Pub Date : 2024-11-01DOI: 10.1016/j.bmcl.2024.130014
Xincheng Ni , Yinze Han , Jiao Yu, Renjie Zhou, Jian Lei
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein performs multiple functions during the viral life cycle, particularly in binding to the viral genomic RNA to form a helical ribonucleoprotein complex. Here, we present that the C-terminal domain of SARS-CoV-2 N protein (N-CTD) specifically interacts with polyguanylic acid (poly(G)). The crystal structure of the N-CTD in complex with 5′-guanylic acid (GMP, also known as guanosine monophosphate) was determined at a resolution of approximately 2.0 Å. A novel GMP-binding pocket in the N-CTD was illustrated. Residues Arg259 and Lys338 were identified to play key roles in binding to GMP through mutational analysis. These two residues are absolutely conserved in the other two highly pathogenic CoVs, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Overall, our findings expand the structural information on N protein interacting with guanylate and reveal a conserved GMP-binding pocket as a potential antiviral target.
严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）核壳（N）蛋白在病毒生命周期中发挥多种功能，特别是与病毒基因组 RNA 结合形成螺旋核糖核蛋白复合物。我们在这里发现，SARS-CoV-2 N 蛋白的 C 端结构域（N-CTD）能与聚鸟苷酸（poly(G)）发生特异性相互作用。N-CTD与5'-鸟苷酸（GMP，又称单磷酸鸟苷）复合物的晶体结构分辨率约为2.0埃。结果表明，在 N-CTD 中有一个新的 GMP 结合口袋。通过突变分析，确定 Arg259 和 Lys338 两个残基在与 GMP 结合过程中起着关键作用。这两个残基在另外两种高致病性 CoV--SARS-CoV 和中东呼吸综合征冠状病毒（MERS-CoV）中是绝对保守的。总之，我们的研究结果扩展了 N 蛋白与鸟苷酸相互作用的结构信息，并揭示了一个保守的 GMP 结合口袋是潜在的抗病毒靶点。
{"title":"Structural basis of the C-terminal domain of SARS-CoV-2 N protein in complex with GMP reveals critical residues for RNA interaction","authors":"Xincheng Ni , Yinze Han , Jiao Yu, Renjie Zhou, Jian Lei","doi":"10.1016/j.bmcl.2024.130014","DOIUrl":"10.1016/j.bmcl.2024.130014","url":null,"abstract":"<div><div>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein performs multiple functions during the viral life cycle, particularly in binding to the viral genomic RNA to form a helical ribonucleoprotein complex. Here, we present that the C-terminal domain of SARS-CoV-2 N protein (N-CTD) specifically interacts with polyguanylic acid (poly(G)). The crystal structure of the N-CTD in complex with 5′-guanylic acid (GMP, also known as guanosine monophosphate) was determined at a resolution of approximately 2.0 Å. A novel GMP-binding pocket in the N-CTD was illustrated. Residues Arg259 and Lys338 were identified to play key roles in binding to GMP through mutational analysis. These two residues are absolutely conserved in the other two highly pathogenic CoVs, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Overall, our findings expand the structural information on N protein interacting with guanylate and reveal a conserved GMP-binding pocket as a potential antiviral target.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130014"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566716","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}
Pub Date : 2024-11-01DOI: 10.1016/j.bmcl.2024.130016
Masooma Abbas, Nuzhat Arshad
1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, 6–8), novel 5-carboxamide derivatives of dihydropyrimidine (series B, 9–14), N,S-dimethyl-dihydropyrimidine (series C, 15–20), N-hydrazinyl derivatives of dihydropyrimidine (series D, 21–24) and tetrazolo dihydropyrimidine derivatives (series E, 25–28), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, 1HNMR, 13CNMR, ESI and HRMS. All of these compounds from series A—E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example 8, 11–14, 15, 17–21, 25 and 28 demonstrated greater α-glucosidase inhibitory effects (IC50 = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC50 = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have van der Waals and alkyl bonds interactions with the targeted site of the human lysosomal acid α-glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC50 = 21.4 0.45 to 92.1 0.38 μM) as compared to the standard butylated hydroxyanisol (IC50 = 44.2 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC50 = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC50 = 21.4 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.
