Bioorganic & Medicinal Chemistry最新文献_第5页

Novel PROTACs with polyhedral alkanes as linkers for enhanced ALK degradation in drug-resistant NSCLC 以多面体烷烃为连接体的新型PROTACs可增强耐药NSCLC中ALK的降解

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-16 DOI: 10.1016/j.bmc.2025.118521

Dongchen Chu , Huijie Han , Chaochun Wei , Xiaokun Zhang , Hong Yan , Juan Wang

The challenge of overcoming drug-resistant mutations in Anaplastic Lymphoma Kinase (ALK), a critical driver of non-small cell lung cancer (NSCLC), remains a pressing clinical concern. This study introduces a novel approach by using polyhedral alkanes as linkers in PROTAC (Proteolysis Targeting Chimera) technology to address resistance mechanisms. Unlike conventional chain-like or planar linkers, five novel ALK-targeting PROTACs (BL-1-BL-5) featuring structurally unique polyhedral alkanes (cubane, homocubane, adamantane, D₃-trihomocubane and norbornene) were designed and synthesized through innovative HAPOD trail and organic synthesis methodologies. Comprehensive in vitro evaluations revealed remarkable antiproliferative activity across all derivatives, with BL-5 (norbornene as linker) demonstrating exceptional potency (IC₅₀ = 36.21 nM) against H3122 cells, surpassing both reference SIAIS164018 (BB-1, IC₅₀ = 78.93 nM) and Brigatinib (IC₅₀ = 44.83 nM). Western blot assay confirmed that BL-5 effectively degraded ALK at 100 nM concentration while effectively inhibiting ALK phosphorylation. Notably, BL-5 exhibited superior efficacy against Ba/F3 cells with the ALK G1202R resistance mutation (IC₅₀ = 118.86 nM) compared to BB-1 (IC₅₀ = 126.41 nM). MD simulations provided critical insights, revealing that the BL-1, BL-4 and BL-5 significantly enhanced the ternary complex stability compared to traditional linkers. These findings establish the polyhedral alkanes as novel linkers in PROTAC design, with BL-5 emerging as a particularly promising candidate for targeting ALK.

间变性淋巴瘤激酶（ALK）是非小细胞肺癌（NSCLC）的一个关键驱动因素，克服其耐药突变的挑战仍然是一个迫切的临床问题。本研究介绍了一种利用多面体烷烃作为连接体的PROTAC （Proteolysis Targeting Chimera）技术来研究耐药机制的新方法。与传统的链状或平面连接剂不同，通过创新的HAPOD实验和有机合成方法，设计并合成了五种新型的alk靶向PROTACs (BL-1-BL-5)，它们具有独特的结构多面体烷烃（立方烷、均立方烷、adamantane、d3 -三立方烷和降冰片烯）。全面的体外评估显示，所有衍生物都具有显着的抗增殖活性，其中BL-5（降木片烯作为连接剂）对H3122细胞表现出卓越的效力（IC₅₀= 36.21 nM），超过参考物SIAIS164018 （BB-1, IC₅₀= 78.93 nM）和Brigatinib （IC₅₀= 44.83 nM）。Western blot实验证实，BL-5在100 nM浓度下能有效降解ALK，同时能有效抑制ALK磷酸化。值得注意的是，与BB-1 （IC₅₀= 126.41 nM）相比，BL-5对具有ALK G1202R抗性突变（IC50 = 118.86 nM）的Ba/F3细胞表现出优越的功效。MD模拟提供了重要的见解，揭示了与传统连接剂相比，BL-1、BL-4和BL-5显著提高了三元配合物的稳定性。这些发现确定了多面体烷烃是PROTAC设计中的新型连接物，其中BL-5是靶向ALK的特别有前途的候选者。

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引用次数: 0

Synthesis and biological evaluation of novel C1 or C3 amino derivatives of A-ring 1,2,3-trisubstituted 19-nor-vitamin D3 a环1,2,3-三取代19-非维生素D3新型C1或C3氨基衍生物的合成及生物学评价。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-14 DOI: 10.1016/j.bmc.2025.118523

