Bioorganic & Medicinal Chemistry最新文献

{"title":"Discovery of N-pyridazin-3-piperidine derivatives acting as p53 activators against breast cancer: In vitro and in silico evaluations","authors":"Aoxuan Zhang ,&nbsp;Bowen Tang ,&nbsp;Siyu Zhou ,&nbsp;Chaoyang Sui ,&nbsp;Sinian He ,&nbsp;Yingying Liu ,&nbsp;Mingdong Li ,&nbsp;Yuqing Qian","doi":"10.1016/j.bmc.2025.118410","DOIUrl":"10.1016/j.bmc.2025.118410","url":null,"abstract":"<div><div>Transcription factor p53 plays an important role in tumor suppression, including apoptosis and cell cycle arrest. Inhibition of murine double minute 2 (MDM2)-p53 interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. In this investigation, we developed an innovative series of N-pyridazin-3-piperidine derivatives as potential p53 activators against breast cancer. Among these, compound <strong>D16</strong> emerged as a highly effective p53 activator, demonstrating strong efficacy against the MCF-7 cell line while maintaining minimal toxicity toward normal human cells. This article demonstrates an efficient protocol to design and synthesize potent biologically active compounds, providing a basis for developing novel p53 activators.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118410"},"PeriodicalIF":3.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119775","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-inspired potent anticancer congeners: chronological advancements, structure-activity relationship (SAR) studies and future perspectives","authors":"Abdul Rahaman T A ,&nbsp;Nandini ,&nbsp;Tanmoy Tantra,&nbsp;Sandeep Chaudhary","doi":"10.1016/j.bmc.2025.118392","DOIUrl":"10.1016/j.bmc.2025.118392","url":null,"abstract":"<div><div>Cancer is among the leading causes of mortality and morbidity globally. Natural products have played a significant role in bringing novel therapies to the clinic for the treatment of various types of cancer. However, several natural products have low potency, chemical instability, poor pharmacokinetics, and high toxicity. Therefore, a natural-product-inspired strategy has been utilized to overcome the limitations of natural products in cancer drug discovery. Herein, we present a critical review to describe how medicinal chemists designed anti-cancer agents <em>via</em> a natural-product-inspired strategy. We have also illustrated how this approach is used to overcome drug resistance in cancer. The natural product-inspired analogues/derivatives were classified into different categories. Our focus extends to reviewing the design strategies, <em>in vitro</em>/<em>in vivo</em> results, and structure-activity relationship (SAR) studies of natural-product-inspired molecules as anti-cancer agents. We expect that this review will inspire the development of more effective and diversified anti-cancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118392"},"PeriodicalIF":3.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197670","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":"Design, in silico study, and efficient synthesis of N-acylhydrazones in deep eutectic solvents: potential anticonvulsant agents","authors":"Rosa Maria B. Alves ,&nbsp;Emelly Suelen F.R. Santos ,&nbsp;Mayara Vitória S. Silva ,&nbsp;Felipe B. Sousa ,&nbsp;Jéssica Jennifer B. Silva ,&nbsp;Malu Maria Lucas dos Reis ,&nbsp;Rhayane O. Santos ,&nbsp;Karen C. Weber ,&nbsp;Claudio Gabriel Lima-Junior ,&nbsp;Dayse N. Moreira","doi":"10.1016/j.bmc.2025.118398","DOIUrl":"10.1016/j.bmc.2025.118398","url":null,"abstract":"<div><div>In medicinal chemistry, the search for effective epilepsy treatments remains critical, as current drugs often show limited efficacy, require combinations, and cause adverse effects. This work aims to synthesize <em>N</em>-acylhydrazones derived from isatin and to explore approaches that combine sustainable organic synthesis methodologies and advanced computational tools for the identification and development of novel antiepileptic drug candidates. The present methods consisted of the synthesis of <em>N</em>-acylhydrazones using a deep eutectic solvent (DES) composed of choline chloride and <em>p</em>-toluene sulfonic acid (<em>p</em>-TSA), which enabled the development of an efficient, selective, and environmentally friendly synthetic route. Eighteen isatin derivatives were synthesized in a few minutes with good to excellent product yields, and the low solubility of some substrates was overcome