline core as a novel hit and preliminary structure-activity relationship (SAR) study around the structure was performed with 16 analogs derivatized in diverse structural points to determine the pharmacophore. The promising antitubercular activity of L16, the lead compound of this series was shown to be non-toxic to eukaryotic cells and had a novel mechanism of action since it lacked activity against known promiscuous targets of the pathogen. Additionally, L16 retained activity against different drug-resistant clinical strains. Although the MIC was improved significantly without any cytotoxicity, flat SAR, no identifiable target and equivalent activities of the two stereoisomers of the hit compound led us to abandon further optimization of this series.

具有抗结核活性的新型化学物质的发现可能会进入结核病（TB）药物发现管道，这解决了开发抑制结核分枝杆菌（Mtb）药敏和耐药菌株生长的新型药物的需求。基于全细胞筛选得到了一个新的2-氨基-3,4-二氢喹唑啉核心，并围绕该结构进行了初步的构效关系（SAR）研究，在不同的结构点衍生了16个类似物，以确定药效团。该系列的先导化合物L16具有良好的抗结核活性，对真核细胞无毒，并具有新的作用机制，因为它对已知的混杂靶点缺乏活性。此外，L16对不同的耐药临床菌株保持活性。虽然在没有细胞毒性的情况下，MIC得到了明显的改善，但由于没有可识别的靶点，并且命中化合物的两个立体异构体的活性相当，因此我们放弃了对该系列的进一步优化。

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引用次数: 0

Design, synthesis and biological evaluation of novel quinolinone derivatives as DprE1 inhibitors against Mycobacterium tuberculosis 新型喹诺啉酮衍生物抗结核分枝杆菌DprE1抑制剂的设计、合成及生物学评价。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-05 DOI: 10.1016/j.bmc.2026.118551

Guoquan Wan , Chao Gao , Fei Teng , Qifan Tang , Jumei Zeng , Luoting Yu

Tuberculosis remains a global health crisis, exacerbated by the emergence of drug-resistant strains and limitations of current therapies. Aiming to the essential enzyme DprE1 in Mycobacterium tuberculosis, we designed and synthesized 34 novel quinolinone derivatives as non-covalent inhibitors. Among them, compound 27 demonstrated remarkable activity against Mtb H37Ra, with an MIC value of 0.2 ng/mL, and displayed low cytotoxicity against A549 cells. Further resistance profiling and molecular docking studies confirmed DprE1 as the primary target of the compounds, with the Y314H mutation being responsible for the development of resistance. These findings highlighted compound 27 as a suitable lead for developing novel and effective DprE1 inhibitors.

结核病仍然是一场全球健康危机，耐药菌株的出现和目前治疗方法的局限性加剧了这一危机。针对结核分枝杆菌必需酶DprE1，设计合成了34种新型喹诺啉酮衍生物作为非共价抑制剂。其中化合物27对Mtb H37Ra具有显著的抑制作用，MIC值为0.2 ng/mL，对A549细胞具有较低的细胞毒性。进一步的耐药性分析和分子对接研究证实，DprE1是这些化合物的主要靶点，Y314H突变是产生耐药性的原因。这些发现突出了化合物27是开发新型有效的DprE1抑制剂的合适先导物。

引用次数: 0

Novel 7-Substituted-1,2,4-Triazolopyrimidines targeting Nav1.2 channels as low-neurotoxicity antiepileptic agents 新型靶向Nav1.2通道的7-取代-1,2,4-三唑嘧啶类低神经毒性抗癫痫药物

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-05 DOI: 10.1016/j.bmc.2026.118550

Yuxi Zhou , Weina Wang , Cui Lv , Jiaqi Wu , Shuo Lv , Luqian He , Xinyu Zhao , Xi Qin , Binbin Tian , Renhao Chen , Chuanlong Guo , Longjiang Huang , Haibo Yu

