Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency.","authors":"Catherine C Rouch, Arnab K Chatterjee, Connor McCarty, Lirui Song, Alan Chu, Kristen Johnson, Mina Heacock, Laura Riva, Case W McNamara, Karen C Wolff, Rebecca Greene-Cramer, Anna De Falco, Gaetano T Montelione, Gennadii A Grabovyi","doi":"10.1016/j.bmcl.2024.130034","DOIUrl":"10.1016/j.bmcl.2024.130034","url":null,"abstract":"<p><p>The papain-like protease (PLpro) is a highly conserved domain encoded by the coronavirus (CoV) genome and it plays an essential role in the replication and maturation of the virus in addition to weakening host immune response. Due to the virus's reliance on PLpro for survival and propagation, small-molecule inhibitors of PLpro serve as an attractive model for direct-acting antiviral therapeutic agents against SARS-CoV-2. Building upon existing work aimed at designing covalent inhibitors against PLpro, we report the synthesis and structure-activity relationship of analogs based on the known covalent inhibitor 1 (Sanders, et al.2023). To evaluate the efficacy of synthesized derivatives, we conducted enzymatic inhibition assays, SARS-CoV-2/HeLa-ACE2 cellular potency and toxicity assays, and profiled the most promising analogs via in vitro ADME and in vivo pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure-activity relationship of compounds based on 1 and offer suggestions for optimizing the potency and selectivity of the electrophilic warhead and improving ADME and PK properties for this chemotype. Relative to the parent compound, new designs demonstrate comparable potency and target selectivity for PLpro. The accomplished SAR campaign provides novel insight for future development of antivirals against SARS-CoV-2.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130034"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694888","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, X-ray studies and antiproliferative activity of novel lasalocid amides.","authors":"Michał Sulik, Zbigniew Kubis, Dagmara Kłopotowska, Jan Janczak, Joanna Wietrzyk, Adam Huczyński","doi":"10.1016/j.bmcl.2024.130041","DOIUrl":"10.1016/j.bmcl.2024.130041","url":null,"abstract":"<p><p>Seeking new drug candidates among compounds of natural origin is an effective and widely used method of fighting various diseases, especially cancer. Lasalocid acid is one of the naturally occurring polyether ionophore antibiotics, which also exhibits interesting anticancer activity. Therefore, to expand the knowledge about the anticancer properties of lasalocid derivatives, a series of its new amides were synthesized and their antiproliferative activity against cancer cell lines was studied. Amides 7-9 with an aromatic substituent, displayed potent antiproliferative activity (IC₅₀: 0.84-5.18 μM) and demonstrated a good selectivity index (SI: 1.4-15.3). Furthermore, almost all of lasalocid amides overcame the drug resistance of the doxorubicin-resistant cancer cell line (LoVo/DX). Because the biological activity of ionophores is strictly connected with their ability to transport the Na⁺ cation through lipid bilayers, the crystal structure of the complex of compound 8 with the Na⁺ cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na⁺ cation.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130041"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737893","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 study of anhydrotetracycline derivatives.","authors":"Yong Wang, He Wu, Guangguang Yang, Karuppu Selvaraj, Gang Chen","doi":"10.1016/j.bmcl.2024.130090","DOIUrl":"https://doi.org/10.1016/j.bmcl.2024.130090","url":null,"abstract":"<p><p>A novel and new type of tetracycline with a different mechanism of action was necessary, due to the drug resistance of existing tetracyclines. This study outlines the synthesis and antibacterial evaluation of anhydro-tetracycline derivatives, which are unconventional tetracyclines with unique mechanisms of action. These derivatives include C4-NH₂, C4-OH, and C9-substituted variations, and our synthetic approach focuses on semi-synthesis using natural tetracyclines as the starting precursors. Several derivatives of C4-NH₂, C4-OH, and C9-substituted compounds have demonstrated effective antibiotic activity against both Gram-positive and Gram-negative bacteria.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130090"},"PeriodicalIF":2.5,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906419","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 triazine derivatives as antimalarial agents.","authors":"Yuko Asamitsu, Aki Ishiyama, Yui Iwamae, Rina Nagao, Rei Hokari, Masato Iwatsuki, Kazuhiko Otoguro, Masaaki Sawa","doi":"10.1016/j.bmcl.2024.130091","DOIUrl":"10.1016/j.bmcl.2024.130091","url":null,"abstract":"<p><p>In a previous study, we reported that nilotinib, a BCR-ABL tyrosine kinase inhibitor, possesses moderate antimalarial activity against PfK1 and PfFCR3. As a part of our efforts to develop novel antimalarial agents, a series of novel triazine analogs was identified as potent antimalarial agents via structure modification of nilotinib. Compound 15a showed strong antimalarial activities against PfK1 and PfFCR3 with IC₅₀ values of 0.28 and 0.29 µM, respectively.