Bioorganic & Medicinal Chemistry最新文献

{"title":"Tissue transglutaminase inhibitors over the past decade","authors":"Brianna Ryan ,&nbsp;Sarah Tribe ,&nbsp;Jeffrey W. Keillor","doi":"10.1016/j.bmc.2025.118476","DOIUrl":"10.1016/j.bmc.2025.118476","url":null,"abstract":"<div><div>Tissue transglutaminase (TG2) is a multifunctional protein that functions as a protein cross-linking enzyme and also as an intracellular G-protein. It has been implicated in numerous disorders such as celiac disease, fibrosis and different cancers. Due to these diverse pathologies, there is a need to develop a range of inhibitors that can target the different functionalities of TG2. In this review, we present the latest inhibitors published over the past decade, specifically focussing on irreversible inhibitors (peptidomimetic and small-molecule), probes, and reversible inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118476"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Psidium meroterpenoids with anti-hepatocellular carcinoma activities","authors":"Zhuo Wang ,&nbsp;Chunngai Hui","doi":"10.1016/j.bmc.2025.118481","DOIUrl":"10.1016/j.bmc.2025.118481","url":null,"abstract":"<div><div>Liver cancer presents as a significant human disease, and hepatocellular carcinoma appears as the most common form of liver cancer. Several therapeutic agents, such as sorafenib, are currently in Phase III clinical trials for the treatment of liver cancer. However, the development of potent and effective pharmaceuticals is undoubtedly crucial to managing the status of liver cancer and improving the quality of life of patients. <em>Psidium</em> meroterpenoids are natural products isolated from the leaves of <em>Psidium guajava</em> L., exhibiting potent cytotoxicity to hepatocellular carcinoma cell lines. Being synthetically accessible, <em>Psidium</em> meroterpenoids show tremendous potential as a therapeutic agent for hepatocellular carcinoma. This perspective outlines the biological profile, biosynthetic pathway, and chemical synthesis of <em>Psidium</em> meroterpenoids, as well as future directions and opportunities.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118481"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacophore-based high-throughput virtual screening (HTVS) to identify new c-Src kinase inhibitors with anticancer potential","authors":"Ali M. Alaseem ,&nbsp;Summya Rashid ,&nbsp;J. Puneetha ,&nbsp;M. Arockia Babu ,&nbsp;Glowi Alasiri ,&nbsp;Thakur Gurjeet Singh ,&nbsp;Yogita Tyagi ,&nbsp;Mohammad Suhail Akhter ,&nbsp;Anand Mohan Singh ,&nbsp;Nisha Bansal","doi":"10.1016/j.bmc.2025.118451","DOIUrl":"10.1016/j.bmc.2025.118451","url":null,"abstract":"<div><div>c-Src is the non-receptor kinase commonly overexpressed in numerous cancer isoforms. As potential anticancer target, these receptors are difficult to target with drugs because of their continuous shuttling between cellular and nuclear compartments and role in relaying of vital signals for gene expression, cell growth, and survival. Besides this high structural homology to other kinases, the involvement of compensatory pathways and the availability of multiple domains within the same proteins further complicate the targeting by drugs. The toxicity and resistance issue with the handful of c-Src inhibitors available, which are again non-selective in approach, further complicate this process. Considering the gap, we employed a drug identification strategy for a plausible c-Src inhibition and its anticancer potential. We selected 500,000 small molecules from the ChemBridge commercial library (database) for the virtual screening. These molecules were filtered via the development of a pharmacophore model, in silico pharmacokinetics (ADME) analysis, and high-throughput virtual screening (HTVS). The top-ranked molecules based on the docking scores, which represent computational binding affinity between a protein and a ligand, were selected and eventually led to 29 best docked molecules. The visual inspection further resulted in refinement of 4 molecules (5280699, 9797370, 11200016, and 71736582), demonstrating protein–ligand interactions the most at the c-Src kinase binding site. To validate their optimal binding, we carried out 200 ns MD simulations on these four selected proteins–ligand complexes. MD analysis revealed that the inhibitors 11200016 and 71736582 were found to be exceptionally stable at the c-Src kinase binding site, meeting the essential prerequisite. The top hit, 71736582, was further corroborated biologically. 