In pursuit of novel antiepileptic agents with improved safety profiles, a series of novel 7-substituted-[1,2,4]triazolo[1,5-a]pyrimidine derivatives were synthesized and evaluated for antiepileptic activity using the subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock seizure (MES) models in vivo. Compound 6c showed significant antiepileptic effects in the MES model, with an ED₅₀ value of 13.70 mg/kg. Its TD₅₀ was greater than 261.85 mg/kg, yielding a protective index (PI) >19.11. The antiepileptic efficacy of 6c surpassed that of the reference drugs phenytoin and valproate. Notably, 6c exhibited no neurotoxicity at its maximum soluble concentration, indicating a favorable safety profile. Docking and molecular dynamics (MD) simulations revealed stable binding of 6c within the cavity of the Nav1.2 subunit (PDB: 6J8E). Further electrophysiological evaluation demonstrated state-dependent blockade of Nav1.2 channels: at 10 μM, compound 6c inhibited the inactivated state by 65 ± 18 % (n = 3), with dose-dependent inhibition characterized by an IC₅₀ value of 5.39 ± 0.81 μM (n = 5). These results suggest that compound 6c is a promising lead candidate for the development of novel antiepileptic agents with high efficacy and low neurotoxicity. Preliminary in vitro assessment in rat liver microsomes indicated moderate metabolic stability for 6c, supporting its potential for further development.

为了寻找具有更高安全性的新型抗癫痫药物，我们合成了一系列新的7-取代-[1,2,4]三唑[1,5-a]嘧啶衍生物，并通过皮下戊四唑（Sc-PTZ）和最大电击发作（MES）体内模型评估了它们的抗癫痫活性。化合物6c在MES模型中显示出显着的抗癫痫作用，ED₅0值为13.70 mg/kg。其TD₅0大于261.85 mg/kg，产生保护指数（PI） >19.11。6c的抗癫痫效果优于苯妥英和丙戊酸。值得注意的是，6c在其最大可溶性浓度下没有神经毒性，表明其具有良好的安全性。对接和分子动力学（MD）模拟显示6c在Nav1.2亚基（PDB: 6J8E）的空腔内稳定结合。进一步的电生理评估证实了对Nav1.2通道的状态依赖阻断：在10 μM时，化合物6c抑制了65±18% （n = 3）的失活状态，其抑制作用的剂量依赖于IC₅0值为5.39±0.81 μM （n = 5）。这些结果表明，化合物6c是一种具有高效、低神经毒性的新型抗癫痫药物。在大鼠肝微粒体中的初步体外评估表明，6c具有中等代谢稳定性，支持其进一步开发的潜力。

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引用次数: 0

AI-aided virtual screening and biological evaluation for discovering new potential poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors 人工智能辅助虚拟筛选和生物学评价发现新的潜在的聚（adp -核糖）聚合酶-1 （PARP-1）抑制剂

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-05 DOI: 10.1016/j.bmc.2026.118548

Xiaofeng Chen, Enyuan Zhang, Pan Wang, Lifeng Ning

Poly (ADP-ribose) polymerase-1 (PARP-1) is a key DNA repair enzyme targeted in cancer therapy. We developed an AI-assisted virtual screening workflow combining RG-MPNN for shape-based screening and PIGNet for docking rescoring to identify novel PARP1 inhibitors from an 18-million compound library. Five hits showed nanomolar activity, with Hit 1 exhibiting 8.03 nM IC₅₀ and a novel tricyclic scaffold. Comprehensive validation confirmed PARP1 inhibition, selective cytotoxicity in BRCA1-deficient cells, and favorable drug-like properties. Hit 1 represents a promising candidate for further development.

聚（adp -核糖）聚合酶-1 （PARP-1）是肿瘤治疗中的关键DNA修复酶。我们开发了一种人工智能辅助的虚拟筛选工作流程，结合RG-MPNN进行基于形状的筛选和PIGNet进行对接评分，从1800万个化合物库中识别出新的PARP1抑制剂。五个Hit显示出纳米摩尔活性，Hit 1显示出8.03 nM IC₅0和一个新的三环支架。综合验证证实了PARP1的抑制作用，brca1缺陷细胞的选择性细胞毒性，以及良好的药物样特性。Hit 1代表了进一步开发的有希望的候选产品。

引用次数: 0

Targeting HPK1 for cancer immunotherapy: An update on recent medicinal chemistry advances 靶向HPK1用于癌症免疫治疗：最新药物化学进展

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-04 DOI: 10.1016/j.bmc.2026.118546

