Bioorganic & Medicinal Chemistry Letters最新文献

Synthesis and biological evaluation of 2-substituted heterocyclic quinolones as inhibitors of Vibrio cholerae sodium pumping NADH-ubiquinone oxidoreductase (NQR). 2取代杂环喹诺酮类药物作为霍乱弧菌钠泵送nadh -泛醌氧化还原酶（NQR）抑制剂的合成及生物学评价

IF 2.3 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-10-17 DOI: 10.1016/j.bmcl.2026.130807

Christian Quinto, Daniela Angarita, Jennifer M Sorescu, Karina Tuz, Oscar X Juárez, Daniel P Becker

{"title":"Synthesis and biological evaluation of 2-substituted heterocyclic quinolones as inhibitors of Vibrio cholerae sodium pumping NADH-ubiquinone oxidoreductase (NQR).","authors":"Christian Quinto, Daniela Angarita, Jennifer M Sorescu, Karina Tuz, Oscar X Juárez, Daniel P Becker","doi":"10.1016/j.bmcl.2026.130807","DOIUrl":"https://doi.org/10.1016/j.bmcl.2026.130807","url":null,"abstract":"<p><p>The rise of multi-drug-resistant bacteria highlights the need for antibiotics that act through novel mechanisms of action. The Na<sup>+</sup>-pumping NADH-Ubiquinone (UQ) oxidoreductase (NQR) is a respiratory enzyme foundin many pathogenic bacteria including Vibrio cholerae and plays a central role in energy production and redox balance. This enzyme is essential to the virulence of V. cholerae and structural motifs that are unique to NQR are not found in the humans, making it an excellent target for antibiotic drug design. Herein we report the synthesis and biological evaluation of 2-substituted heterocyclic quinolones designed to target the ubiquinone binding site of NQR. The most potent quinolone derivative exhibits 45% inhibition at 50 μM and docking studies indicate that it overlaps with the surrogate ubiquinone substrate within the binding pocket. These compounds also show inhibition of NQR while maintaining low toxicity in mammalian HeLa and HFF-1 cells, expanding the chemical space of bacterial respiratory enzyme inhibitors and supporting their development as a potential class of bacteriostatic antibiotics.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130807"},"PeriodicalIF":2.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149214780","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 of potent azabenzothiazoloquinoxalines as protease-activated receptor 4 (PAR4) antagonists. 偶氮苯并噻唑喹啉类蛋白酶激活受体4 （PAR4）拮抗剂的发现。

IF 2.3 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-10-17 DOI: 10.1016/j.bmcl.2026.130796

J Alex Bates, Jeremy M Richter, Xiaojun Zhang, Wen Jiang, Samuel K Reznik, O Scott Halpern, Shana L Posy, Chi Sum, Ji Hua, Jing Yang, Victor R Guarino, David A Gordon, Ruth R Wexler, E Scott Priestley

引用次数: 0

Substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives as anti-invasion agents 取代1-（苯并[d]噻唑-2-基）-3-苯脲衍生物作为抗侵入剂。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-31 DOI: 10.1016/j.bmcl.2026.130568

Reilly K. Gwinn , Padmanabhan Mannangatti , Shahid Maqbool Mir , Shikha Kumari , Mai K. Le , Swadesh K. Das , Paul B. Fisher , Webster L. Santos

{"title":"Substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives as anti-invasion agents","authors":"Reilly K. Gwinn , Padmanabhan Mannangatti , Shahid Maqbool Mir , Shikha Kumari , Mai K. Le , Swadesh K. Das , Paul B. Fisher , Webster L. Santos","doi":"10.1016/j.bmcl.2026.130568","DOIUrl":"10.1016/j.bmcl.2026.130568","url":null,"abstract":"<div><div>Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffolding protein, MDA-9/Syntenin-1 was identified and confirmed as a suitable target uniquely involved in the multiple stages of metastasis. Recently, the first-in class PDZ1 domain inhibitor for MDA-9, PDZ1i, was identified displaying significant anti-invasion activity improving survival in an in vivo glioblastoma and in multiple metastatic cancer mouse models. Herein, we report a focused library of substituted 1-(benzo[<em>d</em>]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[<em>d</em>]thiazol-2-yl)-3-phenylurea analogs bearing 6-trifluoromethyl (<strong>3y</strong>) and 6-bromo (<strong>3aa</strong>) substituents display anti-invasion activity comparable to PDZ1i. However, compounds <strong>3y</strong> and <strong>3aa</strong> displayed overall decreased cancer cell selectivity and MDA-9 activity relative to PDZ1i. Nonetheless, the reported 1-(benzo[<em>d</em>]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future development of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130568"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103294","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

Design, synthesis, and mechanism of anti-cancer activity of novel spiro tetramic acids 新型螺旋体四聚酸的设计、合成及其抗癌作用机理。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-29 DOI: 10.1016/j.bmcl.2026.130566