Tania González-García , Lieve Verlinden , Stefanie Doms , Annemieke Verstuyf , Susana Fernández , Miguel Ferrero

Two new analogs of 1α,25-dihydroxy-19-nor-vitamin D₃ with an additional hydroxyl group at position 2 and an amino group at C1 or C3 using quinic acid as starting substrate for the A-ring precursor are described. Key step was the deprotection of the N-benzyl group mediated by an efficient biocatalytic system of Laccase from Trametes versicolor together with TEMPO. The synthesized analogs did not exhibit any significant affinity for binding to either the VDR or hDBP when compared to the natural hormone and 1α,25-dihydroxy-19-nor-vitamin D₃. In terms of their antiproliferative activity in MCF-7 and HL-60 cells, the reported influence of the hydroxyl group at C1 on biological activity of vitamin D analogs is observed. The 1α,2α-dihydroxy-3α-amino derivative was most active than 1β-Amino-2β,25-dihydroxy-19-nor-vitamin D₃, exhibiting an antiproliferative activity in breast cancer MCF-7 cells at a concentration of 10⁻⁶ M comparable with 1α,25-(OH)₂-D₃ and 1α,25-(OH)₂–19-nor-D₃, but this compound was five times less potent than the natural hormone at the EC₅₀ concentration.

本文描述了两个新的1α，25-二羟基-19-非维生素D3的类似物，它们在2位有一个羟基，在C1或C3有一个氨基，使用奎宁酸作为a环前体的起始底物。关键步骤是利用花衣曲菌漆酶的高效生物催化系统和TEMPO对n -苄基进行脱保护。与天然激素和1α，25-二羟基-19-非维生素D3相比，合成的类似物与VDR或hDBP的结合没有明显的亲和力。就其在MCF-7和HL-60细胞中的抗增殖活性而言，已报道的C1羟基对维生素D类似物生物活性的影响被观察到。1α，2α-二羟基-3α-氨基衍生物比1β- 2β，25-二羟基-19-no -维生素D3活性最高，在10-6 M浓度下对乳腺癌MCF-7细胞的抗增殖活性与1α，25-(OH)2-D3和1α，25-(OH)2-19-no -D3相当，但在EC50浓度下，该化合物的效力比天然激素低5倍。

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引用次数: 0

Sequence-dependent RNA cleavage by the 8–17 DNAzyme: Identification of preferred tetranucleotide motifs 8-17 DNAzyme的序列依赖性RNA切割：优选四核苷酸基序的鉴定

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-14 DOI: 10.1016/j.bmc.2025.118520

Satoko Nakajima , Shuhei Miyakawa , Shu Ohno , Haruki Ikemoto , Rikuto Maruyama , Kosuke Chiba , Ryota Suginaka , Chihiro Oda , Yuuya Kasahara , Kaori Fukuzawa , Satoshi Obika , Takao Yamaguchi

In recent years, deoxyribozymes (DNAzymes) capable of catalyzing RNA cleavage have attracted growing attention for their potential therapeutic applications. Among these, the 8–17 DNAzyme is one of the most extensively studied motifs, owing to its compact catalytic core and robust catalytic activity. Although it is well established that the 8–17 DNAzyme preferentially cleaves GG and AG (5′ → 3′) dinucleotide junctions within substrate RNA strands, the influence of flanking nucleotides on catalytic efficiency has not been systematically examined. Here, we comprehensively evaluated the tetranucleotide sequence preferences of the 8–17 DNAzyme. By assessing cleavage efficiencies across diverse tetranucleotide contexts in which the scissile phosphodiester bond lies between the second and third ribonucleosides, we identified three motifs—UGGG, UGGU, and UGGA—that were cleaved with markedly enhanced efficiency. Molecular dynamics and quantum chemical calculations suggested that stable formation of the noncanonical rG12·dA24 base pair in the UGGG motif facilitates a cleavage-competent structure, whereas this base pair is relatively disrupted in the GGGG motif, a less cleavable sequence. This sequence preference was further validated using 8–17 DNAzymes targeting mouse coagulation factor XI (FXI) mRNA. Collectively, these findings reveal a practical sequence preference of the 8–17 DNAzyme and provide a rational framework for designing highly active DNAzyme-based therapeutics.