Yiyun Song , Zepeng Liao , Xiang Ni , Dexiang Wang, Zhihao Qi, Qi Miao, Sheng Jiang, Kuojun Zhang

Hematopoietic progenitor kinase 1 (HPK1), a pivotal negative regulator of immune signaling pathways, represents an attractive therapeutic target for cancer immunotherapy. Supported by encouraging preliminary clinical data showing promising efficacy and manageable safety profiles in clinical trials, the rapid development of structurally diverse small-molecule HPK1 inhibitors continues. However, achieving high selectivity for HPK1 remains challenging due to significant sequence homology among the related kinase family. Emerging evidence also implicates HPK1's non-catalytic scaffolding function in tumor immune regulation, complicating traditional inhibition strategies. Notably, PROteolysis-TArgeting Chimeras (PROTAC) technology offers distinct advantages for targeting HPK1, driving significant momentum in the development of novel HPK1 PROTACs. This article provides a comprehensive update on recent advances in HPK1-targeted therapeutics, highlighting key progress in the evolution of structurally distinct small-molecule HPK1 inhibitors with improved selectivity, ADME and safety profiles, the development and pharmacological outcomes of HPK1-targeted PROTACs, as well as translational progress of clinical-stage candidates. Finally, we discuss future perspectives and challenges in this rapidly evolving field.

造血祖激酶1 （HPK1）是免疫信号通路的关键负调节因子，是癌症免疫治疗的一个有吸引力的治疗靶点。令人鼓舞的初步临床数据显示，在临床试验中有希望的疗效和可管理的安全性，结构多样的小分子HPK1抑制剂的快速发展仍在继续。然而，由于相关激酶家族之间具有显著的序列同源性，实现HPK1的高选择性仍然具有挑战性。新出现的证据也暗示HPK1在肿瘤免疫调节中的非催化支架功能，使传统的抑制策略复杂化。值得注意的是，PROteolysis-TArgeting Chimeras （PROTAC）技术为靶向HPK1提供了明显的优势，推动了新型HPK1 PROTACs的发展。本文全面介绍了HPK1靶向治疗的最新进展，重点介绍了结构独特的小分子HPK1抑制剂的发展进展，这些小分子HPK1抑制剂具有更高的选择性、ADME和安全性，HPK1靶向PROTACs的开发和药理学结果，以及临床阶段候选药物的转化进展。最后，我们讨论了这一快速发展领域的未来前景和挑战。

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引用次数: 0

Carboxylesterase 1d-mediated aglycone recognition is crucial for substrate processing and allosteric activation of endo-α-mannosidase in the endoplasmic reticulum 羧酸酯酶1介导的苷元识别对于内质网底物加工和内切α-甘露糖苷酶的变构激活至关重要

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.bmc.2026.118547

Akito Taira , Taiki Kuribara , Mitsuaki Hirose , Kiichiro Totani

Most nascent glycoproteins entering the endoplasmic reticulum (ER) undergo quality control via the calnexin/calreticulin (CNX/CRT) cycle, wherein Glc₁Man₉GlcNAc₂ (G1M9)-type glycans play a crucial role in monitoring protein folding. We have recently identified an endo-α-mannosidase activity within the ER, designated as ER-EM, which facilitates the release of misfolded glycoproteins from this cycle by converting G1M9-proteins into Man_8AGlcNAc₂ (M8A)-proteins in a single step. ER-EM appears to function as a complex comprising UDP-Glc:glycoprotein glucosyltransferase 1 (UGGT1), ERp57, and carboxylesterase 1D (Ces1d), although the role of Ces1d—primarily recognized for its involvement in lipid metabolism—in glycan-associated substrate recognition remains unclear. To elucidate the molecular basis of Ces1d-dependent recognition, we semi-synthesized a glycoprobe, G1M9-va-JW972, by conjugating the Ces1d-specific inhibitor JW972 to the aglycone of G1M9 using a linker via a click reaction. In the ER-EM reaction with this probe, M8A-va-piperidine was detected as an ER-EM product with the aglycone structural conversion via Ces1d-mediated hydrolysis of the JW972 moiety, demonstrating recognition of the substrate aglycone by the Ces1d component of ER-EM complex. Inhibition of the lipolysis site of Ces1d with WWL229 significantly reduced ER-EM activity, indicating that this site is essential for recognizing hydrophobic aglycones. Furthermore, the inactive substrate GlcMan-4MU was efficiently hydrolyzed in the presence of the Ces1d lipolysis site-specific inhibitor WWL229, demonstrating that the association of the hydrophobic compound WWL229 with the Ces1d lipolysis site contributes to allosteric activation of ER-EM. Our findings provide important insights into the functional regulation of ER-EM complex, a novel therapeutic target for protein misfolding diseases.

