Bioorganic & Medicinal Chemistry Letters最新文献_第6页

A convenient approach for generating dimeric nucleic acid dyes via click-chemistry 通过点击化学生成二聚核酸染料的便捷方法。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-30 DOI: 10.1016/j.bmcl.2024.130013

Guorui Li , Guanghua Liu , Yawen Ruan , Chaoshui Liu , Xingnan Lian , Yangli Zheng

{"title":"A convenient approach for generating dimeric nucleic acid dyes via click-chemistry","authors":"Guorui Li , Guanghua Liu , Yawen Ruan , Chaoshui Liu , Xingnan Lian , Yangli Zheng","doi":"10.1016/j.bmcl.2024.130013","DOIUrl":"10.1016/j.bmcl.2024.130013","url":null,"abstract":"<div><div>Fluorescent dyes are essential tools for visualizing DNA and RNA. Dimeric dyes like GelGreen have gained popularity as safer alternatives to ethidium bromide (EB) due to their reduced mutagenicity and genotoxicity. In this study, we present a straightforward method to synthesize novel acridine orange (AO)-based dimeric dyes using click chemistry. Starting from acridine orange, these dyes can be synthesized in just two steps. Compared to GelGreen, these new dyes incorporate additional triazole groups in their linkers. They exhibit a maximum absorption wavelength of approximately 472 nm, which shifts to around 503 nm upon binding with DNA, allowing excitation by blue light. These dyes show minimal fluorescence in aqueous solutions, indicating that they adopt a closed conformation where the fluorescence of acridine orange is quenched due to intramolecular aggregation. The presence of DNA significantly enhances their fluorescence at around 526 nm, suggesting that DNA binding induces an open conformation. This “light-up” property makes them highly sensitive DNA dyes with a strong signal-to-noise ratio. We successfully applied these novel dyes in agarose gel electrophoresis, where they demonstrated excellent performance.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130013"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563478","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}

引用次数: 0

Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor 发现并评估 HW161023 作为一种强效口服活性 AAK1 抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-30 DOI: 10.1016/j.bmcl.2024.130012

Jinping Li , Yang Li , Lifei Liu , Wen Jiang , Yimin Jia , Jun Yang , Lie Li , Xuejun Zhang , Jiangtao Su , Shivansh Kaushik

引用次数: 0

Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants 含[1,2,5]噁二唑并[3,4-b]吡嗪的可乐定佐剂的扩展结构-活性关系研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI: 10.1016/j.bmcl.2024.130008

Susan L. Harris, Somnath Dutta, Nianzi Liu, Tilmann Wollenberg, Xiang Wang

{"title":"Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants","authors":"Susan L. Harris, Somnath Dutta, Nianzi Liu, Tilmann Wollenberg, Xiang Wang","doi":"10.1016/j.bmcl.2024.130008","DOIUrl":"10.1016/j.bmcl.2024.130008","url":null,"abstract":"<div><div>Antimicrobial resistance (AMR) is a formidable global health challenge. Multidrug-resistant (MDR) Gram-negative bacterial infections are of primary concern due to diminishing treatment options and high morbidity and mortality. Colistin, a polymyxin family antibiotic, is a last-resort treatment for MDR Gram-negative infections, but its wider use has resulted in escalating resistance. In 2022, using a screening approach, we discovered that a [1,2,5]oxadiazolo[3,4-<em>b</em>]pyrazine (ODP)-containing compound selectively re-sensitized various MDR Gram-negative bacteria to colistin. Initial structure–activity relationship (SAR) studies confirmed that bisanilino ODP compounds are colistin adjuvants with low mammalian toxicity. Herein, we report our extended SAR studies on a wide range of ODP analogs bearing alkyl- or arylalkylamines. Specifically, we discovered two new compounds, <strong>5q</strong> and <strong>8g</strong>, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130008"},"PeriodicalIF":2.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142556563","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}

引用次数: 0

Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents 4,7,9-三取代苯并氧氮杂卓作为抗利什曼病药物的合成和生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI: 10.1016/j.bmcl.2024.130003

Tara Man Kadayat , Stefan Kwiatkowski , Diana Ortiz , Gaurav Shoeran , Jared T. Hammill , Ho Shin Kim , Joanna Cholewo , Scott M. Landfear , R. Kiplin Guy

引用次数: 0

Design, synthesis and evaluation of 3-(2-(substituted benzyloxy)benzylidene) pyrrolidine-2,5-dione derivatives for novel ATX inhibitor 3-(2-(取代的苄氧基)亚苄基)吡咯烷-2,5-二酮衍生物作为新型 ATX 抑制剂的设计、合成和评估。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1016/j.bmcl.2024.130006