近年来，能够催化RNA裂解的脱氧核酶（DNAzymes）因其潜在的治疗应用而受到越来越多的关注。其中，8-17 DNAzyme是研究最广泛的基序之一，因为它具有紧凑的催化核心和强大的催化活性。虽然已经确定8-17 DNAzyme优先切割底物RNA链内的GG和AG（5 ‘→3 ’）二核苷酸连接，但侧翼核苷酸对催化效率的影响尚未得到系统的研究。在这里，我们综合评估了8-17 DNAzyme的四核苷酸序列偏好。通过评估不同四核苷酸背景下的裂解效率，其中可剪切的磷酸二酯键位于第二和第三核糖核苷之间，我们确定了三个基序：uggg、UGGU和uggg，它们的裂解效率显著提高。分子动力学和量子化学计算表明，ugg基序中非规范rG12·dA24碱基对的稳定形成有利于切割，而GGGG基序中非规范rG12·dA24碱基对的断裂程度较低。使用靶向小鼠凝血因子XI (FXI) mRNA的8-17 DNAzymes进一步验证了这种序列偏好。总的来说，这些发现揭示了8-17 DNAzyme的实际序列偏好，并为设计高活性DNAzyme治疗提供了合理的框架。

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引用次数: 0

The development of anti-HIV agents targeting APOBEC3G/Vif axis 靶向APOBEC3G/Vif轴的抗hiv药物的研制

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-11 DOI: 10.1016/j.bmc.2025.118519

Qiqi Bao , Jiajia Wen , Fengjiao Xiang , Ling Ma , Jiwei Ding , Xinlu Wang , Shan Cen , Jinming Zhou

The human host restriction factor APOBEC3G (Apolipoprotein B mRNA editing enzyme-catalytic polypeptide-like 3G, A3G) potently inhibits the replication of human immunodeficiency virus type 1 (HIV-1). To counteract this restriction, HIV-1 encodes the viral infectivity factor (Vif), which mediates the degradation of A3G and thereby abrogates A3G's antiviral activity. Previously, we identified IMB-301 via virtual screening coupled with biological validation, which protects A3G from Vif-induced degradation through binding specifically to A3G, thereby preserving A3G's deaminase activity to suppress HIV-1 replication. Herein, we performed structural optimization of IMB-301, yielding a library of 64 analogs. Most of these analogs retained HIV-1 inhibitory activity, with several exhibiting significantly enhanced potency relative to IMB-301. Further investigations demonstrated that these active analogs block the Vif-A3G interaction, restore intracellular A3G levels, and ultimately inhibit HIV-1 proliferation in an A3G-dependent manner. Collectively, this work highlights a promising avenue for the development of novel anti-HIV-1 therapeutic strategies and candidate molecules.

人宿主限制性因子APOBEC3G（载脂蛋白B mRNA编辑酶催化多肽样3G， A3G）能有效抑制人类免疫缺陷病毒1型（HIV-1）的复制。为了抵消这种限制，HIV-1编码病毒感染因子（Vif），该因子介导A3G的降解，从而消除A3G的抗病毒活性。之前，我们通过虚拟筛选和生物学验证鉴定了IMB-301，它通过与A3G特异性结合，保护A3G免受vif诱导的降解，从而保持A3G的脱氨酶活性，抑制HIV-1复制。在此，我们对IMB-301进行了结构优化，得到了64个类似物的库。这些类似物中的大多数保留了HIV-1抑制活性，其中一些表现出相对于IMB-301显著增强的效力。进一步的研究表明，这些活性类似物阻断Vif-A3G相互作用，恢复细胞内A3G水平，最终以A3G依赖的方式抑制HIV-1的增殖。总的来说，这项工作为开发新的抗hiv -1治疗策略和候选分子提供了一条有希望的途径。