Shi Xiang , Mengjiao Lv , Chenghao Wang , Zhichao Wang , Hui Chen , Pei Lv , Chao Yang

{"title":"Design, synthesis, and mechanism of anti-cancer activity of novel spiro tetramic acids","authors":"Shi Xiang , Mengjiao Lv , Chenghao Wang , Zhichao Wang , Hui Chen , Pei Lv , Chao Yang","doi":"10.1016/j.bmcl.2026.130566","DOIUrl":"10.1016/j.bmcl.2026.130566","url":null,"abstract":"<div><div>Targeted therapies have pioneered a more effective new pathway in cancer treatment by leveraging their precision-targeting advantages. Spiro tetramic acids are a kind of unique pyrrolidine-2,4-dione core structure containing a spiro ring structure, primarily employed as agro-chemicals with limited application in the field of anti-cancer. In this paper, fourteen novel 3-acetyl and 3-phenyl spiro tetramic acids were designed, synthesized, and evaluated for anti-proliferation in cancer cells. 3-Acetyl and 3-phenyl spirotetramic acids exhibited toxic effects against tested cancer cell lines. Among the 14 compounds, compound <strong>8d</strong> was the most effective against RKO and H1299 with Half Maximal Inhibitory Concentration (IC<sub>50</sub>) 3 ± 1 and 19 ± 2 μM. Further molecular structural prediction, bioinformatics analysis, and molecular docking revealed that compound <strong>8d</strong> may target MMP1, MMP7 and PLK1. Additionally, <strong>8d</strong> induced cell cycle arrest in G1 phase by increasing the expression of p21 protein and decreasing the expression of CCND1 and CCNB1 proteins. <strong>8d</strong> also induced cell apoptosis through the mitochondrial pathways, as evidenced by alterations in the expressions of pertinent proteins, including Bcl-2 and Bax. These results indicated that the novel spirotetramine derivative <strong>8d</strong> is a potential anti-cancer candidate drug and provides a new structural basis for the development of anti-cancer drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130566"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096765","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

Integrated approach to design 5-indolyl-pyrazoles as anti-TB agent 5-吲哚吡唑抗结核药物的综合设计。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-30 DOI: 10.1016/j.bmcl.2026.130534

K. Mohammed Zabiulla , Prabodh Ranjan , Archakam Ranganatham , Mohd Athar , Shivaraj Yellappa

{"title":"Integrated approach to design 5-indolyl-pyrazoles as anti-TB agent","authors":"K. Mohammed Zabiulla , Prabodh Ranjan , Archakam Ranganatham , Mohd Athar , Shivaraj Yellappa","doi":"10.1016/j.bmcl.2026.130534","DOIUrl":"10.1016/j.bmcl.2026.130534","url":null,"abstract":"<div><div>This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A series of 5-indolyl-pyrazole derivatives (n = <strong>z1</strong>–<strong>z44</strong>) were synthesized and characterized through <sup>1</sup>H/<sup>13</sup>C NMR and HR-MS analysis. The synthesized compounds were screened against <em>H37Rv</em> and two multidrug-resistant clinically isolated <em>strains M.tb*</em> and <em>M.tb**</em>. Several derivatives (notably <strong>z</strong><strong>1</strong> and <strong>z</strong><strong>8</strong>) showed potent inhibition at concentrations as low as 25 μg/mL may be even more potent at lower concentrations and a comparative analysis could be possible. Complementary molecular docking studies were conducted using the <em>InhA</em> enzyme (PDB ID: <span><span>4TZK</span><svg><path></path></svg></span>), a validated target in mycolic acid biosynthesis. Lead compounds demonstrated favorable binding energies (e.g., −6.35 kcal/mol for <strong>z1</strong>), engaging key active-site residues (PHE97, MET103, PHE149, TYR158) through hydrophobic, π-stacking, and <em>van der Waals</em> interactions, alongside critical contact with the <em>NAD</em><sup><em>+</em></sup> cofactor. Interaction fingerprint analysis correlated ligand-residue contacts with biological activity, underscoring the importance of aromatic planarity and substituent modulation for effective <em>InhA</em> inhibition. This integrated synthetic-biological-computational workflow lays a promising foundation for the development of next-generation anti-TB agents with improved efficacy against resistant strains.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130534"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099891","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 anticancer activity of parthenolide-based PROTACs for IKKβ degradation 基于parthenolide的IKKβ降解PROTACs的合成及抗癌活性研究

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-02-05 DOI: 10.1016/j.bmcl.2026.130571