Seung Hyeong Lee , Su Jin Park , Mi Young Lee , Jun Young Choi , Woo Dae Jang , Jidon Jang , Jeong Hyun Lee , Chae Jo Lim , Kwang-Seok Oh

引用次数: 0

Novel drug discovery approaches for MMP-13 inhibitors in the treatment of osteoarthritis 治疗骨关节炎的 MMP-13 抑制剂的新型药物发现方法。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1016/j.bmcl.2024.130009

Yi Wang

{"title":"Novel drug discovery approaches for MMP-13 inhibitors in the treatment of osteoarthritis","authors":"Yi Wang","doi":"10.1016/j.bmcl.2024.130009","DOIUrl":"10.1016/j.bmcl.2024.130009","url":null,"abstract":"<div><div>Recently, the key role of matrix metalloproteinase-13 (MMP-13) in a variety of diseases has attracted much attention. In the field of osteoarthritis (OA) treatment, the study of MMP-13 inhibitors has become a hotspot, and the development of selective MMP-13 inhibitors is a key direction of OA treatment strategies. This paper aims to summarize the latest research progress on MMP-13 inhibitors in drug design and delivery systems in OA treatment, in order to provide new ideas and strategies for the development of MMP-13 inhibitors. In the context of drug design, researchers have utilized innovative drug discovery strategies to developed a number of potential MMP-13 inhibitors by accurately simulating the active site and analyzing the structure of known inhibitors. With regard to delivery systems, nanotechnology has been extensively employed to enhance the targeting and bioavailability of MMP-13 inhibitors, effectively improving therapeutic efficacy through precise delivery to the lesion site. The latest research developments not only reveal the significant potential of MMP-13 inhibitors in disease treatment, but also provide new directions and challenges for future research.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130009"},"PeriodicalIF":2.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542466","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}

引用次数: 0

Diastereomeric pure pyrazolyl-indolyl dihydrofurans: Unveiling isomeric selectivity in antibacterial action via in vitro and in silico insights 非对映纯吡唑-吲哚基二氢呋喃：通过体外和硅学研究揭示异构体在抗菌作用中的选择性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-24 DOI: 10.1016/j.bmcl.2024.130005

Hari Prakash , Sandhya Chahal , Jayant Sindhu , Prateek Tyagi , Deepansh Sharma , Mridula Guin , Noopur Srivastava , Kuldeep Singh

{"title":"Diastereomeric pure pyrazolyl-indolyl dihydrofurans: Unveiling isomeric selectivity in antibacterial action via in vitro and in silico insights","authors":"Hari Prakash , Sandhya Chahal , Jayant Sindhu , Prateek Tyagi , Deepansh Sharma , Mridula Guin , Noopur Srivastava , Kuldeep Singh","doi":"10.1016/j.bmcl.2024.130005","DOIUrl":"10.1016/j.bmcl.2024.130005","url":null,"abstract":"<div><div>Developing pure diastereoisomeric molecular hybrids for the selective inhibition of bacterial growth opened new avenues for combating the ever-increasing microbial resistance. Considering this, a series of diastereoisomeric pure pyrazolyl-dihydrofurans (<strong>7a-7y</strong>) were synthesized and characterized using NMR, LCMS, and X-ray crystallography. DFT based method was used to explore the configurational stability of <em>cis</em> over <em>trans</em> isomeric form. Considering <strong>7a</strong> and <strong>8a</strong> as representative isomeric forms with same structural framework, the difference in their bio-efficacy against bacterial and fungal strains was assessed using serial dilution method. The relatively high inhibition of bacterial growth by the <em>cis</em> isomeric form (<strong>7a</strong>) (MIC = 1.562 µg/mL), amoxicillin (MIC = 3.125 µg/mL) inspired us to broaden the substrate scope for synthesizing a series of pure diastereoisomeric <em>cis</em> forms as selective anti-bacterial agents. However, both the isomers displayed antifungal activity less than the standard drug (Fluconazole) employed in the study. All the reactions proceeded smoothly and yielded a diverse array of dihydrofuran derivatives. The developed synthetics were found to be non-cytotoxic against mouse fibroblast cells and didn’t affect the seed germination of <em>Brassica nigra</em> seeds when treated at 1 mg/mL concentration. The experimentally determined <em>in vitro</em> results were further validated using <em>in silico</em> molecular docking and dynamics studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130005"},"PeriodicalIF":2.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491795","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}

引用次数: 0

Pyridine and Pyrimidine hybrids as privileged scaffolds in antimalarial drug discovery: A recent development 吡啶和嘧啶杂化物作为抗疟药物发现的特殊支架：最新进展。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129992