大多数进入内质网（ER）的新生糖蛋白通过calnexin/calreticulin （CNX/CRT）循环进行质量控制，其中Glc1Man9GlcNAc2 （G1M9）型聚糖在监测蛋白质折叠中起关键作用。我们最近在内质网中发现了一种内切α-甘露糖苷酶活性，称为ER- em，它通过将g1m9蛋白转化为Man8AGlcNAc2 （M8A）蛋白，从而促进错误折叠的糖蛋白从这个循环中释放出来。ER-EM似乎是由UDP-Glc、糖蛋白葡萄糖基转移酶1 （UGGT1）、ERp57和羧酸酯酶1D （Ces1d）组成的复合物，尽管Ces1d（主要被认为参与脂质代谢）在聚糖相关底物识别中的作用尚不清楚。为了阐明ces1d依赖性识别的分子基础，我们通过点击反应将ces1d特异性抑制剂JW972偶联到G1M9的苷元上，半合成了糖探针G1M9-va-JW972。在用该探针进行的ER-EM反应中，通过Ces1d介导的JW972部分的水解，检测到M8A-va-piperidine作为ER-EM产物与糖元结构转化，表明ER-EM配合物的Ces1d组分识别底物糖元。WWL229抑制Ces1d的脂解位点可显著降低ER-EM活性，表明该位点对识别疏水苷元至关重要。此外，无活性底物GlcMan-4MU在Ces1d脂肪分解位点特异性抑制剂WWL229的存在下被有效水解，这表明疏水化合物WWL229与Ces1d脂肪分解位点的结合有助于ER-EM的变构激活。我们的研究结果为ER-EM复合物的功能调控提供了重要的见解，ER-EM复合物是蛋白质错误折叠疾病的新治疗靶点。

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引用次数: 0

Synthesis and evaluation of novel 4-thiazolidinone-5-nitrofuran hybrids as promising antimicrobial agents 新型4-噻唑烷酮-5-硝基呋喃杂合物的合成与评价。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.bmc.2026.118545

Volodymyr Horishny , Dmytro Mural , Iryna Kovalenko , Nataliya Finiuk , Iryna Ivasechko , Yulian Konechnyi , Iryna Tymchuk , Stepan Nedzelskyi , Yuliia Kozak , Tetyana Rumynska , Krzysztof Niemczuk , Monika Szymańska-Czerwińska , Victoriya Georgiyants , Rostyslav Stoika , Roman Lesyk , Serhii Holota

Searching for new effective small molecules targeting resistant strains of microorganisms is an emerging task for modern medicinal chemistry. Taking into account potential antimicrobial features of 4-thiazolidinone and 5-nitrofurane pharmacophores, two series of hybrid molecules were synthesized based on 5-nitrofuran-2-carbaldehyde, bioisosteric (E)-3-(5-nitrofuran-2-yl)acrylaldehyde, and structure-modified 4-thiazolidinone scaffolds. For all synthesized compounds, antimicrobial activity screening and cytotoxicity evaluation were performed. Novel highly active hybrid molecules with a low level of toxicity were identified, showing high broad-spectrum activity towards Gram-positive and Gram-negative bacteria, fungi, in particular Staphylococcus aureus, Klebsiella pneumoniae, Corynebacterium diphtheriae, and Aspergillus niger. A preliminary SAR analysis was performed, and key structural features that influence the manifestation of antimicrobial activity were highlighted. The obtained results will contribute to the rational design of novel agents of this pharmacological profile among 4-thiazolidinone-5-nitrofuran hybrids and related heterocyclic molecules.

