Bioorganic & Medicinal Chemistry Letters最新文献

Discovery of the new active ingredient tigolaner, an allosteric modulator of the GABA-gated chloride channel for use as a spot-on ectoparasiticide in animal health.

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-29 DOI: 10.1016/j.bmcl.2025.130352

Anne Décor, Michael Maue, Hans-Georg Schwarz, Ulrich Ebbinghaus-Kintscher, Klaus Raming, Andreas Turberg, Norbert Mencke, Julia Hahn Neumann, Reiner Fischer, Werner Hallenbach, Johannes Köbberling, Walter Hübsch, Thomas Bretschneider, Kerstin Ilg, Peter Lösel, Ulrich Görgens, Niels Lindner, Katharina Wölfel, Martin Adamczewski

{"title":"Discovery of the new active ingredient tigolaner, an allosteric modulator of the GABA-gated chloride channel for use as a spot-on ectoparasiticide in animal health.","authors":"Anne Décor, Michael Maue, Hans-Georg Schwarz, Ulrich Ebbinghaus-Kintscher, Klaus Raming, Andreas Turberg, Norbert Mencke, Julia Hahn Neumann, Reiner Fischer, Werner Hallenbach, Johannes Köbberling, Walter Hübsch, Thomas Bretschneider, Kerstin Ilg, Peter Lösel, Ulrich Görgens, Niels Lindner, Katharina Wölfel, Martin Adamczewski","doi":"10.1016/j.bmcl.2025.130352","DOIUrl":"https://doi.org/10.1016/j.bmcl.2025.130352","url":null,"abstract":"<p><p>Parasiticides play a crucial role in animal health. The need for innovative ectoparasiticides for companion animals has been growing, driven by the risks posed by parasites to both animals and humans. We detail here the discovery pathway of tigolaner, an ectoparasiticide, offering up to 13 weeks protection against fleas and ticks to cats. Felpreva® employs this active ingredient for ectoparasite control together with the endoparasiticides emodepside and praziquantel. It was approved by the European Medicines Agency in November 2021. The discovery of tigolaner resulted from research at Bayer focused on finding novel molecules inhibiting GABA-gated chloride channels (GABA-Cls), with an improved toxicological profile and resistance-breaking potential when compared to dieldrin and fipronil. A high-throughput in vitro screening campaign on GABA-Cls, followed by a \"mix-match\" synthetic approach, led to the identification of several lead compounds acting as allosteric modulators. The GABA lead class compounds showed a different binding site when compared to fipronil. They have a unique chemotype based on a pyrazole moiety. Further variations of the central ring led to the discovery of tigolaner. Selected structure-activity relationships from the project are presented. Some synthetic pathways for tigolaner and its analogs are also described. This publication also outlines the efficacy of tigolaner against various parasites, making it a key compound of the Felpreva® product.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130352"},"PeriodicalIF":2.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758832","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 anti-HIV-1 Vif inhibitors based on prodrug strategy. 基于前药策略的抗hiv -1 Vif抑制剂的设计、合成及生物学评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-27 DOI: 10.1016/j.bmcl.2025.130351

Weilin Wang, Rui Deng, Rong-Hua Luo, Hongjia Zhang, Dan Luo, Shirui Wang, Su Yu, Xinyu Ma, Chunlan Pu, Yuanyuan Liu, Qing Huang, Liu-Meng Yang, Yong-Tang Zheng, Rui Li

引用次数: 0

Synthesis of novel isoflavene derivatives with anti-tumour activity 新型抗肿瘤异黄酮衍生物的合成

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-27 DOI: 10.1016/j.bmcl.2025.130350

Valerio Falasca , Daniel S. Wenholz , Tsz Tin Yu , Naresh Kumar

引用次数: 0

Discovery of anthraquinone-triazene derivatives as novel antitumor agents causing DNA damage 蒽醌-三氮烯衍生物作为新型DNA损伤抗肿瘤药物的发现

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-24 DOI: 10.1016/j.bmcl.2025.130347

Zi-Han Jia , Qing Xu , Yun-Hao Liu , Ri-Lei Yu , Qin Wang , Ya-Mu Xia , Wei-Wei Gao

