Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis.","authors":"Yuebiao Zhou, Ignacio Aliagas, Shumei Wang, Chun Sing Li, Zhiguo Liu, Christine M Bowman, Daniel J Burdick, Kevin R Clark, Tahnee J Dening, John Flygare, Anjani Ganti, Hany S Girgis, Emily J Hanan, Seth F Harris, Chloe Hu, Sharookh B Kapadia, Michael F T Koehler, Tommy Lai, Jun Liang, Xingrong Liu, Fang Ma, Jialin Mao, Jeremy Nicolai, Jessica Sims, Savita Unhayaker, John Wai, Xiaojing Wang, Ping Wu, Yiming Xu, Chun-Wan Yen, Renwei Zhang, Torben F Elfert, Man-Wah Tan, Eric M Kofoed, Terry D Crawford","doi":"10.1016/j.bmcl.2024.130026","DOIUrl":"10.1016/j.bmcl.2024.130026","url":null,"abstract":"<p><p>Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5'-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130026"},"PeriodicalIF":2.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613400","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":"The synthesis and antileukemic activity of 5-substituted thiazolyl urea derivatives","authors":"Cheng Peng ,&nbsp;Li Sheng ,&nbsp;Gao-Ya Xu ,&nbsp;Xiao-Lei Qi ,&nbsp;Yu-Bo Zhou ,&nbsp;Jia-Li ,&nbsp;Yong-Mei Cui","doi":"10.1016/j.bmcl.2024.130018","DOIUrl":"10.1016/j.bmcl.2024.130018","url":null,"abstract":"<div><div>A series of novel 5-substituted thiazolyl urea derivatives were synthesized and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (THP-1 and MV-4-11). Results showed that the activities of the investigated compounds were quite sensitive to the positions and properties of the aromatic substituents. Among these compounds, compound <strong>12k</strong> showed the highest activity with IC₅₀ values of 29 ± 0.3 nM for THP-1 cells and 98 ± 10 nM for MV-4-11 cells.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130018"},"PeriodicalIF":2.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613402","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":"Pentamethine cyanine dyes with alkynyl group as perspective structure for conjugation with targeting moiety","authors":"Anastasiia A. Uspenskaia ,&nbsp;Irina A. Doroshenko ,&nbsp;Kseniia A. Popovicheva ,&nbsp;Nazar V. Shmychkov ,&nbsp;Ekaterina V. Pryakhina ,&nbsp;Radik R. Shafikov ,&nbsp;Dmitrii A. Skvortsov ,&nbsp;Mikhail K. Beklemishev ,&nbsp;Olga V. Zaborova ,&nbsp;Tatiana A. Podrugina ,&nbsp;Aleksei E. Machulkin ,&nbsp;Elena K. Beloglazkina","doi":"10.1016/j.bmcl.2024.130025","DOIUrl":"10.1016/j.bmcl.2024.130025","url":null,"abstract":"<div><div>We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φ_fl = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130025"},"PeriodicalIF":2.5,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613401","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":"Cladophorol-A is an inhibitor of cyclic GMP-AMP synthase","authors":"Mildred Kissai ,&nbsp;Emily N. Chin ,&nbsp;Francisco Martínez-Peña ,&nbsp;Ariana Sulpizio ,&nbsp;E. Paige Stout ,&nbsp;Ippei Usui ,&nbsp;Farhana Barmare ,&nbsp;Brittany Sanchez ,&nbsp;Eduardo Esquenazi ,&nbsp;Robyn L. Stanfield ,&nbsp;Ian A. Wilson ,&nbsp;Luke L. Lairson","doi":"10.1016/j.bmcl.2024.130007","DOIUrl":"10.1016/j.bmcl.2024.130007","url":null,"abstract":"<div><div>Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is an enzyme sensor of double-stranded DNA (dsDNA) that serves to trigger activation of the cGAS-stimulator of interferon genes (STING) pathway. Excessive activation of this pathway has been demonstrated to contribute to various forms of inflammatory disease. As such, cGAS has arisen as a potential therapeutic target with broad potential applications. Using a pathway-targeted cell-based screening approach, we identified the natural product Cladophorol-A as a new class of non-cytotoxic cGAS inhibitor (cell-based IC₅₀ = 370 nM). An X-ray co-crystal structure at 2.75 Å resolution revealed that Cladophorol-A inhibits cGAS by binding to its active site within the conserved adenosine nucleobase binding site.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130007"},"PeriodicalIF":2.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613399","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":"Mechanism-based inactivators of sirtuin 5: A focused structure–activity relationship study","authors":"Tobias N. Hansen,&nbsp;Xinyi Yuan ,&nbsp;Marc S. I Santana ,&nbsp;Christian A. Olsen","doi":"10.1016/j.bmcl.2024.130017","DOIUrl":"10.1016/j.bmcl.2024.130017","url":null,"abstract":"<div><div>Sirtuin 5 (SIRT5) is a lysine deacylase enzyme that cleaves negatively charged ε-<em>N</em>-acyllysine posttranslational modifications, arising from short dicarboxylic acids. Inhibition of SIRT5 has been suggested as a target for treatment of leukemia and breast cancer. In this work, we performed a focused structure–activity relationship study that identified highly potent inhibitors of SIRT5. Examples of these inhibitors were shown by kinetic evaluation to function as mechanism-based inactivators. Masking of a crucial carboxylate functionality in the inhibitors provided prodrugs, which were demonstrated to bind SIRT5 in cells. This work underscores the importance of kinetic characterization of enzyme inhibitors and provides insights for the further optimization of inhibitors of SIRT5 with potential for in vivo applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130017"},"PeriodicalIF":2.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613403","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}

{"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 ,&nbsp;Yinze Han ,&nbsp;Jiao Yu,&nbsp;Renjie Zhou,&nbsp;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}

{"title":"Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus","authors":"Masooma Abbas,&nbsp;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, 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 <strong>8, 11</strong>–<strong>14, 15, 17</strong>–<strong>21, 25 and 28</strong> 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 <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 (IC₅₀ = 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 (IC₅₀ = 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 (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 <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}

{"title":"Synthesis and evaluation of N-arylindazole-3-carboxamide derivatives as novel antiviral agents against SARS-CoV-2","authors":"Jun Young Lee ,&nbsp;Sangeun Jeon ,&nbsp;Jung-Eun Cho ,&nbsp;Sungmin Kim ,&nbsp;Hyoung Rae Kim ,&nbsp;Hyeung-geun Park ,&nbsp;Seungtaek Kim ,&nbsp;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 (EC₅₀ = 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}

{"title":"Design, synthesis, and biological evaluation of dithiocarbamate derivatives as SARS-CoV-2 Mpro inhibitors","authors":"Jin-Qi Peng ,&nbsp;Ya-Qi Xiao ,&nbsp;Jiao Long ,&nbsp;Shuang-Shuang Zhang ,&nbsp;Yuan-Yuan Zhu ,&nbsp;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^pro) 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^pro inhibitors. Notably, compound <strong>L2</strong> exhibited an IC₅₀ value of 9.1 ± 2.0 nM against SARS-CoV-2 M^pro, 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}

{"title":"Computational approach based on freely accessible tools for antimicrobial drug design","authors":"Gisele Strieder Philippsen ,&nbsp;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}