71736582 portrayed excellent anticancer potential towards various cancer cell lines (A549, MDAMB-231, HCT-116, DU-145, and PC-3). It was found to inhibit the c-Src-mediated kinase activity (IC₅₀: 517 nM) in comparison to the positive control, bosutinib (IC₅₀: 408 nM). The compound was also able to increase the oxidative stress and induce apoptosis in the colorectal cancer cells employed. The study thus may pave the way for exploration of the top identified ligands further to develop and establish their potential as c-Src kinase inhibitors with anticancer potential.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118451"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery, SAR, and molecular basis of (R)-1-((3R,4S)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-3-(3-fluorophenyl)-2-methylpropan-1-one as a novel potent analgesic","authors":"Xiaodi Xu ,&nbsp;Haoran Zhu ,&nbsp;Qingbo Shao ,&nbsp;Baiyu Chen ,&nbsp;Jing Lin ,&nbsp;Yang Gao ,&nbsp;Zhenzhou He ,&nbsp;Wei Fu ,&nbsp;Wei Li","doi":"10.1016/j.bmc.2025.118474","DOIUrl":"10.1016/j.bmc.2025.118474","url":null,"abstract":"<div><div>Opioid analgesics remain a cornerstone of pain management, among which μ-opioid receptor (MOR) agonists dominate clinical practice due to their well-established efficacy. However, dose related adverse effects (<em>e.g.</em>, respiratory depression, addiction potential) constrain their therapeutic utility, driving sustained efforts to develop novel MOR agonists with improved safety profiles. Building upon our previously identified lead compound <strong>FWB2</strong>, a series of 3-((dimethylamino)methyl)-4-(3-methoxyphenyl)piperidin-4-ol derivatives was designed <em>via</em> structure-based drug design (SBDD), synthesized, and systematically evaluated through comprehensive <em>in vitro</em> and <em>in vivo</em> pharmacological profiling. Systematic structure-activity relationship (SAR) exploration identified (<em>R,</em> (3<em>R,</em>4<em>S</em>))-<strong>6c</strong> as a novel and selective MOR agonist (MOR <em>K</em>_<em>i</em> = 0.9 nM, MOR: DOR: KOR = 1: 561.1: 188.3; MOR EC₅₀ = 89.9 nM), demonstrating potent antinociceptive activity (ED₅₀ = 1.63 mg/kg) in the hot plate model. Molecular docking studies elucidated the binding mode of (<em>R,</em>(3<em>R,</em>4<em>S</em>))-<strong>6c</strong> with the MOR, identifying its molecular interactions with four critical residues W318^7.35, D147^3.32, H54 and W293^6.48, while delineating the structural features of the ligand-receptor binding pocket.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118474"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of N-type calcium channels by phenoxyanilide analogues","authors":"Anjie S. Bispat ,&nbsp;Fernanda C. Cardoso ,&nbsp;Mahadhi Hasan ,&nbsp;Callum E. Adams ,&nbsp;Richard J. Lewis ,&nbsp;Peter J. Duggan ,&nbsp;Kellie L. Tuck","doi":"10.1016/j.bmc.2025.118449","DOIUrl":"10.1016/j.bmc.2025.118449","url":null,"abstract":"<div><div>A series of <em>N,N</em>-dimethylated phenoxyanilide analogues were synthesised and evaluated for their activity at Ca_V2.2 and Ca_V3.2 channels. The SAR study conducted, highlighted that steric and hydrophobic interactions primarily enhanced the affinity for the Ca_V2.2 channel, while an electron-rich aromatic phenoxy ring (R) favoured Ca_V3.2 inhibition. Whilst the -CF₃ phenoxyanilide compounds exhibited a high potency for the Ca_V2.2 channel, their low CNS MPO scores and high lipophilicity were indicative of a reduced likelihood of crossing the blood-brain barrier (BBB) and suboptimal physicochemical characteristics. The outcomes of this investigation provided valuable insights into the development of selective calcium channel inhibitors for the treatment of neuropathic pain, while building on previous SAR studies performed within the research group.