{"title":"Discovery of anthraquinone-triazene derivatives as novel antitumor agents causing DNA damage","authors":"Zi-Han Jia , Qing Xu , Yun-Hao Liu , Ri-Lei Yu , Qin Wang , Ya-Mu Xia , Wei-Wei Gao","doi":"10.1016/j.bmcl.2025.130347","DOIUrl":"10.1016/j.bmcl.2025.130347","url":null,"abstract":"<div><div>In this study, 40 anthraquinone-triazene derivatives were designed, and <strong>AT-9</strong> and <strong>AT-10</strong> were screened out as potential antitumor candidates based on their strong binding affinities to DNA and topoisomerase II using molecular docking and molecular dynamics simulations. Antiproliferative assays revealed that <strong>AT-9</strong> and <strong>AT-10</strong> exhibited significantly stronger inhibitory effects on A549 and HeLa cell lines compared to the reference mitoxantrone. The binding modes of <strong>AT-9</strong> and <strong>AT-10</strong> with DNA were confirmed by spectra and gel electrophoresis. Metabolic pathway investigations showed that <strong>AT-9</strong> and <strong>AT-10</strong> were susceptible to nucleophilic attack by water molecules, leading to the release of nitrogen and degradation into an anthraquinone-amide compound. Thus, the synergistic antitumor mechanism arises from the DNA intercalation of the anthraquinone ring and the alkylating effect mediated by the triazene moiety. Furthermore, ADME analysis revealed that <strong>AT-9</strong> and <strong>AT-10</strong> possessed favorable drug-likeness and pharmacokinetic properties, indicating strong potential for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130347"},"PeriodicalIF":2.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712848","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, molecular docking and suppression on NF-κB activity of sinomenine hybrid derivatives. 青藤碱杂化衍生物的设计、分子对接及对NF-κB活性的抑制

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-24 DOI: 10.1016/j.bmcl.2025.130348

Jian Tang, Chunbao Jiang, Yuling Zhu, Chongwei Wen, Xiuquan Xu, Haiping Xia

引用次数: 0

Synthesis and evaluation of novel substituted N-(2-phenylbutyl)-5,6,7,8-tetrahydro-quinazolin-4-amines as allosteric modulators of HIV-DAT-tat interaction 新型取代N-（2-苯基丁基）-5,6,7,8-四氢喹唑啉-4胺作为HIV-DAT-tat相互作用变构调节剂的合成与评价

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-23 DOI: 10.1016/j.bmcl.2025.130345

Theresa H. Nguyen , Omar Moukha-Chafiq , Shuklendu Karyakarte , Ana C. Jimenez-Torres , Ganesh Shrestha , Sixue Zhang , Jun Zhu , Corinne E. Augelli-Szafran

{"title":"Synthesis and evaluation of novel substituted N-(2-phenylbutyl)-5,6,7,8-tetrahydro-quinazolin-4-amines as allosteric modulators of HIV-DAT-tat interaction","authors":"Theresa H. Nguyen , Omar Moukha-Chafiq , Shuklendu Karyakarte , Ana C. Jimenez-Torres , Ganesh Shrestha , Sixue Zhang , Jun Zhu , Corinne E. Augelli-Szafran","doi":"10.1016/j.bmcl.2025.130345","DOIUrl":"10.1016/j.bmcl.2025.130345","url":null,"abstract":"<div><div>Allosteric modulation of interaction between Dopamine Transporter (DAT) and HIV-1 transactivator of transcription (Tat) by small molecules suggests a potential therapeutic intervention for HIV-infected patients with concurrent cocaine abuse. We have previously reported <em>in vitro</em> and <em>in vivo</em> studies on a novel allosteric modulator, <strong>SRI-32743</strong>, which was shown to attenuate Tat-induced inhibition of [<sup>3</sup>H]DA uptake and decrease the cocaine-mediated dissociation of [<sup>3</sup>H]WIN35,428 binding in CHO-K1 cells expressing hDAT. Herein we report our initial structure-activity relationship (SAR) studies on <strong>SRI-32743</strong> with the goal of identifying more potent analogs with improved absorption, distribution, metabolism, and excretion (ADME) properties, that can evolve into a pre-clinical candidate against HIV-1 associated neurocognitive disorders (HAND). Our investigation led to the discovery of a novel <em>N</em>-(2-phenylbutyl)-5,6,7,8-tetrahydroquinazolin-4-amine <strong>4e</strong> (<strong>SRI-45949</strong>), which exhibited comparable inhibitory potency and improved solubility as compared to <strong>SRI-32743</strong>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130345"},"PeriodicalIF":2.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714423","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 and synthesis of imidazo[2,1-b]thiazole derivatives as potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors for antiviral activity 咪唑[2,1-b]噻唑衍生物作为有效的选择性磷脂酰肌醇4-激酶IIIβ抑制剂的设计和合成