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130091"},"PeriodicalIF":2.5,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906417","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 camptothecin analogue FL118 as a payload for antibody-drug conjugates in targeted cancer therapy.","authors":"Gangadhar Rao Mathi, Byeong Sung Lee, Younghwa Chun, Seunggun Shin, Sohui Kweon, Areum Go, Jin Kyo Jung, Jin Soo Lee, Hyun Yong Cho, Doo Young Jung","doi":"10.1016/j.bmcl.2024.130085","DOIUrl":"10.1016/j.bmcl.2024.130085","url":null,"abstract":"<p><p>FL118, a camptothecin derivative with dual mechanisms of action through topoisomerase I inhibition and proteasome-mediated degradation of anti-apoptotic proteins exhibits potent anti-tumor activity while remaining resistant to drug efflux transporters. This work describes the targeted delivery of FL118 to tumors via antibody-drug conjugates (ADCs) using the pH-sensitive CL2A linker. ADCs targeting Trop2, HER2, and EGFR exhibited potent in vitro cytotoxicity, with IC₅₀ values as low as 0.025 nM in Trop2-positive FaDu cells. In vivo, Sac-CL2A-FL118 showed 130 % tumor growth inhibition (TGI) at 7 mg/kg in Trop2-expressing xenografts surpassing Trodelvy®. Pharmacokinetic evaluations revealed that FL118-ADCs exhibited a 2.6-fold increase in AUC and approximately 1.7-fold higher C_max compared to Trodelvy®, confirming their favorable profiles and supporting their potential as a promising therapeutic approach.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130085"},"PeriodicalIF":2.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890853","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 substituted quinolines containing piperazine moieties against Influenza A virus.","authors":"Hongxuan Li, Jianyuan Zhao, Fangyi Jiang, Chenghong Zheng, Guoning Zhang, Mei Zhu, Shan Cen, Minghua Wang, Yucheng Wang, Juxian Wang","doi":"10.1016/j.bmcl.2024.130081","DOIUrl":"10.1016/j.bmcl.2024.130081","url":null,"abstract":"<p><p>Influenza A virus (IAV) poses a serious global threat to public health. There is an urgent need to develop new anti-IAV agents due to the limitations of the current antiviral drugs in clinical practice. Herein, based on compound I-13e, we designed and synthesized 23 substituted quinoline derivatives containing piperazine moieties and evaluated their in vitro anti-IAV activity. The results showed that compounds 4a, 4c, 6c, 6f, 6g, 6i and 9a-9d (IC₅₀s: 0.88-4.92 μM) were more active against IAV than Ribavirin. In particular, compound 9b exhibited broad-spectrum antiviral activity (IC₅₀: 0.88-6.33 μM) and acceptable cytotoxicity. The preliminary studies on its mechanism of action indicated an inhibition of viral RNA transcription and replication. These results suggested its potential as a promising anti-IAV candidate for further investigation.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130081"},"PeriodicalIF":2.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890855","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 structures with anti-tumor effects: Targeting telomere G-quadruplex and hTERT.","authors":"Xutong Wang, Zeyu Gao, Yu Liu, Peiying Wang, Xiaodong Fang, Meng Sun, Kejing Ma, Bing Wang, Weina Han","doi":"10.1016/j.bmcl.2024.130083","DOIUrl":"10.1016/j.bmcl.2024.130083","url":null,"abstract":"<p><p>The telomeric G-quadruplex (G4) along with the telomerase catalytic subunit hTERT are crucial in the extension of telomeres. Tumor cells can establish replicative immortality by activating the telomere-maintenance mechanism (TMM).Small molecule ligands can limit cancer telomere lengthening by by targeting at G4 and hTERT. The 144 structures were designed by summarising the common structure-activity relationship of G4 stabilisers and hTERT inhibitors.Molecular docking and mtQSAR activity prediction experiments finally identified a16 and a35 as the optimal structures. Subsequently their derivative compounds b1-b6 were synthesised,with b4 exhibiting the most pronounced inhibitory effect on tumour cells. The ability of b4 to distinguish single-stranded DNA, double-stranded DNA and telomere G4 was verified by fluorescence experiment, and the stable combination of b4 and hTERT was verified by molecular dynamics simulation. This suggests that the structural design of targeting G4 and hTERT is reasonable and has anti-tumor potential.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130083"},"PeriodicalIF":2.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890851","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":"Photocrosslinking and capture for the analysis of carbohydrate-dependent interactions.","authors":"Matthew R Pratt","doi":"10.1016/j.bmcl.2024.130077","DOIUrl":"10.1016/j.bmcl.2024.130077","url":null,"abstract":"<p><p>Carbohydrates play crucial roles in biological systems, including by mediating cell and protein interactions. The complexity and transient nature of carbohydrate-dependent interactions pose significant challenges for their characterization, as traditional techniques often fail to capture these low-affinity binding events. This review highlights the increasing utility of photocrosslinkers in studying carbohydrate-mediated interactions. Photocrosslinkers, such as aryl azides, benzophenones, and diazirines, allow for the capture of fleeting interactions by forming covalent bonds upon UV irradiation, enabling the downstream application of standard biochemical techniques. I discuss the three primary strategies for incorporating photocrosslinkers: synthetic small molecules, metabolic labeling, and exo-enzymatic labeling. I predict that the continued development and application of these methodologies will enhance our understanding of glycan-mediated interactions and their implications in health and disease.