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引用次数: 0

Corrigendum to “Redox-cleavable disulfide linker enhances siRNA delivery by prodrug-type bifunctional cell-penetrating peptide” [Bioorg. Med. Chem. 130 (2025) 118383] “氧化还原可切割的二硫连接体通过前药型双功能细胞穿透肽增强siRNA递送”的更正[Bioorg]。医学化学，130(2025)118383]。

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-10 DOI: 10.1016/j.bmc.2025.118513

Keita Wakamori, Yuzuki Hashikawa, Hidehito Urata, Shun-ichi Wada

引用次数: 0

Design, synthesis, and biological evaluation of quinazoline–benzohydrazide and quinazoline–benzothiazole hybrids uncovering a dual EGFR/VEGFR-2 inhibitor with pronounced cytotoxic activity against triple-negative breast Cancer 喹唑啉-苯并肼和喹唑啉-苯并噻唑复合物的设计、合成和生物学评价，揭示了一种对三阴性乳腺癌具有明显细胞毒活性的EGFR/VEGFR-2双重抑制剂

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-06 DOI: 10.1016/j.bmc.2025.118515

Noura F.M. El Hamaky , Abdelrahman Hamdi , Waleed A. Bayoumi , Abdullah A. Elgazar , Magda N.A. Nasr

Novel series of quinazoline–benzohydrazide 7a–f and quinazoline–benzothiazole 10a–f hybrids were designed and synthesized as potential dual-target inhibitors of EGFR and VEGFR-2. Their anti-proliferative activity was assessed against HeLa, HepG2, MCF-7 and HCT116 cancer cell lines. Among the tested compounds, 7a demonstrated the most potent activity, with IC₅₀ values ranging from 3.98 to 9.67 μM, comparable with doxorubicin. Most derivatives showed minimal cytotoxicity toward normal WI-38 fibroblasts, indicating a favorable selectivity profile. Notably, compound 7a exerted significant cytotoxic effect against triple-negative breast cancer (TNBC) MDA-MB-231 cells (IC₅₀ = 7.33 μM), approaching the activity of doxorubicin (IC₅₀ = 2.22 μM). It also markedly inhibited EGFR and VEGFR-2 with IC₅₀ values of 1.67 and 6.72 μM, compared to Erlotinib and Sorafenib, respectively. Flow cytometric analysis revealed that 7a induced cell cycle arrest at the G0/G1 phase (85.11 %) and promoted apoptosis (29.49 %). Apoptotic profiling further indicated a substantial upregulation of pro-apoptotic Bax (11.73-fold) and downregulation of anti-apoptotic Bcl-2 (0.23-fold), resulting in a striking increase in the Bax/Bcl-2 ratio (51:1). Additionally, 7a increased the expression levels of caspase-3 and caspase-9 by approximately 7.55- and 5.76-fold, respectively, compared to control/ MDA-MB-231 cells. Molecular docking studies confirmed the strong binding affinity of 7a within the active sites of both EGFR and VEGFR-2, supporting its proposed mechanism of action. These findings position compound 7a as a promising lead for further development as a dual EGFR/VEGFR-2-targeting anticancer agent, particularly for aggressive cancers such as TNBC.