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1016/j.bmcl.2025.130346

Koji Ochiai, Masahiko Kinebuchi, Takekazu Kondo, Takahiro Suezawa, Morio Higuchi, Motomichi Fujita, Akinobu Yokoyama, Hitomi Matsui, Makoto Rembutsu, Yuji Ishibashi, Yuta Tanaka, Aki Yonezawa, Hirotaka Ando, Yoshiaki Kitamura, Michiaki Nagasawa, Masahiro Ueno

{"title":"Design and synthesis of imidazo[2,1-b]thiazole derivatives as potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors for antiviral activity","authors":"Koji Ochiai, Masahiko Kinebuchi, Takekazu Kondo, Takahiro Suezawa, Morio Higuchi, Motomichi Fujita, Akinobu Yokoyama, Hitomi Matsui, Makoto Rembutsu, Yuji Ishibashi, Yuta Tanaka, Aki Yonezawa, Hirotaka Ando, Yoshiaki Kitamura, Michiaki Nagasawa, Masahiro Ueno","doi":"10.1016/j.bmcl.2025.130346","DOIUrl":"10.1016/j.bmcl.2025.130346","url":null,"abstract":"<div><div>The type III phosphatidylinositol 4-kinase beta (PI4KB, PI4KIIIβ) is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol at the 4-position. PI4KB is widely understood to play a critical role in supporting viral replication, and PI4KB inhibitors are under investigation as potential host-targeting antivirals. In this study, we report potent and selective imidazo[2,1-<em>b</em>]thiazole inhibitors of PI4KB with antiviral activity. Guided by ligand efficiency, optimization efforts yielded potent PI4KB inhibitors, and reducing proton donor count enhanced cellular potency (anti HRV: EC<sub>50</sub> 0.027 μM for compound <strong>29</strong>, 0.007 μM for compound <strong>30</strong>). Furthermore, compound <strong>30</strong> selectively inhibited PI4KB, with minimal off-target kinase activity, as confirmed by profiling.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130346"},"PeriodicalIF":2.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697224","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

Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold 以5,8-二氢吡啶[4,3-d]嘧啶-7(6H)- 1为支架的新型SOS1抑制剂的开发和生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1016/j.bmcl.2025.130344

Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang

{"title":"Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold","authors":"Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang","doi":"10.1016/j.bmcl.2025.130344","DOIUrl":"10.1016/j.bmcl.2025.130344","url":null,"abstract":"<div><div>SOS1 plays a pivotal role in RAS activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-<em>d</em>]pyrimidin-7(6<em>H</em>)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, <strong>A15f</strong> and <strong>B5a</strong> emerged as the most potent compounds comparable to BI-3406. <strong>A15f</strong> and <strong>B5a</strong> exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in pERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced <em>in vitro</em> efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130344"},"PeriodicalIF":2.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697225","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

Structure–activity relationship studies of tanzawaic acid A, an antifungal agent against Rhizopus oryzae 抗米根霉药坦桑酸A的构效关系研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-16 DOI: 10.1016/j.bmcl.2025.130343

Kotaro Tanaka , Shiho Arima , Daiki Lee , Satoshi Ohte , Hiroshi Tomoda , Ryuji Uchida , Taichi Ohshiro , Tohru Nagamitsu

引用次数: 0

Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects 发现新的苯并噻吩啉衍生物作为具有降尿酸作用的URAT1抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-14 DOI: 10.1016/j.bmcl.2025.130342

Yongcheng Wang , Lei Zhang , Mengjie Shao , Xianxin Hou , Ying Yang , Yifan Yang , Fei Ye , Xuechen Li , Zhiyan Xiao

{"title":"Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects","authors":"Yongcheng Wang , Lei Zhang , Mengjie Shao , Xianxin Hou , Ying Yang , Yifan Yang , Fei Ye , Xuechen Li , Zhiyan Xiao","doi":"10.1016/j.bmcl.2025.130342","DOIUrl":"10.1016/j.bmcl.2025.130342","url":null,"abstract":"<div><div>Urate transporter 1 (URAT1) is a clinically validated therapeutic target for hyperuricemia and gout. To obtain structurally novel URAT1 inhibitors, a series of benzomorpholine derivatives were designed by adopting a pharmacophore guided molecular hybridization strategy. Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound <strong>7</strong> exhibited an IC<sub>50</sub> of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone. The possible interaction mode of compound <strong>7</strong> with URAT1 was revealed by molecular modeling. Cell viability assays indicated that compound <strong>7</strong> was less cytotoxic than Benzbromarone in Hep-G2 cells. The urate-lowering effects of compounds <strong>1</strong> and <strong>7</strong> were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130342"},"PeriodicalIF":2.5,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648103","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