Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Identification of hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of potential antibacterial agents","authors":"Xing Lu ,&nbsp;Shao-Lin Zhang ,&nbsp;Cheng-He Zhou","doi":"10.1016/j.bmcl.2025.130258","DOIUrl":"10.1016/j.bmcl.2025.130258","url":null,"abstract":"<div><div>Unique hydroxyphenyl cyanovinyl thiazoles (HCTs) as new structural scaffolds of potential antibacterial agents were developed to overcome global increasingly serious drug resistance. Some synthesized HCTs could suppress the growth of the tested strains, especially, benzothiophenyl HCT <strong>5c</strong> exhibited superior anti-<em>Escherichia coli</em> activity with a lower MIC of 0.5 μg/mL to norfloxacin (MIC = 1 μg/mL). The active benzothiophenyl HCT <strong>5c</strong> displayed no obvious hemolysis, low cytotoxicity and a much lower trend for the development of drug-resistance than norfloxacin. Further exploration revealed that benzothiophenyl HCT <strong>5c</strong> could intercalate to DNA to form a DNA–<strong>5c</strong> complex, which disturbed the biological functions to facilitate bacterial death. ADME analysis indicated that compound <strong>5c</strong> possessed favorable druggability and promising pharmacokinetic properties. This work provided an insight into further developing hydroxyphenyl cyanovinyl thiazoles as new structural scaffold of promising antibacterial candidates.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130258"},"PeriodicalIF":2.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and evaluation of a fluorescent PI3K inhibitor as a dual-function agent toward Cancer Theranostics","authors":"Ge Shi ,&nbsp;Hua Tian ,&nbsp;Shiji Chu ,&nbsp;Dan Liu ,&nbsp;Zheng Yan ,&nbsp;Min Yang ,&nbsp;Heng Xu","doi":"10.1016/j.bmcl.2025.130255","DOIUrl":"10.1016/j.bmcl.2025.130255","url":null,"abstract":"<div><div>The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound <strong>1</strong>) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. <strong>1</strong> demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that <strong>1</strong> effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and <em>in vivo</em> imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130255"},"PeriodicalIF":2.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of novel sulfanilamide derivatives as aminopeptidase N inhibitors","authors":"Hong Zhu ,&nbsp;Xiaoyan Zhang ,&nbsp;Baojun Zhang ,&nbsp;Chunhua Ma","doi":"10.1016/j.bmcl.2025.130257","DOIUrl":"10.1016/j.bmcl.2025.130257","url":null,"abstract":"<div><div>Guided by the structural architecture of the aminopeptidase N (APN) active site, we designed and synthesized a series of novel APN inhibitors featuring sulfanilamide scaffold coupled with hydroxamate zinc-binding motifs. Among the series, compound <strong>2k</strong> exhibited the inhibitory activity (IC₅₀ = 4.3 μM) as effectively as a positive control drug Bestatin. Notably, our compounds exhibited pronounced selectivity against zinc-dependent metallopeptidase MMP-2. The SAR research indicated that ortho-disubstitution in the phenyl group could lead to an order of magnitude improvement. A molecular docking study validated the novel binding mode of compound <strong>2k</strong>. The predicted ADME properties highlighted the improved hydrophilicity, cell permeability, and human oral absorption of <strong>2k</strong> than that of bestatin. These results validated simultaneously occupying S1’ and S2’ pockets as a viable design strategy for discovering APN inhibitors with a non-canonical binding modality. We anticipate that compound <strong>2k</strong> with high selectivity will be harnessed as a structurally distinctive probe candidate to investigate the pathophysiological roles of APN in tumor angiogenesis and metastasis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130257"},"PeriodicalIF":2.