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118449"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural product-derived antifungals against Candida albicans: Chemical diversity and mechanisms of action","authors":"Runchu Li ,&nbsp;Xiaoxu Yang ,&nbsp;Wenjia Dan ,&nbsp;Jiangkun Dai","doi":"10.1016/j.bmc.2025.118435","DOIUrl":"10.1016/j.bmc.2025.118435","url":null,"abstract":"<div><div><em>Candida albicans</em> is a pathogenic fungus responsible for both superficial mucosal infections and life-threatening systemic candidiasis, presenting a substantial challenge to global health. The discovery of novel antifungal agents against <em>C. albicans</em> remains a critical priority in medicinal chemistry. Natural products and their derivatives have historically played a pivotal role in antifungal drug development. This review systematically summarizes recent advances in natural products exhibiting activity against <em>C. albicans</em> from 2020 to the first half of 2025, with an emphasis on their structural diversity including aldehydes, alkaloids, fatty acids, flavonoids, glycosides, peptides, phenylpropanoids, polyketides, tannins, and terpenoids. Furthermore, the antifungal mechanisms of these compounds are discussed, focusing on their interactions with critical targets such as the cell wall, cell membrane, virulence factors, and intracellular targets. By compiling these findings, this review aims to provide valuable insights and lead compounds to guide the design of next-generation antifungals against <em>C. albicans</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118435"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfonium-stabilized anoplin cyclic peptides with enhanced electro-positivity for effective antimicrobial activity, stability, and biocompatibility","authors":"Wenjun Li ,&nbsp;Junlong Chen ,&nbsp;Yunyan Liu ,&nbsp;Qizhi Chen ,&nbsp;Yanjin Li ,&nbsp;Fangzhou Linli ,&nbsp;Sisi Feng ,&nbsp;Xianggui Chen","doi":"10.1016/j.bmc.2025.118428","DOIUrl":"10.1016/j.bmc.2025.118428","url":null,"abstract":"<div><div>The overuse of antibiotics has highlighted the antimicrobial peptides (AMPs) as critical agents against pathogenic bacteria. However, natural AMPs like anoplin face significant limitations, including instability and suboptimal antimicrobial efficacy. Although previous studies have demonstrated the crucial role of stable secondary structures in enhancing antimicrobial activity, concerns have arisen regarding the increased hemolytic toxicity associated with hydrophobic side chains introduced by the RCM stapling strategy. To address this challenge, we propose a sulfonium-stabilized cyclization strategy that stabilizes peptide conformation through covalent cyclization and enhances cationic charge density via sulfur-based positive charges. Notably, the improved cationic charge could help to increase the peptide's antimicrobial activity while avoiding the enhancement of hemolytic toxicity. Experimental validation revealed that sulfonium-stabilized anoplin cyclic peptides (AP[5,9]-Ph) exhibited potent antibacterial activity, extended proteolytic stability, and preserved biocompatibility. Murine wound infection models demonstrated accelerated healing rates and reduced bacterial loads in treated groups. These findings suggest that sulfonium-stabilized anoplin cyclic peptides are promising candidates for novel antimicrobial agents. Moreover, the sulfonium-stabilized stapling strategy holds potential as a powerful approach for optimizing the bioactivity of natural antimicrobial peptides like anoplin, advancing the development of new antimicrobial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118428"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145360024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Halogenated N-(1,3,4-oxadiazol-2-yl) benzamides are effective eradicators of methicillin-resistant Staphylococcus aureus biofilms","authors":"George A. Naclerio ,&nbsp;Christopher S. Vennard ,&nbsp;Kenneth I. Onyedibe ,&nbsp;Dielson da S. Vieira ,&nbsp;Nader S. Abutaleb ,&nbsp;Marxa L. Figueiredo ,&nbsp;Mohamed N. Seleem ,&nbsp;Herman O. Sintim","doi":"10.1016/j.bmc.2025.118437","DOIUrl":"10.1016/j.bmc.2025.118437","url":null,"abstract":"<div><div>Due to the ever-increasing threat of methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), we have embarked on a campaign to discover novel antibacterial agents which are effective at eradicating both MRSA, as well as acting on pre-formed MRSA