Zhenxi Su , Yiwu Wu , Yijie Su , Yuhan He , Jieyin Liu , Deng-Gao Zhao

引用次数: 0

Allyl-functionalized calix[4]resorcinarenes against breast cancer cells: Synthesis, cytotoxicity, apoptosis induction, and computational insights 烯丙基功能化杯状[4]间苯二甲酸脂抗乳腺癌细胞：合成、细胞毒性、细胞凋亡诱导和计算见解。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-13 DOI: 10.1016/j.bmcl.2026.130540

Anggit Fitria , Yehezkiel Steven Kurniawan , Eti Nurwening Sholikhah , Harno Dwi Pranowo , Jumina

{"title":"Allyl-functionalized calix[4]resorcinarenes against breast cancer cells: Synthesis, cytotoxicity, apoptosis induction, and computational insights","authors":"Anggit Fitria , Yehezkiel Steven Kurniawan , Eti Nurwening Sholikhah , Harno Dwi Pranowo , Jumina","doi":"10.1016/j.bmcl.2026.130540","DOIUrl":"10.1016/j.bmcl.2026.130540","url":null,"abstract":"<div><div>The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (<strong>4a–4f</strong>) as cytotoxic agents. These derivatives were obtained <em>via</em> the <em>O</em>-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their <em>in vitro</em> anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue <strong>4a</strong> exhibited moderate cytotoxicity in breast cancer cell lines, <em>i.e.</em>, MCF-7 cells (IC<sub>50</sub> = 8.27 μM), showing notable cytotoxicity in the low micromolar range, comparable to that of cisplatin and within the same order of magnitude as doxorubicin. Accompanied by apoptosis profiling, compound <strong>4a</strong> at 1 × and 2 × IC<sub>50</sub> showed a concentration-dependent increase in apoptosis cell death compared to untreated controls. Meanwhile, computational studies were conducted to explore potential interactions with EGFR as a putative target, suggesting that compound <strong>4a</strong> may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130540"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987614","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

Combined antitumor efficacy of a new tanshinone IIA analog and irinotecan with alleviating gastrointestinal side effect 新型丹参酮IIA类似物与伊立替康联合抗肿瘤及减轻胃肠道副作用的疗效观察。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-27 DOI: 10.1016/j.bmcl.2026.130563

Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li

{"title":"Combined antitumor efficacy of a new tanshinone IIA analog and irinotecan with alleviating gastrointestinal side effect","authors":"Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li","doi":"10.1016/j.bmcl.2026.130563","DOIUrl":"10.1016/j.bmcl.2026.130563","url":null,"abstract":"<div><div>1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-<em>b</em>]furan-7,10,11(6<em>H</em>)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated <em>in vitro</em>. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both <em>in vitro</em> and <em>in vivo</em>. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed <em>in vivo</em>. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130563"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083769","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

Design, synthesis, and biological evaluation of cytochrome P450 CYP11A1 inhibitors 细胞色素P450 CYP11A1抑制剂的设计、合成和生物学评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-01-31 DOI: 10.1016/j.bmcl.2026.130567

Dongyu Wang , Shengkai Cui , Jingyi Yuan, Yuyang Li, Yujie Zhang, Yuao Zhang, Weizheng Fan, Chunlei Tang

引用次数: 0

Synthesis and characterization of bicyclo[1.1.0]butane amides and 5-methylene-3-azabicyclo[5.1.0]octan-4-ones as covalent modifiers 双环[1.1.0]丁烷酰胺和5-亚甲基-3-氮杂环[5.1.0]辛烷-4-酮共价改性剂的合成与表征。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2026-06-01 Epub Date: 2026-02-05 DOI: 10.1016/j.bmcl.2026.130572

Karis Texidor , Dilhumar Uyghur , Noah Wiese , Lindsey O. Davis , Mandy Green , Farjana Sharmen , Adil Ijaz , Kamani M. Barnes , Madison Bagett , Jishi Ye , Stacy M. Abbang , Wenying Piao , Jason Ying Kuen Chan , Yuen-Keng Ng , Vivian W.Y. Lui , Marco Orecchioni , Matteo Borgini

{"title":"Synthesis and characterization of bicyclo[1.1.0]butane amides and 5-methylene-3-azabicyclo[5.1.0]octan-4-ones as covalent modifiers","authors":"Karis Texidor , Dilhumar Uyghur , Noah Wiese , Lindsey O. Davis , Mandy Green , Farjana Sharmen , Adil Ijaz , Kamani M. Barnes , Madison Bagett , Jishi Ye , Stacy M. Abbang , Wenying Piao , Jason Ying Kuen Chan , Yuen-Keng Ng , Vivian W.Y. Lui , Marco Orecchioni , Matteo Borgini","doi":"10.1016/j.bmcl.2026.130572","DOIUrl":"10.1016/j.bmcl.2026.130572","url":null,"abstract":"<div><div>Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate “undruggable” proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of <em>N</em>-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both <em>N</em>-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected <em>N</em>-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130572"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137021","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