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antibacterial activity of 3-(arylazo)indoles and related azoheterocycles","authors":"Carson W. King ,&nbsp;Puppala Sathish ,&nbsp;Danielle N. Turner ,&nbsp;Arben Zejnelovski ,&nbsp;Vincent T. Do ,&nbsp;Robert Rubiano ,&nbsp;David Schilter ,&nbsp;Todd W. Hudnall ,&nbsp;Snezna Rogelj ,&nbsp;Alexander Kornienko","doi":"10.1016/j.bmcl.2025.130256","DOIUrl":"10.1016/j.bmcl.2025.130256","url":null,"abstract":"<div><div>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) is a major cause of hospitalizations and mortality from bacterial infections and is considered a national priority for disease control. In this work we synthesized and evaluated twenty novel C-3 arylazo-coupled indoles and one 4-arylazo-benzo[<em>d</em>]imidazole. The substituents on the C3-aromatic moiety included alkyl, halogen, amino, alkoxy, alkylsulfonyl at positions <em>ortho</em>, <em>meta</em> and <em>para</em>. The indoles utilized were 4-bromo, 5,6-methylenedioxy, 7-aza. In this effort, several azo-indoles showed promising anti-MRSA activities with MIC values as low as 3 μM. Another important finding of this work that sets that stage for a further larger investigation is that 4-arylazo-benzo[<em>d</em>]imidazole is a previously unexplored scaffold with potent anti-MRSA activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130256"},"PeriodicalIF":2.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoquinocycline B induces G0/G1 cell cycle arrest and apoptosis in MDA-MB-231 cancer cells","authors":"Gyeong Han Jeong ,&nbsp;Hanui Lee ,&nbsp;Ja Young Cho ,&nbsp;Jung-Rae Rho ,&nbsp;Byung Yeoup Chung ,&nbsp;Sanghwa Park ,&nbsp;Hyoung-Woo Bai","doi":"10.1016/j.bmcl.2025.130244","DOIUrl":"10.1016/j.bmcl.2025.130244","url":null,"abstract":"<div><div>Breast cancer remains one of the leading causes of cancer-related deaths, with therapeutic resistance and limited treatment options posing significant challenges. This study investigated the anticancer properties of isoquinocycline B (IQCB), an anthraquinone derivative obtained from a freshwater sponge microbiome <em>Micromonospora</em> sp. MS-62 (FBCC-B8445), against the MDA-MB-231 human breast cancer cell line. IQCB showed the greatest activity against cytotoxicity with an IC₅₀ values of 9.2 ± 1.0 μM. IQCB treatment led to G0/G1 cell cycle arrest and apoptosis through mitochondrial pathways by suppressing cyclin D1/CDK4 expression, enhancing p27 levels, and reducing phosphorylated Akt levels. Furthermore, IQCB induced oxidative stress by promoting excessive reactive oxygen species (ROS) production, thereby activating JNK and p38-MAPK signaling while simultaneously inhibiting ERK phosphorylation. Apoptotic markers such as PARP cleavage and caspase-3 activation confirmed that mitochondrial-mediated apoptosis was a key mechanism of action. These results highlight the potential of IQCB as a therapeutic candidate for breast cancer and underscore the need for further research to explore its efficacy and mechanisms.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130244"},"PeriodicalIF":2.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mini review: SHEN26, a novel oral antiviral drug for COVID-19 treatment","authors":"Peisen Zheng ,&nbsp;Guanguan Li ,&nbsp;Yuanguang Chen ,&nbsp;Shuo Li ,&nbsp;Sidi Yang ,&nbsp;Deyin Guo ,&nbsp;Qifan Zhou ,&nbsp;Xumu Zhang","doi":"10.1016/j.bmcl.2025.130243","DOIUrl":"10.1016/j.bmcl.2025.130243","url":null,"abstract":"<div><div>Over two years into the pandemic, global collaboration led to effective antiviral drugs targeting SARS-CoV-2's RdRp and 3CL protease. However, the virus continues to evolve, and certain low-virulence variants still circulate. Despite reduced virulence, ongoing transmission raises the risk of new mutations, underscoring the need for continued vigilance, research, and expansion of our antiviral and vaccine strategies. Our research team has developed SHEN26, a promising small-molecule antiviral drug for the treatment of COVID-19. This mini-review explores its development, including history, synthesis, preclinical evaluations, and findings from Phase I and II clinical trials. Data from each research phase further underscores SHEN26's potential as a safe and effective oral antiviral treatment for COVID-19, while also emphasizing its broader relevance in combating emerging RNA viral infections.