Lekkala Ravindar , Siti Aishah Hasbullah , K.P. Rakesh , Saki Raheem , Norzila Ismail , Lau Yee Ling , Nurul Izzaty Hassan

{"title":"Pyridine and Pyrimidine hybrids as privileged scaffolds in antimalarial drug discovery: A recent development","authors":"Lekkala Ravindar , Siti Aishah Hasbullah , K.P. Rakesh , Saki Raheem , Norzila Ismail , Lau Yee Ling , Nurul Izzaty Hassan","doi":"10.1016/j.bmcl.2024.129992","DOIUrl":"10.1016/j.bmcl.2024.129992","url":null,"abstract":"<div><div>Malaria continues to pose a significant threat to global health, which is exacerbated by the emergence of drug-resistant strains, necessitating the urgent development of new therapeutic options. Due to their substantial bioactivity in treating malaria, pyridine and pyrimidine have become the focal point of drug research. Hybrids of pyridine and pyrimidine offer a novel and promising avenue for developing effective antimalarial agents. The ability of these hybrids to overcome drug resistance is tinted, offering a potential solution to this critical obstacle in the treatment of malaria. By targeting multiple pathways, these hybrid compounds reduce the likelihood of resistance development, providing a promising strategy for combating drug-resistant strains of malaria. The review focuses on the most recent developments in 2018 in the structural optimization of pyridine and pyrimidine hybrid compounds, highlighting modifications that have been shown to improve antimalarial activity. Structure-activity studies have elucidated the essential characteristics required for potency, selectivity, and pharmacokinetics. Molecular docking and virtual screening expedite the identification of novel compounds with enhanced activity profiles. This analysis could aid in developing the most effective pyridine and pyrimidine hybrids as antimalarial agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129992"},"PeriodicalIF":2.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454438","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}

引用次数: 0

Biological evaluation of signal transducer and activator of transcription 3 (STAT3) targeting by phaeosphaeride A and its analogs 对 phaeosphaeride A 及其类似物靶向信号转导子和转录激活子 3 (STAT3) 的生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.130004

Yuichiro Hirayama, Masahiro Matsunaga, Ayaka Fukao, Kenichi Kobayashi

引用次数: 0

Evaluating delivery of peptide nucleic acids to Gram-negative bacteria using differently linked membrane-active peptides and their stapled analogs 评估使用不同连接的膜活性肽及其订书钉类似物向革兰氏阴性菌输送肽核酸的情况。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI: 10.1016/j.bmcl.2024.129993

Izabela Siekierska, Michał Burmistrz, Joanna Trylska

{"title":"Evaluating delivery of peptide nucleic acids to Gram-negative bacteria using differently linked membrane-active peptides and their stapled analogs","authors":"Izabela Siekierska, Michał Burmistrz, Joanna Trylska","doi":"10.1016/j.bmcl.2024.129993","DOIUrl":"10.1016/j.bmcl.2024.129993","url":null,"abstract":"<div><div>Antisense oligonucleotides have been developed as therapeutic compounds, with peptide nucleic acid (PNA) emerging as a promising nucleic acid mimic for antimicrobial applications. To be effective, PNAs must be internalized into bacterial cells, as they are not naturally absorbed. A strategy to improve PNA membrane penetration and cellular uptake involves covalently conjugating them to cell-penetrating peptides. However, these membrane-active peptides can exhibit cytotoxicity, and their efficiency as PNA carriers needs to be enhanced. Therefore, we explored new peptide–PNA conjugates and their linkers to understand how they affect PNA uptake into bacteria. We conjugated PNA to two peptides, anoplin and (KFF)<sub>3</sub>K, along with their structurally stabilized hydrocarbon-stapled derivatives, and evaluated their transport into various bacterial strains. The PNA sequence targeted bacterial mRNA encoding the essential acyl carrier protein. As linkages, we used either a non-cleavable 8-amino-2,6-dioxaoctanoyl (ethylene glycol, eg1) linker or a reducible disulfide bridge. We found that the hydrocarbon-stapled peptides did not enhance PNA delivery, despite the strong inner- and outer-membrane-penetrating capabilities of the standalone peptides. Additionally, the disulfide bridge linkage, which is cleavable in the bacterial cytoplasm, decreased the antimicrobial activity of the peptide–PNA conjugates. Notably, we identified anoplin as a new potent PNA carrier peptide, with the anoplin–eg1–PNA conjugate demonstrating antibacterial activity against <em>E. coli</em> and <em>S.</em> Typhimurium strains in the 2–4 µM range.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129993"},"PeriodicalIF":2.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0