{"title":"Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus","authors":"Masooma Abbas, Nuzhat Arshad","doi":"10.1016/j.bmcl.2024.130016","DOIUrl":"10.1016/j.bmcl.2024.130016","url":null,"abstract":"<div><div>1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, <strong>6</strong>–<strong>8</strong>), novel 5-carboxamide derivatives of dihydropyrimidine (series B, <strong>9</strong>–<strong>14</strong>), N,S<strong>-</strong>dimethyl<strong>-</strong>dihydropyrimidine (series C, <strong>15</strong>–<strong>20)</strong>, <em>N</em>-hydrazinyl derivatives of dihydropyrimidine (series D, <strong>21</strong>–<strong>24)</strong> and tetrazolo dihydropyrimidine derivatives (series E, <strong>25</strong>–<strong>28</strong>), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, <sup>1</sup>HNMR, <sup>13</sup>CNMR, ESI and HRMS. All of these compounds from series A—E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example <strong>8, 11</strong>–<strong>14, 15, 17</strong>–<strong>21, 25 and 28</strong> demonstrated greater α-glucosidase inhibitory effects (IC<sub>50</sub> = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC<sub>50</sub> = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have <em>van der Waals</em> and alkyl bonds interactions with the targeted site of the human lysosomal acid α-glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC<sub>50</sub> = 21.4 <span><math><mo>±</mo></math></span> 0.45 to 92.1 <span><math><mo>±</mo></math></span> 0.38 μM) as compared to the standard butylated hydroxyanisol (IC<sub>50</sub> = 44.2 <span><math><mo>±</mo></math></span> 0.36 μM). Among all, compound <strong>13, 14 and 19</strong> with potent α-glucosidase inhibition (IC<sub>50</sub> = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC<sub>50</sub> = 21.4 <span><math><mo>±</mo></math></span> 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130016"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566728","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}
Pub Date : 2024-11-01DOI: 10.1016/j.bmcl.2024.130015
Jun Young Lee , Sangeun Jeon , Jung-Eun Cho , Sungmin Kim , Hyoung Rae Kim , Hyeung-geun Park , Seungtaek Kim , Chul Min Park
N-Arylindazole-3-carboxamide derivatives synthesized from an anti-MERS-CoV hit compound showed potent inhibitory activities against SARS-CoV-2. Among them, 5-chloro-N-(3,5-dichlorophenyl)-1H-indazole-3-carboxamide (4a) exhibited a potent inhibitory effect (EC50 = 0.69 µM), low cytotoxicity, and satisfactory in vitro PK profiles. Thus, N-arylindazole-3-carboxamide 4a provides a novel template for future development of anti-coronavirus agents.
{"title":"Synthesis and evaluation of N-arylindazole-3-carboxamide derivatives as novel antiviral agents against SARS-CoV-2","authors":"Jun Young Lee , Sangeun Jeon , Jung-Eun Cho , Sungmin Kim , Hyoung Rae Kim , Hyeung-geun Park , Seungtaek Kim , Chul Min Park","doi":"10.1016/j.bmcl.2024.130015","DOIUrl":"10.1016/j.bmcl.2024.130015","url":null,"abstract":"<div><div><em>N</em>-Arylindazole-3-carboxamide derivatives synthesized from an anti-MERS-CoV hit compound showed potent inhibitory activities against SARS-CoV-2. Among them, 5-chloro-<em>N</em>-(3,5-dichlorophenyl)-1<em>H</em>-indazole-3-carboxamide (<strong>4a</strong>) exhibited a potent inhibitory effect (EC<sub>50</sub> = 0.69 µM), low cytotoxicity, and satisfactory <em>in vitro</em> PK profiles. Thus, <em>N</em>-arylindazole-3-carboxamide <strong>4a</strong> provides a novel template for future development of anti-coronavirus agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130015"},"PeriodicalIF":2.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566721","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}
SARS-CoV-2 continues to mutate, spread, and impact public health and daily life. The main protease (Mpro) is essential for the replication and maturation of SARS-CoV-2, making it an ideal target for anti-coronaviral drug discovery and development due to its high conservation and lack of homologous proteases in humans. Herein, we designed and synthesized a series of dithiocarbamate derivatives as potent SARS-CoV-2 Mpro inhibitors. Notably, compound L2 exhibited an IC50 value of 9.1 ± 2.0 nM against SARS-CoV-2 Mpro, underscoring its potential as a promising candidate for anti-coronaviral therapy and justifying further research and development.