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130243"},"PeriodicalIF":2.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological evaluation as antimalarial of two families of biscationic compounds featuring two different sulphur linkers","authors":"Pilar M. Luque Navarro ,&nbsp;M. Paz Carrasco-Jiménez ,&nbsp;Emilio Parisini ,&nbsp;Daniela Lanari ,&nbsp;Laura M. Odina ,&nbsp;Atis Jekabsons ,&nbsp;Sonia Perales ,&nbsp;Diana Zelencova-Gopejenko ,&nbsp;Guiomar Pérez-Moreno ,&nbsp;Cristina Bosch-Navarrete ,&nbsp;Dolores González-Pacanowska ,&nbsp;Luisa Carlota López-Cara","doi":"10.1016/j.bmcl.2025.130241","DOIUrl":"10.1016/j.bmcl.2025.130241","url":null,"abstract":"<div><div><em>Plasmodium falciparum</em> kinases have been widely studied due to their potential as targets for the discovery of alternatives to artemisinin-combined therapies. Their role in parasite blood-stage replication and their homology with human kinases has led to the exploitation of already tested antitumoral kinase inhibitors as antiplasmodial drugs. <em>Plasmodium falciparum</em> choline kinase (<em>Pf</em>CK), a cytosolic enzyme involved in phospholipid synthesis, is a promising target for parasite resistant strains. <em>Pf</em>CK uses the host choline and catalyzes its transformation in phosphocholine, a key step for the formation of the lipid membranes required by the new parasite progeny inside the erythrocyte. Previously, we described the synthesis of two libraries (<strong>PL</strong> and <strong>FP</strong>) of human choline kinase (hCK) inhibitors, which we generated following a <em>green by design</em> approach. Some of these compounds were found to exhibit antitumoral properties. Here, we evaluated the same compounds as potential inhibitors of <em>Pf</em>CK and antimalarial agents. Interestingly, while the compounds of the <strong>FP</strong> library, which feature a disulphide linker, show <em>Pf</em>CK inhibition in the nM range independently of the cationic head (<strong>FP3</strong> being the most active compound, <em>Pf</em>CK IC₅₀ = 0.16 μM), they show no effect on infected erythrocytes. On the other hand, the compounds of the <strong>PL</strong> library, which feature a dithioethane linker, show in vitro activity against the parasite but no inhibitory activity against the isolated enzyme (<strong>PL40</strong> exhibits the highest antimalarial activity, with IC₅₀ = 10 nM). This lack of correlation could be due to either cellular disulphide degradation in vitro or to the existence of alternative targets for the dithioethane library. Considering the previously reported anticancer potential of the <strong>PL</strong> family and the antiparasitic activity reported herein, these compounds may be considered as good starting points for the development of multifunctional drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130241"},"PeriodicalIF":2.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of 2,4-diaminopyrimidine inhibitors of hematopoietic progenitor kinase 1","authors":"Chunting Li ,&nbsp;Jiuyu Liu ,&nbsp;Le Ren ,&nbsp;Long Zhang ,&nbsp;Na Zhang ,&nbsp;Shaoxuan Yan ,&nbsp;Yu Wang ,&nbsp;Siyu Fu ,&nbsp;Jiakuan Wei ,&nbsp;Hao Yue ,&nbsp;Yongshuo Wu ,&nbsp;Minghui Tong ,&nbsp;Xuan Shi ,&nbsp;Han Wang ,&nbsp;Dong Zhao ,&nbsp;Qingfeng Shao ,&nbsp;Yuanle Zhang ,&nbsp;Yanfang Zhao ,&nbsp;Yunlei Hou","doi":"10.1016/j.bmcl.2025.130242","DOIUrl":"10.1016/j.bmcl.2025.130242","url":null,"abstract":"<div><div>Cancer immunotherapy is an emerging anti-cancer strategy that enhances immune circulation by targeting the immune system. Among the various targets, HPK1, a member of the mammalian Ste20-like protein serine/threonine kinase family, serves as a crucial negative regulator of immune-mediated mechanisms, positioning it as a promising target for immunotherapy. Herein, based on the reported HPK1 inhibitors characterized by 2,4-diaminopyrimidine components, four series of derivatives were obtained through structural optimization methods. Compound <strong>10c</strong> demonstrates significant inhibitory effects on HPK1 kinase, with an IC₅₀ of 0.09 nM. Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC₅₀ of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC₅₀ of 84.24 nM. These findings suggest that compound <strong>10c</strong> holds considerable promise for applications in immunotherapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130242"},"PeriodicalIF":2.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer","authors":"Mengrong Lei ,&nbsp;Hanxue Huang ,&nbsp;Jiayi Li ,&nbsp;Jinlin Zhang ,&nbsp;Geng Yu ,&nbsp;Xin Jin ,&nbsp;Junyan Liu ,&nbsp;Fenghua Kang ,&nbsp;Zhaoqian Liu","doi":"10.1016/j.bmcl.2025.130240","DOIUrl":"10.1016/j.bmcl.2025.130240","url":null,"abstract":"<div><div>A series of hybrids (<strong>8a-h</strong> and <strong>11a-h</strong>) containing 2,4-diphenylpyrimidine scaffold and coumarin moiety were designed and synthesized as novel focal adhesion kinase (FAK) inhibitors for the intervention of non-small-cell lung cancer (NSCLC). Most compounds effectively suppressed the proliferative of NSCLC cells, and compound <strong>8a</strong> was identified as the most active compound with IC₅₀ value of 0.28 μM in H1299 cells, superior to TAE226 (IC₅₀ = 2.28 μM). In addition, <strong>8a</strong> was also found to inhibit the invasion and migration of NSCLC cells. Furthermore, <strong>8a</strong> exhibited potent kinase inhibitory activity of FAK (IC₅₀ = 4.968 nM) with a considerable selectivity profile against various kinase families, subsequently resulting in cell cycle arrest, apoptosis- inducing as well as the decrease of MMP-2 and MMP-9 expression in H1299 cells dose-dependently. Moreover, <strong>8a</strong> was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, <strong>8a</strong> may be a promising candidate for the treatment of NSCLC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130240"},"PeriodicalIF":2.5,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of diastereomeric natural products: Discovery of a novel synergistic combination for α-glucosidase inhibition","authors":"Thang M. Le ,&nbsp;Huyen N. Nguyen ,&nbsp;Ngoc T. Vu ,&nbsp;Phong Q. Le","doi":"10.1016/j.bmcl.2025.130239","DOIUrl":"10.1016/j.bmcl.2025.130239","url":null,"abstract":"<div><div>Cabraleahydroxylactone (<strong>1a</strong>) and 3-epi-cabraleahydroxylactone (<strong>1b</strong>) are naturally diastereomers found in <em>Aglaia abbreviata</em>, known for their biological potential. While <strong>1b</strong> has been synthesized and studied as an anti-diabetic agent, the activity of <strong>1a</strong> remained unexplored. This study successfully enhanced <strong>1a</strong> in the reaction mixture through the reduction of cabralealactone (<strong>2</strong>), increasing its ratio from trace levels to 9.5:1 (<strong>1b</strong>:<strong>1a</strong>). Molecular docking revealed distinct binding interactions of these diastereomers with α-glucosidase allosteric sites, suggesting a drug synergy mechanism. Kinetic studies confirmed non-competitive inhibition by both compounds, with <strong>1a</strong> exhibiting superior binding affinity (lower Ki). Synergistic α-glucosidase inhibition was observed in specific <strong>1b</strong>:<strong>1a</strong> ratios (9:1, 8:2, 2:8, and 1:9). Furthermore, these combinations displayed reduced hemolytic toxicity compared to individual compounds. The findings highlight the <strong>1b</strong>:<strong>1a</strong> diastereomeric combination as a promising lead for anti-diabetic drug development, offering enhanced efficacy and safety through synergistic interactions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130239"},"PeriodicalIF":2.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}