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130077"},"PeriodicalIF":2.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875551","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 of newly synthesized α-benzil monoxime thiocarbohydrazide derivatives as an antimicrobial and anticancer agent: In vitro screening and ADMET predictions.","authors":"Navnath Zaware, Nishant Rasal, Vinayak Lambate, Sangeeta Jagtap","doi":"10.1016/j.bmcl.2024.130079","DOIUrl":"10.1016/j.bmcl.2024.130079","url":null,"abstract":"<p><p>The current comprehensive study showcases a meticulous synthesis of novel class of α-benzilmonoxime thiocarbohydrazide (BMOTC) derivatives, and manifesting their multifaceted potential as antibacterial, antifungal, and anticancer agents. The synthesis of target compounds was performed in three phases using literature methods. In the first step, benzilmonoxime is synthesized using benzil and hydroxyl amine hydrochloride, followed by benzilmonoxime imine using thiocarbohydrazide. The final stage involves combining BMOTC imine with various aldehydes and ketones. The antibacterial and antifungal activities of the synthesized derivatives against five bacterial panels, both Gram-positive and Gram-negative, and one fungal pathogen have been screened. Twelve of the twenty-four synthetic derivatives showed noteworthy activity; eight derivatives exhibited growth inhibition (GI) >73 % against Acinetobacter baumannii, two exhibited GI >95 % against Escherichia coli, and two exhibited GI >93 % against Candida albicans at concentration 32 μg/mL. Further assessment revealed that two derivatives 5v and 5w, exhibited negligible cytotoxicity towards human embryonic kidney cells (HK-293) and human red blood cells (RBC), signifying their promising safety profile at concentration 32 μg/mL (GI against Candida albicans - 97.51 % and 93.71 % respectively). The synthesized compounds were subjected to in vitro cytostatic activity, where a rigorous scrutiny against a diverse panel of NCI 60 cancer cell lines representing various malignancies was carried out. A total of eleven compounds emerged as promising candidates, demonstrating significant growth percent (GP) at a concentration of 10 µM. Notably, compounds 5d, 5h, and 5x, turned up as standout performers, exhibiting potent anticancer activity across multiple cancer types, including colon, CNS, melanoma, and breast cancers. Of particular interest, compound 5d displayed notable antiproliferative effects against leukemia cancer cell lines RPMI-8226 & SR, while maintaining non-cytotoxicity against the same. Compound 5h showcased activity against ovarian, non-small cell lung, and prostate cancers, without inducing cytotoxic effects. Compound 5x demonstrated remarkable anticancer activity against leukemia and breast cancer cell lines, further bolstered by its non-cytotoxic nature. A compelling aspect of this study is the comparative analysis with the established drug molecule sunitinib, revealing that compounds 5d, 5h, and 5x exhibit superior potency. These findings not only highlight the therapeutic potential of the BMOTC derivatives but also underscore their viability as promising candidates for future drug development endeavours. This study serves as a pivotal step towards harnessing the untapped therapeutic potential of BMOTC derivatives in combating microbial infections and advancing cancer therapy.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130079"},"PeriodicalIF":2.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875454","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":"Diamino variants of piperazine-based tissue transglutaminase inhibitors.","authors":"Brianna Ryan, Alana M M Rangaswamy, Sammir Shad, Jeffrey W Keillor","doi":"10.1016/j.bmcl.2024.130078","DOIUrl":"https://doi.org/10.1016/j.bmcl.2024.130078","url":null,"abstract":"<p><p>Tissue transglutaminase (TG2) is a multifunctional protein that can catalyze the cross-linking between proteins, and function as a G-protein. TG2's unregulated behaviour has been associated with fibrosis, celiac disease and cancer metastasis. Recently, small molecule irreversible inhibitors have been designed, bearing an electrophilic warhead that can react with the catalytic cysteine, abolishing TG2's catalytic and G-protein capabilities. Several research groups have converged on inhibitors comprising piperazine scaffolds, but no structure-activity relationships (SAR) of the piperazine core have been reported. In this study we synthesize a series of inhibitors with various diamino linkers, to understand what structural requirements are necessary for the core to help align the terminal acrylamide warhead in the optimal position. Kinetic evaluation using an in vitro biochemical assay provided the kinetic parameters k_inact and K_I for each inhibitor. This study revealed that adding a methyl group to the piperazine core can improve inhibitor efficiency.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130078"},"PeriodicalIF":2.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870619","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}