biofilms. Using the known scaffold of <em>N</em>-(1,3,4-oxadiazol-2-yl)benzamides, we performed a halogenation study which has led to the identification of <strong>HSGN-2241</strong>. This novel compound was found to effectively kill many multi-drug resistant Gram-positive clinical isolates in a bactericidal manner. The growth inhibition mechanism of <strong>HSGN-2241</strong> was found to be via potassium ion release and subsequent depolarization of the cell membrane. As an initial safety test, <strong>HSGN-2241</strong> was found to not lyse human red blood cells, so it is a promising lead compound for the treatment of bacterial infections caused by <em>Staphylococcus aureus.</em></div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118437"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening and identification of covalent Nrf2 activators with α,β-unsaturated imide structures","authors":"Yasuhiko Izumi ,&nbsp;Norihiko Takeda ,&nbsp;Shuzo Nishimoto ,&nbsp;Honoka Niimi ,&nbsp;Sayuri Ishizu ,&nbsp;Natsumi Muneyasu ,&nbsp;Yuto Takamatsu ,&nbsp;Emi Mishiro-Sato ,&nbsp;Keiko Kano ,&nbsp;Kouya Yamaki ,&nbsp;Takahiro Yamada ,&nbsp;Yutaka Koyama ,&nbsp;Masafumi Ueda","doi":"10.1016/j.bmc.2025.118454","DOIUrl":"10.1016/j.bmc.2025.118454","url":null,"abstract":"<div><div>The Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is a central regulator of cellular defense mechanisms against oxidative stress. The pharmacological activation of this pathway has emerged as a promising strategy for the treatment of diseases such as neurodegeneration and inflammation. In this study, we performed a high-throughput luciferase reporter assay to screen the original compound library comprising small molecules synthesized at Kobe Pharmaceutical University. Initial screening identified KU-0016, KU-0017, and KU-0171 as moderate activators of the Nrf2 pathway. Furthermore, structural comparison revealed a common α,β-unsaturated imide motif, which led to the synthesis of KU-0017-based analogs for structure–activity relationship analysis. Among them, KU-0479 exhibited potent Nrf2 activation and low cytotoxicity. Further assays demonstrated that KU-0479 increased the intracellular glutathione (GSH) levels and protected cells from hydrogen peroxide–induced oxidative damage in a GSH-dependent manner. Moreover, LC–MS analysis confirmed the formation of mono-GSH adducts, and covalent docking simulations suggested covalent binding at the Cys151 residue of Keap1. These findings highlight KU-0479 as a synthetically accessible covalent Nrf2 activator with favorable redox-modulating properties and therapeutic potential.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118454"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design, synthesis, and evaluation of tetrahydrotriazolothiazepine derivatives as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors","authors":"Yukinobu Numata ,&nbsp;Toru Hasegawa ,&nbsp;Makoto Mori ,&nbsp;Tsuyoshi Shinozuka ,&nbsp;Yuko Yamamoto ,&nbsp;Masatoshi Honzumi ,&nbsp;Chinami Kanayama ,&nbsp;Atsushi Aoyagi ,&nbsp;Manabu Abe ,&nbsp;Yuka Ofune ,&nbsp;Kanae Suzuki ,&nbsp;Yuichiro Imamura ,&nbsp;Chizuko Yahara ,&nbsp;Wataru Obuchi ,&nbsp;Ayako Moritomo ,&nbsp;Mizuki Takahashi","doi":"10.1016/j.bmc.2025.118418","DOIUrl":"10.1016/j.bmc.2025.118418","url":null,"abstract":"<div><div>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that converts cortisone to cortisol, and the therapeutic inhibition of this enzyme has attracted substantial attention for the treatment of various disorders including metabolic syndrome, cognitive decline, skin diseases, liver fibrosis, glaucoma, and osteoporosis. With the aim of developing a novel and potent 11β-HSD1 inhibitor, we designed and synthesized a series of tetrahydrotriazolothiazepine derivatives containing a sulfur atom in the seven-membered ring. An optimization study guided by structure-based drug design led to the discovery of compound <strong>3f</strong> as a potent and orally bioavailable 11β-HSD1 inhibitor. The oral administration of <strong>3f</strong> demonstrated good pharmacokinetic profiles and <em>in vivo</em> inhibition of 11β-HSD1 in mice and monkeys.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118418"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}