设计并合成了一系列新的喹唑啉-苯并肼7a-f和喹唑啉-苯并噻唑10a-f复合物，作为潜在的EGFR和VEGFR-2双靶点抑制剂。测定了它们对HeLa、HepG2、MCF-7和HCT116癌细胞的抗增殖活性。在所测试的化合物中，7a表现出最有效的活性，IC₅0值范围为3.98至9.67 μM，与阿霉素相当。大多数衍生物对正常的WI-38成纤维细胞显示最小的细胞毒性，表明良好的选择性。值得注意的是，化合物7a对三阴性乳腺癌（TNBC） MDA-MB-231细胞（IC₅₀= 7.33 μM）具有显着的细胞毒作用，接近阿霉素（IC₅₀= 2.22 μM）的活性。与厄洛替尼和索拉非尼相比，它还显着抑制EGFR和VEGFR-2， IC₅0值分别为1.67和6.72 μM。流式细胞分析显示，7a诱导细胞周期阻滞于G0/G1期（85.11%），促进细胞凋亡（29.49%）。凋亡谱进一步表明，促凋亡Bax显著上调（11.73倍），抗凋亡Bcl-2显著下调（0.23倍），导致Bax/Bcl-2比值显著升高（51:1）。此外，与对照/ MDA-MB-231细胞相比，7a使caspase-3和caspase-9的表达水平分别提高了约7.55倍和5.76倍。分子对接研究证实了7a在EGFR和VEGFR-2活性位点的强结合亲和力，支持了其提出的作用机制。这些发现使得化合物7a有望成为进一步开发的EGFR/ vegfr -2双重靶向抗癌药物，特别是针对侵袭性癌症，如TNBC。

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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 : 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

Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids 天然稀缺大戟二萜类化合物的仿生半合成、结构优化及抗hiv活性研究

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-05 DOI: 10.1016/j.bmc.2025.118516

Wei Cheng , Peng Wen , Pei-Yin Song , Yang Zhang , Jin-Bu Xu , Steven De Jonghe , Dominique Schols , Feng Gao

Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce Euphorbia diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare Euphorbia diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the Euphorbia diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester 2t showed the best anti-HIV-1 activity, with an EC₅₀ of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.

基于天然稀缺骨架构建结构多样的化合物文库是天然产物药物化学研究的关键挑战。在这项研究中，通过仿生骨架转换策略，实现了三种天然稀缺的大戟二萜（包括5/7/7/4大戟酮，6/11/3 lathyranones和5/11整合烯）的结构多样化，产生了72种罕见的大戟二萜类类似物，并研究了它们作为HIV复制的潜在抑制剂。大戟拉松型酯类具有较强的抗hiv活性，是大戟二萜类化合物中最有前途的一类抗hiv药物。构效关系分析表明，大胡拉松支架C6羟基是增强抗hiv效力的关键位置，其中芳香酯对增强抗hiv效力尤为有利。其中，大eupholathone酯2t的抗hiv -1活性最高，EC50为1.51 μM，选择性指数大于66.2，表明其具有进一步开发抗病毒药物的潜力。

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引用次数: 0

Broad-spectrum anti-influenza activity of the NMPA-approved drug Pamiparib is uncovered by virtual docking to the evolutionarily conserved domain of IAV-M2 protein 通过虚拟对接IAV-M2蛋白的进化保守结构域，揭示了nmpa批准的药物Pamiparib的广谱抗流感活性

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-05 DOI: 10.1016/j.bmc.2025.118518

Min Chen , Huifang Jiao , Dandan Lu , Wenhuan Chen , Zhen Yang , Xue Liang , Pengcheng Wei , Kunpeng Liu

Influenza viruses generate new strains or subtypes through antigenic drift and antigenic shift, leading to the failure of existing antiviral drugs and potentially causing widespread viral infection and influenza epidemics. However, during evolution, certain influenza virus proteins remain unchanged or undergo only minor mutations. Therefore, drugs targeting these evolutionarily conserved viral protein regions may exhibit broad-spectrum antiviral activity across subtypes and against mutations. The purpose of this study is to target the evolutionarily conserved domain of influenza A virus M2 protein and screen for drugs with cross-strain, mutation-resistant, and broad-spectrum antiviral activity. This study used AlphaFold3 to predict the M2 conserved domain structure and employed AutoDock to perform virtual screening of the NMPA database, identifying seven potential candidate drugs. Molecular dynamics simulations indicated that pamiparib exhibits strong affinity for the M2 conserved domain. It demonstrates excellent physiological activity in vitro in inhibiting the replication of H1N1 replication, while showing no effect on other viruses. CETSA experiments confirmed that pamiparib has the potential to bind to the M2 proteins of various influenza virus subtypes. In addition, pamiparib suppresses effectively viral infection in vivo. Ultimately, this study verifies that antiviral drugs designed to target the evolutionarily conserved regions of the influenza virus M2 protein indeed possess broad-spectrum antiviral activity across different strains.