by moderate heating. DES demonstrated high recyclability, being reused for up to four cycles without any loss of activity. Additionally, <em>in silico</em> analyses were performed to evaluate the ligand-receptor interactions between the compounds and the GABA_A receptor, a key therapeutic target for modulating epileptic seizures. The synthesized compounds exhibit favorable interactions within the GABA_A receptor binding site, including hydrogen bonds, hydrophobic contacts, and aromatic stacking interactions. Compounds <strong>3d</strong>, <strong>3e</strong>, and <strong>3o</strong> are noteworthy for interacting with key residues associated with biological activity, showing promising binding profiles compared to reference ligands. This study reinforces the potential of DES and virtual screening as modern and effective approaches in the development of antiepileptic drugs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118398"},"PeriodicalIF":3.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119774","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 of N-(4-(pyridin-4-yloxy)phenyl)-1,2-dihydropyridine-3-carboxamide derivatives as potential type II c-Met inhibitors","authors":"Qingwang Xin ,&nbsp;Chao Fang ,&nbsp;Baojian Xing ,&nbsp;Jikang Du ,&nbsp;Simin Ren","doi":"10.1016/j.bmc.2025.118394","DOIUrl":"10.1016/j.bmc.2025.118394","url":null,"abstract":"<div><div>The c-Met receptor tyrosine kinase plays a pivotal role in oncogenesis and tumor progression, with its dysregulation frequently contributing to therapeutic resistance. Through structure-based virtual screening of the ChemDiv database, we prioritized 20 candidates, including type II and III inhibitors, with compounds <strong>A3</strong> and <strong>A17</strong> emerging as initial hits. Subsequent optimization yielded <strong>A30</strong>, a hybrid scaffold inhibitor demonstrating potent activity against both wild-type and mutant c-Met, comparable to the reference inhibitor BMS-777607. Cellular assays revealed that <strong>A30</strong> significantly suppressed proliferation, migration, and colony formation in NCI-H1993 and HCT-116 cells, while inducing apoptosis. These findings highlight <strong>A30</strong> as a promising lead compound for targeting c-Met-driven resistance.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118394"},"PeriodicalIF":3.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098480","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":"Design and synthesis of 4-azaindoles derivatives: targeting the cardiac troponin I-interacting kinase (TNNI3K)","authors":"Ke Chen,&nbsp;Meng Sun,&nbsp;Kejing Ma,&nbsp;Bing Wang,&nbsp;Xiaodong Fang,&nbsp;Qiming Li,&nbsp;Zihan Ye,&nbsp;Yifei Ren,&nbsp;Weina Han","doi":"10.1016/j.bmc.2025.118395","DOIUrl":"10.1016/j.bmc.2025.118395","url":null,"abstract":"<div><div>Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific protein kinase, whose overexpression is closely linked to heart failure and ventricular remodeling. TNNI3K inhibitors regulate the phosphorylation of serine residues in downstream cardiac troponin I (cTnI) and affect the p38 pathway to prevent ventricular remodeling and myocardial cell damage. This study designed 120 compounds based on the reported quantitative structure-activity relationships (QSAR) of TNNI3K inhibitors. Following virtual screening, 4-azaindole was identified as the optimal scaffold. Subsequent synthesis of derivatives SK1–SK5 demonstrated their protective effects on damaged cardiomyocytes. Importantly, molecular dynamics (MD) simulations confirmed that compound SK5 forms a stable complex with TNNI3K and elucidated key binding residues and their interaction modes. These findings collectively validate the rational design of TNNI3K-targeted compounds and support SK5's potential as an anti-heart failure lead candidate.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118395"},"PeriodicalIF":3.