{"title":"Design, synthesis, and biological evaluation of dithiocarbamate derivatives as SARS-CoV-2 Mpro inhibitors","authors":"Jin-Qi Peng , Ya-Qi Xiao , Jiao Long , Shuang-Shuang Zhang , Yuan-Yuan Zhu , Shuang-Xi Gu","doi":"10.1016/j.bmcl.2024.130011","DOIUrl":"10.1016/j.bmcl.2024.130011","url":null,"abstract":"<div><div>SARS-CoV-2 continues to mutate, spread, and impact public health and daily life. The main protease (M<sup>pro</sup>) is essential for the replication and maturation of SARS-CoV-2, making it an ideal target for anti-coronaviral drug discovery and development due to its high conservation and lack of homologous proteases in humans. Herein, we designed and synthesized a series of dithiocarbamate derivatives as potent SARS-CoV-2 M<sup>pro</sup> inhibitors. Notably, compound <strong>L2</strong> exhibited an IC<sub>50</sub> value of 9.1 ± 2.0 nM against SARS-CoV-2 M<sup>pro</sup>, underscoring its potential as a promising candidate for anti-coronaviral therapy and justifying further research and development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130011"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563481","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}
Pub Date : 2024-10-30DOI: 10.1016/j.bmcl.2024.130010
Gisele Strieder Philippsen , Flavio Augusto Vicente Seixas
Antimicrobial drug development is crucial for public health, especially with the emergence of pandemics and drug resistance that prompts the search for new therapeutic resources. In this context, in silico assays consist of a valuable approach in the rational drug design because they enable a faster and more cost-effective identification of drug candidates compared to in vitro screening. However, once a potential drug is identified, in vitro and in vivo assays are essential to verify the expected activity of the compound and advance it through the subsequent stages of drug development. This work aims to outline an in silico protocol that utilizes only freely available computational tools for identifying new potential antimicrobial agents, which is also suitable in the broad spectrum of drug design. Additionally, this paper reviews relevant computational methods in this context and provides a summary of information concerning the protein–ligand interaction.
{"title":"Computational approach based on freely accessible tools for antimicrobial drug design","authors":"Gisele Strieder Philippsen , Flavio Augusto Vicente Seixas","doi":"10.1016/j.bmcl.2024.130010","DOIUrl":"10.1016/j.bmcl.2024.130010","url":null,"abstract":"<div><div>Antimicrobial drug development is crucial for public health, especially with the emergence of pandemics and drug resistance that prompts the search for new therapeutic resources. In this context, <em>in silico</em> assays consist of a valuable approach in the rational drug design because they enable a faster and more cost-effective identification of drug candidates compared to <em>in vitro</em> screening. However, once a potential drug is identified, <em>in vitro</em> and <em>in vivo</em> assays are essential to verify the expected activity of the compound and advance it through the subsequent stages of drug development. This work aims to outline an <em>in silico</em> protocol that utilizes only freely available computational tools for identifying new potential antimicrobial agents, which is also suitable in the broad spectrum of drug design. Additionally, this paper reviews relevant computational methods in this context and provides a summary of information concerning the protein–ligand interaction.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130010"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563479","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}
Pub Date : 2024-10-30DOI: 10.1016/j.bmcl.2024.130013
Guorui Li , Guanghua Liu , Yawen Ruan , Chaoshui Liu , Xingnan Lian , Yangli Zheng
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.
荧光染料是可视化 DNA 和 RNA 的重要工具。像 GelGreen 这样的二聚染料因其诱变性和基因毒性较低，作为溴化乙锭（EB）更安全的替代品而广受欢迎。在本研究中，我们提出了一种利用点击化学合成新型吖啶橙（AO）基二聚体染料的简单方法。从吖啶橙开始，这些染料只需两步即可合成。与 GelGreen 相比，这些新型染料在其连接体中加入了额外的三唑基团。它们的最大吸收波长约为 472 nm，与 DNA 结合后会转移到 503 nm 左右，从而可以被蓝光激发。这些染料在水溶液中的荧光最小，表明它们采用了封闭构象，由于分子内聚集，吖啶橙的荧光被淬灭。DNA 的存在会大大增强它们在 526 纳米波长处的荧光，这表明 DNA 结合会诱导它们形成开放构象。这种 "发光 "特性使它们成为高灵敏度、高信噪比的 DNA 染料。我们成功地将这些新型染料应用于琼脂糖凝胶电泳中，它们表现出了卓越的性能。
{"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}
Pub Date : 2024-10-30DOI: 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
AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the μ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211.