流感病毒通过抗原漂移和抗原转移产生新的毒株或亚型，导致现有抗病毒药物失效，并可能引起广泛的病毒感染和流感流行。然而，在进化过程中，某些流感病毒蛋白保持不变或只发生轻微突变。因此，靶向这些进化上保守的病毒蛋白区域的药物可能在亚型和突变中表现出广谱抗病毒活性。本研究旨在针对甲型流感病毒M2蛋白的进化保守结构域，筛选具有跨株、抗突变和广谱抗病毒活性的药物。本研究使用AlphaFold3预测M2保守结构域结构，并使用AutoDock对NMPA数据库进行虚拟筛选，鉴定出7种潜在的候选药物。分子动力学模拟表明pamiparib对M2保守结构域具有较强的亲和力。在体外对H1N1病毒的复制有良好的抑制作用，而对其他病毒无抑制作用。CETSA实验证实帕米帕尼有可能与各种流感病毒亚型的M2蛋白结合。此外，帕米帕尼还能有效抑制体内病毒感染。最终，本研究验证了针对流感病毒M2蛋白进化保守区域设计的抗病毒药物确实在不同菌株中具有广谱抗病毒活性。

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引用次数: 0

Design, synthesis, and biological evaluation of a focused pyrrolo- and pyrido-quinazolinone natural products-templated library for anti-fungal and anthelmintic activities 吡咯和吡啶喹唑啉酮天然产物模板库的设计、合成和生物学评价

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-12-05 DOI: 10.1016/j.bmc.2025.118517

Romina E. D'Almeida , Paulina Chen , Yanchang Huang , Emily Goetz , Vamshikrishna Reddy Sammeta , Bo Yang , Reeta P. Rao , Sivappa Rasapalli , Mostafa A. Elfawal

A focused pyrrolo- and pyrido-quinazoline natural products-templated library has been designed and synthesized using two novel synthetic approaches: an aza-Nazarov approach and a Dieckmann cyclization strategy. This privileged scaffold-based collection was screened against pathogenic fungi and parasitic helminths. Three compounds (23b, 25a, 13f) emerged as potent inhibitors of Candida auris adhesion, each causing more than 50 % inhibition at 10 μM, and two compounds (13k, 14h) displayed strong anthelmintic activity, demonstrating 7- to 28-fold enhanced activity against human hookworms relative to albendazole. These molecules represent promising leads for the design and synthesis of focused quinazolinone analogs to support SAR driven optimization against C. auris or helminth pathogens. Ongoing efforts aim to refine these bioactive leads by improving their pharmacokinetic and activity profiles through targeted structural modifications.

采用aza-Nazarov法和Dieckmann环化策略，设计并合成了一种聚焦吡咯和吡啶-喹唑啉天然产物模板库。这种特殊的基于支架的收集对病原真菌和寄生蠕虫进行了筛选。3个化合物（23b, 25a, 13f）是耳念珠菌粘附的有效抑制剂，在10 μM下均有50%以上的抑制作用，2个化合物（13k, 14h）表现出很强的驱虫活性，对人钩虫的活性比阿苯达唑增强7- 28倍。这些分子为设计和合成聚焦喹唑啉酮类似物提供了有希望的线索，以支持SAR驱动的针对金黄色葡萄球菌或蠕虫病原体的优化。正在进行的工作旨在通过有针对性的结构修饰来改善这些生物活性先导物的药代动力学和活性概况。

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引用次数: 0