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098479","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 of hydroxamate derivatives as potent anti-gastric cancer agents via inducing oxidative stress and DNA damage","authors":"Yi-Chao Xu ,&nbsp;Yu Zhang ,&nbsp;Yao-Jie Xue,&nbsp;Kai-Li Lv,&nbsp;Ya-Jing Chen","doi":"10.1016/j.bmc.2025.118396","DOIUrl":"10.1016/j.bmc.2025.118396","url":null,"abstract":"<div><div>Gastric cancer (GC) remains one of the most malignant cancers with high morbidity and mortality, necessitating the development of new agent for GC treatment. Herein, we evaluated the anti-proliferative activities of a series of hydroxamate derivatives <strong>3a-3</strong><strong>k</strong> against GC cells, and found that compound <strong>3i</strong> could inhibit the proliferation of GC cells at micromolar level. The subsequent cell growth curve, cell morphology, cell cycle and cell apoptosis experiments indicated that compound <strong>3i</strong> inhibited the growth of GC cells <em>via</em> inducing cell apoptosis rather than suppressing cell cycle. Besides, the rescue experiments showed that antioxidants (<em>N</em>-acetylcysteine and dithiothreitol) instead of cell apoptosis, necrosis or ferroptosis inhibitors could totally rescue the proliferation of GC cells prevented by compound <strong>3i</strong>. Then, RNA-seq, western blotting and alkaline comet assay studies showed that compound <strong>3i</strong> could cause DNA damage. Consistently, the <em>in vivo</em> experiments indicated that compound <strong>3i</strong> could obviously inhibit the growth of tumor and induce the expression of p53 and γH2AX. Overall, compound <strong>3i</strong> exhibited its anti-proliferative activity through increasing ROS level and inducing DNA damage, thus resulting in cell apoptosis of GC cells. Furthermore, docking study exposed the ability of compound <strong>3i</strong> to chelate Zn²⁺ located within HDACs active site. Therefore, compound <strong>3i</strong> provides an important strategy on developing lead compounds for GC therapy <em>via</em> oxidative stress.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118396"},"PeriodicalIF":3.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098481","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":"Decades old glitazones still find niche in drug discoveries as PPAR-γ agonists: medicinal chemistry perspective, structure-activity relationships and therapeutic implications","authors":"P. Archana ,&nbsp;T. Durai Ananda Kumar ,&nbsp;N. Vijaya Ganesh ,&nbsp;Manal Mohammed ,&nbsp;Harshal Pundalik Tavanoji ,&nbsp;R. Deepikarani ,&nbsp;B.R. Prashantha Kumar","doi":"10.1016/j.bmc.2025.118393","DOIUrl":"10.1016/j.bmc.2025.118393","url":null,"abstract":"<div><div>Diabetes Mellitus, specifically type 2 diabetes mellitus (T2D), remains a serious global health challenge owing to the physiological changes linked with insulin resistance and hyperglycemia. It causes morbidity, mortality, and thereby financial burden on healthcare systems. Thiazolidinediones or glitazones, a decade-old, well-established pharmacophore, continue to play an important role in drug discovery as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, offering valuable insights into medicinal chemistry in terms of structure-activity relationships and therapeutic applications. This comprehensive review explores the biology of glitazones and their interactions with the PPAR-γ receptor, with a particular emphasis on their role in modulating glucose metabolism in T2D. Discussed the progression of glitazones from first- to third-generation, highlighting advances in selective PPAR-γ modulators (SPPAR-γMs) aimed to enhance efficacy and safety while minimizing adverse effects like fluid retention, weight gain, and cardiovascular risks.</div><div>This review mainly focuses on medicinal chemistry, SAR/QSAR, molecular docking, and pharmacophore modelling and outlines the synthetic strategies for glitazones. Both conventional methods and the exploitation of natural substrates as bioisosteric replacements to enhance potency and safety profiles are explained. In addition to antidiabetic effects, glitazones are known to exhibit pleiotropic roles as anticancer, neuroprotective, anti-inflammatory, and hepatoprotective agents. Their therapeutic relevance extends to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and polycystic ovary syndrome (PCOS) supported by recent clinical trials. This review also discusses limitations and toxicity, including the need for safer and more efficacious PPAR modulators. Overall, this review emphasizes the importance of glitazones in metabolic disease, highlights new breakthroughs, and identifies exciting new directions for drug discoveries.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118393"},"PeriodicalIF":3.