寻找新的有效的小分子靶向微生物耐药菌株是现代药物化学的一个新兴任务。考虑到4-噻唑烷酮和5-硝基呋喃药效团潜在的抗菌特性，以5-硝基呋喃-2-醛、生物等构(E)-3-（5-硝基呋喃-2-基）丙烯醛和结构修饰的4-噻唑烷酮为支架，合成了两个系列的杂化分子。对所有合成的化合物进行抗菌活性筛选和细胞毒性评价。鉴定出具有低毒性的新型高活性杂交分子，对革兰氏阳性和革兰氏阴性细菌、真菌，特别是金黄色葡萄球菌、肺炎克雷伯菌、白喉链杆菌和黑曲霉具有高广谱活性。进行了初步的SAR分析，并强调了影响抗菌活性表现的关键结构特征。所得结果将有助于在4-噻唑烷酮-5-硝基呋喃杂环及相关杂环分子中合理设计具有这种药理特征的新型药物。

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引用次数: 0

Computationally guided design of N4-(2-methyl-2H-indazol-6-yl)-N2-phenylpyrimidine-2,4-diamine inhibitors of EGFR kinase targeting Cys797 N4-（2-甲基- 2h -茚唑-6-基）- n2 -苯基嘧啶-2,4-二胺EGFR激酶抑制剂靶向Cys797的计算指导设计

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.bmc.2025.118544

Adchata Konsue , Duangkamol Gleeson , Kiattawee Choowongkomon , Donald J.L. Jones , Pimkhuan Hannanta-anan , Robert G. Britton , M. Paul Gleeson

The epidermal growth factor receptor kinase (EGFR) is a tyrosine kinase (TK) implicated in the uncontrolled growth of non-small cell lung cancer. EGFR-TK inhibitors have been used extensively, however inhibitor resistance often develops leading to disease progression. In this work, we report the computationally guided design and preparation of novel covalent 2,4-diaminopyrimidine EGFR-TK inhibitors, inspired by Osimertinib. Molecular dynamics simulations and quantum mechanical (QM) calculations were performed on novel designs incorporating a 2-methyl-2H-indazol-6-amine at the 4-position of pyrimidine as well as various linkers and electrophiles. Calculations suggested swapping the 5-pyrimidine H atom for Cl would lead to a preferential “out” ligand conformation that favored T790M enzyme which was later confirmed experimentally. Compound 19 was the most potent inhibitor of WT EGFR (3.0 nM) observed, more potent than the EGFR WT inhibitor Erlotinib (5.9 nM). Compounds 48 and 49 demonstrated better activity for the double-mutant EGFR (3.0 & 2.0 nM, respectively) than Osimertinib (12.8 nM). The selectivity of these compounds for the DM was found to be comparable to Osimertinib (∼20 fold) while their phosphate buffer solubilities were > 50-fold better than both marketed drugs. Kinetic evaluation of 48 (propenamide moiety) vs 49 (acrylamide electrophile) confirms k_inact/K_i values consistent with a covalent mode of action for the latter, but not the former.

表皮生长因子受体激酶（EGFR）是一种酪氨酸激酶（TK），与非小细胞肺癌不受控制的生长有关。EGFR-TK抑制剂已被广泛使用，但抑制剂的耐药往往导致疾病进展。在这项工作中，我们报告了受奥西替尼启发的新型共价2,4-二氨基嘧啶EGFR-TK抑制剂的计算指导设计和制备。分子动力学模拟和量子力学（QM）计算的新设计纳入了2-甲基- 2h -吲哚-6-胺在嘧啶的4位，以及各种连接剂和亲电试剂。计算表明，将5-嘧啶H原子交换为Cl原子将导致优先的“out”配体构象，这有利于T790M酶，后来实验证实了这一点。化合物19是观察到的最有效的WT EGFR抑制剂（3.0 nM），比EGFR WT抑制剂厄洛替尼（5.9 nM）更有效。化合物48和49对双突变EGFR的活性（分别为3.0和2.0 nM）优于奥西替尼（12.8 nM）。发现这些化合物对糖尿病的选择性与奥西替尼相当（约20倍），而它们的磷酸盐缓冲液溶解度比两种上市药物好50倍。对48（丙烯酰胺部分）和49（丙烯酰胺亲电试剂）的动力学评价证实了后者的kinact/Ki值与共价作用模式一致，而不是前者爱思唯尔有限公司版权所有。

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引用次数: 0