Bioorganic & Medicinal Chemistry Letters最新文献

Corrigendum to "Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids" [Bioorg. Med. Chem. Lett. 27(18) (2017) 4358-4369].

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-02-03 DOI: 10.1016/j.bmcl.2025.130119

Eman K A Abdelall, Abdou O Abdelhamid, Amany A Azouz

引用次数: 0

Synthesis, cytotoxic evaluation, and molecular docking of novel zerumbone oxime esters and azazerumbone derivatives

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2025.130120

Pham The Chinh , Pham Thi Tham , Hoang Thi Thanh , Vu Thi Lien , Le Thi Thuy Loan , Kim Thi Phuong Oanh , Vu Tuan Kien , Phan Thanh Phuong , Dinh Thuy Van , Cao Thanh Hai

引用次数: 0

Synthesis and Structure-Activity Relationship of Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease with Antiviral Potency 具有抗病毒效力的 SARS-CoV-2 木瓜蛋白酶类共价抑制剂的合成及结构-活性关系。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2024.130034

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

{"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":"<div><div>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 <strong>1</strong> (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 <em>in vitro</em> ADME and <em>in vivo</em> pharmacokinetic studies. Additionally, we describe computational docking of profiled compounds bound to PLpro to elucidate the structure–activity relationship of compounds based on <strong>1</strong> 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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis, X-ray studies and antiproliferative activity of novel lasalocid amides 新型 lasalocid 酰胺的合成、X 射线研究和抗增殖活性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-02-01 DOI: 10.1016/j.bmcl.2024.130041

Michał Sulik , Zbigniew Kubis , Dagmara Kłopotowska , Jan Janczak , Joanna Wietrzyk , Adam Huczyński

{"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":"<div><div>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 <strong>7–9</strong> with an aromatic substituent, displayed potent antiproliferative activity (IC<sub>50</sub>: 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<sup>+</sup> cation through lipid bilayers, the crystal structure of the complex of compound <strong>8</strong> with the Na<sup>+</sup> cation was resolved. Lasalocid amides exhibit a pseudocyclic structure and are able to coordinate the Na<sup>+</sup> cation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 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}

引用次数: 0

Synthesis, antibacterial and anticancer activity of azo-based and aminomethylene derivatives of cyclic β-keto sulfones

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130115

Demyd S. Milokhov , Mykola O. Balabushko , Anna Y. Kolomiets , Sofiia D. Rabotnikova , Pavlo A. Virych , Anton O. Poliudov , Svitlana V. Shishkina , Yulian M. Volovenko , Alexey V. Dobrydnev

{"title":"Synthesis, antibacterial and anticancer activity of azo-based and aminomethylene derivatives of cyclic β-keto sulfones","authors":"Demyd S. Milokhov , Mykola O. Balabushko , Anna Y. Kolomiets , Sofiia D. Rabotnikova , Pavlo A. Virych , Anton O. Poliudov , Svitlana V. Shishkina , Yulian M. Volovenko , Alexey V. Dobrydnev","doi":"10.1016/j.bmcl.2025.130115","DOIUrl":"10.1016/j.bmcl.2025.130115","url":null,"abstract":"<div><div>Herein we describe efficient and cost-effective synthesis of azo-based and aminomethylene derivatives of cyclic β-keto sulfones, specifically, 4,4-disubstituted (<em>E</em>)-2-(2-phenylhydrazineylidene)dihydrothiophen-3(2<em>H</em>)-one 1,1-dioxides and 4,4-disubstituted (<em>E</em>)-2-((methylamino)methylene)dihydrothiophen-3(2<em>H</em>)-one 1,1-dioxides. The azo-based derivatives were prepared through the azo coupling of cyclic β-keto sulfones with aromatic diazonium acetates, <em>in situ</em> prepared by diazotization of appropriate substituted amino benzenes. The aminomethylene derivatives were synthesized through the condensation of cyclic β-keto sulfones with DMF-DMA followed by a transamination reaction with primary amines. The target products were obtained in good yields and their structure was unambiguously established based on NMR spectra data, X-ray diffraction study, and DFT calculations. These compounds were designed as cost-effective and multitarget biologically active compounds. Further <em>in vitro</em> study showed antibacterial activity against <em>Staphylococcus aureus</em> and cytotoxicity against the MDA-MB-231 breast cancer cell line without affecting non-malignant cells MAEC. The molecular docking study confirmed good binding affinity of the studied compounds for DHPS, crucial for the bacterial life cycle and for CLK4 and IDO1, which are the therapeutic targets in cancer treatment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130115"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073025","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

Solid-phase supported direct ¹⁸F-radiofluorination of peptides. 多肽的固相直接 18F 放射氟化。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130118

Eduardo F A Fernandes, Line B S Knudsen, Andreas Kjaer, Kristian Strømgaard, Matthias M Herth

引用次数: 0

Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-30 DOI: 10.1016/j.bmcl.2025.130117

Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang

{"title":"Discovery of dual PARP/NAMPT inhibitors for the treatment of BRCA wild-type triple-negative breast cancer","authors":"Jie Mao , Kaizhen Wang , Jun Tong , Wanheng Zhang, Guoqing Shen, Dexiang Wang, Zepeng Liao, Zhiyi Zhang, Qi Miao, Sheng Jiang, Kuojun Zhang","doi":"10.1016/j.bmcl.2025.130117","DOIUrl":"10.1016/j.bmcl.2025.130117","url":null,"abstract":"<div><div>Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound <strong>13j</strong> with potent inhibitory activity against both PARP1 and NAMPT (IC<sub>50</sub> <em>=</em> 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, <strong>13j</strong> disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound <strong>13j</strong> is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130117"},"PeriodicalIF":2.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072939","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

Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-29 DOI: 10.1016/j.bmcl.2025.130116

Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie

{"title":"Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury","authors":"Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie","doi":"10.1016/j.bmcl.2025.130116","DOIUrl":"10.1016/j.bmcl.2025.130116","url":null,"abstract":"<div><div>The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (<em>P <</em> 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (<em>P <</em> 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (<em>P <</em> 0.05, <em>P <</em> 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (<em>P <</em> 0.05, <em>P <</em> 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (<em>P <</em> 0.05, <em>P <</em> 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (<em>P <</em> 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130116"},"PeriodicalIF":2.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073023","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 evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130114

Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon

引用次数: 0

A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130113

Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar

{"title":"A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus","authors":"Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar","doi":"10.1016/j.bmcl.2025.130113","DOIUrl":"10.1016/j.bmcl.2025.130113","url":null,"abstract":"<div><div>Vancomycin intermediate-resistant <em>Staphylococcus aureus</em> (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical <strong><em>1</em></strong>) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of <strong><em>1</em></strong> enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. <strong><em>1</em></strong> shows ∼30 % inhibition of ATPase activity in VraS and reduces <em>vra</em> gene auto-upregulation typical upon vancomycin exposure. Therefore, <strong><em>1</em></strong> inhibits VraS to block normal <em>vra</em> operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests <strong><em>1</em></strong> does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130113"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062784","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