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119776","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":"A comprehensive review on indole-chalcone hybrid as promising scaffold with diverse therapeutic potential","authors":"Harshal Tavanoji ,&nbsp;Ganesh Latambale ,&nbsp;Kapil Juvale","doi":"10.1016/j.bmc.2025.118391","DOIUrl":"10.1016/j.bmc.2025.118391","url":null,"abstract":"<div><div>Indole-chalcone hybrids have emerged as a highly promising class of compounds in modern medicinal chemistry, owing to their unique dual pharmacophore structure that integrates the bioactive indole and chalcone units. Recent studies have highlighted these hybrids' diverse and potent pharmacological activities, including anticancer, antimicrobial, anti-inflammatory, antidiabetic, antiviral, and neuroprotective effects. The combination of the indole ring and chalcone scaffold, achieved through molecular hybridization, facilitates a synergistic mechanism of action, enabling these hybrids to modulate multiple biological pathways and thereby enhance their therapeutic potential. This review focuses on indole-chalcone hybrids' structure-activity relationship (SAR) to identify the key molecular determinants that contribute to their bioactivity. Furthermore, the multifunctional nature of these hybrids is discussed, offering promising prospects for developing novel, more effective therapeutic agents with optimized efficacy and reduced toxicity. By consolidating current findings, this review aims to provide a comprehensive resource to guide future research efforts and facilitate the continued exploration of indole-chalcone hybrids as versatile scaffolds in drug discovery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118391"},"PeriodicalIF":3.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098470","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":"GSPT1 degraders: research progress, development strategies and challenges","authors":"Chen Liu ,&nbsp;Hongkang Peng ,&nbsp;Peng Chen ,&nbsp;Yuxiang Li ,&nbsp;Zihao Deng ,&nbsp;Shaojie Li ,&nbsp;Tong Yang ,&nbsp;Ke Liu ,&nbsp;Zhen Wang ,&nbsp;Linyi Liu","doi":"10.1016/j.bmc.2025.118390","DOIUrl":"10.1016/j.bmc.2025.118390","url":null,"abstract":"<div><div>Dysregulation of GSPT1 which is a critical translation termination factor plays an important role in oncogenesis and cancer progression. However, GSPT1 lacks suitable binding pockets and has long been considered an “undruggable” target. Recent studies have revealed that Cereblon E3 Ligase Modulators (CELMoDs), a class of molecular glue-type protein degraders, can bind to the E3 ubiquitin ligase substrate receptor Cereblon and induce Cereblon to recruit GSPT1, leading to GSPT1 degradation. This breakthrough provides a novel therapeutic strategy for GSPT1-related cancers. Currently, several selective GSPT1-degraders have entered clinical trials. This review summarized the research progress of various GSPT1 degraders with an emphasis on their design, activity studies and development strategy, aiming to provide valuable insights for the further development of GSPT1 degraders.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118390"},"PeriodicalIF":3.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156523","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":"A bottomless well: 1,2,4-Triazoles continue to inspire scientific researchers to develop more and more anticancer molecules","authors":"Hamada S. Abulkhair","doi":"10.1016/j.bmc.2025.118389","DOIUrl":"10.1016/j.bmc.2025.118389","url":null,"abstract":"<div><div>1,2,4-Triazoles represent an endless source of clinically bioactive molecules, captivating scientific researchers with their diverse biological activities. This review explores the recent approaches employed by chemists and biologists in the synthesis and biological activity assessment of more than two hundred 1,2,4-triazole anticancer candidates that have been reported throughout 2020–2025. The review also explores the different biological targets these compounds act upon, like A2B, STAT, VEGFR, EGFR, p97, aromatase, and ferroptosis. Mechanistic insights into how these derivatives exert their actions are discussed, highlighting their potential uses in medicine. Given that comprehensive overview in the field, this review tries to inspire and guide future research.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118389"},"PeriodicalIF":3.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060008","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}