{"title":"Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor","authors":"Jinping Li , Yang Li , Lifei Liu , Wen Jiang , Yimin Jia , Jun Yang , Lie Li , Xuejun Zhang , Jiangtao Su , Shivansh Kaushik","doi":"10.1016/j.bmcl.2024.130012","DOIUrl":"10.1016/j.bmcl.2024.130012","url":null,"abstract":"<div><div>AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the μ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130012"},"PeriodicalIF":2.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563480","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}
Pub Date : 2024-10-29DOI: 10.1016/j.bmcl.2024.130008
Susan L. Harris, Somnath Dutta, Nianzi Liu, Tilmann Wollenberg, Xiang Wang
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-b]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, 5q and 8g, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.
{"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}
Pub Date : 2024-10-29DOI: 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
Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1-methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure–activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46, which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L. mexicana amastigotes, modest selectivity towards host macrophages (J774A.1 line), and good aqueous solubility.
在此，我们报告了一系列抗利什曼病类似物，它们来自 4-[(3,5-二甲基-4-异恶唑基)乙酰基]-9-[(1-甲基-3-哌啶基)甲氧基]-7-(5-甲基-2-噻吩基)-2,3,4,5-四氢-1,4-苯并氧氮杂卓（1），该类似物是通过之前报告的高通量表型筛选确定的。我们设计、合成了该类似物系列，并对其进行了抗利什曼病活性评估，以建立药效元素和初步的结构-活性关系，作为验证该系列的关键步骤，以便进一步优化。这项研究最终确定了早期的先导化合物 46，它对巨噬细胞内的 L. mexicana amastigotes 具有亚微摩级的增殖抑制活性，对宿主巨噬细胞（J774A.1 株）具有适度的选择性，并且具有良好的水溶性。
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Pub Date : 2024-10-28DOI: 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
Autotaxin (ATX) has emerged as a promising therapeutic target for liver diseases. In this study, we identified potential drug candidates through in silico high-throughput screening. Subsequently, we synthesized a series of small molecules, specifically KR-40795 (2c), a pyrrolidine-2,5-dione-based analogue that binds to the allosteric tunnel and hydrophobic pocket of ATX. This compound was designed to inhibit the enzymatic activity of ATX for the treatment of liver diseases. The inhibitory potency of KR-40795 was evaluated using a biochemical assay that measured the hydrolysis of a specific substrate (FS-3). Notably, KR-40795 demonstrated significant inhibition of both collagen formation and lipid accumulation in liver cells, suggesting its potential as a therapeutic agent for liver diseases, particularly fibrosis and steatosis.
{"title":"Design, synthesis and evaluation of 3-(2-(substituted benzyloxy)benzylidene) pyrrolidine-2,5-dione derivatives for novel ATX inhibitor","authors":"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","doi":"10.1016/j.bmcl.2024.130006","DOIUrl":"10.1016/j.bmcl.2024.130006","url":null,"abstract":"<div><div>Autotaxin (ATX) has emerged as a promising therapeutic target for liver diseases. In this study, we identified potential drug candidates through <em>in silico</em> high-throughput screening. Subsequently, we synthesized a series of small molecules, specifically KR-40795 (<strong>2c</strong>), a pyrrolidine-2,5-dione-based analogue that binds to the allosteric tunnel and hydrophobic pocket of ATX. This compound was designed to inhibit the enzymatic activity of ATX for the treatment of liver diseases. The inhibitory potency of KR-40795 was evaluated using a biochemical assay that measured the hydrolysis of a specific substrate (FS-3). Notably, KR-40795 demonstrated significant inhibition of both collagen formation and lipid accumulation in liver cells, suggesting its potential as a therapeutic agent for liver diseases, particularly fibrosis and steatosis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 130006"},"PeriodicalIF":2.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542451","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}
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