Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Synthesis and evaluation of novel dihydropyrimidine–oxadiazole hybrid scaffolds as anticholinesterase agents: SAR and in-silico studies","authors":"Ramesh Ambatwar ,&nbsp;Pooja Singh ,&nbsp;Lokesh Chandrakar ,&nbsp;Suman Ghosh ,&nbsp;Ashok K. Datusalia ,&nbsp;Gopal L. Khatik","doi":"10.1016/j.bmcl.2025.130327","DOIUrl":"10.1016/j.bmcl.2025.130327","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently, available drugs only slow the progression of this disease rather than provide a proper cure for it. Acetylcholinesterase (AChE) enzyme is mainly responsible for the progression of AD, and its management can be done by developing its inhibitors, such as anticholinesterases. We have synthesized a series of novel dihydropyrimidine–oxadiazole hybrids (<strong>8a–8ad</strong>) via one-pot economic Biginelli reaction using cobalt perchlorate catalyst. The synthesized compounds were subjected to anticholinesterase activity, which showed promising inhibition of the AChE enzyme. Among all the compounds, <strong>8u</strong> (IC₅₀ = 0.050 ± 0.007 μM) and <strong>8v</strong> (IC₅₀ = 0.057 ± 0.004 μM) were found to be the most potent. Furthermore, molecular docking and molecular dynamics simulations were employed to gain deeper insights into the interactions at the enzyme's active site. The results demonstrated that the compound exhibited conformational stability similar to the reference inhibitor, donepezil.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130327"},"PeriodicalIF":2.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574581","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}

{"title":"Orthosteric inhibition of MutSβ ATPase function: First disclosure of MSH3-bound small molecule inhibitors","authors":"Gareth N. Brace ,&nbsp;Karsten Tillack ,&nbsp;Peter D. Johnson ,&nbsp;Markus Ritzefeld ,&nbsp;Sabine Schaertl ,&nbsp;Elizabeth Frush ,&nbsp;Becka Warfield ,&nbsp;George Ballantyne ,&nbsp;Jung-Hoon Lee ,&nbsp;Gabriel Thieulin-Pardo ,&nbsp;Stefan Steinbacher ,&nbsp;Maren Thomsen ,&nbsp;David Witte ,&nbsp;Michael Finley ,&nbsp;Brinda C. Prasad ,&nbsp;Edith Monteagudo ,&nbsp;Nikolay V. Plotnikov ,&nbsp;Robert E. Pacifici ,&nbsp;Michel Maillard ,&nbsp;Hilary A. Wilkinson ,&nbsp;Tasir S. Haque","doi":"10.1016/j.bmcl.2025.130326","DOIUrl":"10.1016/j.bmcl.2025.130326","url":null,"abstract":"<div><div>Orthosteric inhibitors of the human heterodimeric DNA mismatch repair complex MutSβ were identified by high-throughput screening. Following extensive hit confirmation to remove false positives, two series were found to give consistent activity free of likely artefactual effects. Extensive hit profiling confirmed an ATP-competitive mode of action and resulted in our obtaining the first reported X-ray and cryo-EM structures of small molecule inhibitors of MutSβ occupying the ATP-binding site of MSH3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130326"},"PeriodicalIF":2.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563961","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}

{"title":"Discovery and characterization a new collagenase from Hathewaya massiliensis for effective subcutaneous adipolysis","authors":"Shaozhou Zhu ,&nbsp;Jinhui Mi ,&nbsp;Jiabei Sun ,&nbsp;Jing Yao ,&nbsp;Haiwei Huang","doi":"10.1016/j.bmcl.2025.130324","DOIUrl":"10.1016/j.bmcl.2025.130324","url":null,"abstract":"<div><div>Collagenases hydrolyze peptide bonds in collagen and have established therapeutic applications in connective tissue disorders and medical aesthetics, including treatment of Peyronie's disease, Dupuytren's contracture and localized adipose accumulation. Here, we describe HmCol, a novel collagenase from Hathewaya massiliensis. A rationally truncated, codon optimized HmCol gene was cloned into pET30a and expressed in <em>Escherichia coli</em> BL21(DE3). The purified enzyme exhibits robust collagenolytic activity, with an optimum at pH 7.5 and 45 °C, underscoring its clinical potential. A single site mutant, HmColM, retains substrate affinity but displays a five-fold reduction in specific activity compared with wild type HmCol. In vitro assays on porcine skin explants show that HmCol induces rapid and dose dependent adipocyte lysis, whereas HmColM produces a milder effect. These results expand the collagenase toolkit, offering HmCol as a highly active enzyme and HmColM as a tunable variant for next generation therapeutic strategies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130324"},"PeriodicalIF":2.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563962","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}

{"title":"Improvement of MNAzyme derived from 17EV1 by modification on the split catalytic core for biosensor design","authors":"Mengyan Qin ,&nbsp;Fumei Zhang ,&nbsp;Huanhuan Liu ,&nbsp;Weiguo Shi ,&nbsp;Shihui Liu ,&nbsp;Junlin He","doi":"10.1016/j.bmcl.2025.130325","DOIUrl":"10.1016/j.bmcl.2025.130325","url":null,"abstract":"<div><div>MNAzymes were derived from catalytic DNAzymes (10–23, 8–17, 17E, et al) with a split catalytic core at certain positions, an extra oligonucleotide (termed as initiating oligonucleotide) was introduced to recover the catalytic core and the catalytic activity. With this initiating oligonucleotide, thus, the applications of MNAzymes as the detection biosensors have been expanded dramatically to a wide range of analytes of interest. However, the split catalytic core of MNAzymes is less active than the intact DNAzymes, many designs were concentrated on the signaling methods for a better performance. Here, MNAzymes from 17EV1 were constructed with miR-21 and miR-155 as the initiating oligonucleotides, and chemical modification on the split catalytic core was conducted, by the substitution of the residue A15 with 6-(3-aminopropyl)-2′-deoxyadenosine (compound <strong>1</strong>), two modified MNAzymes (MNAzyme-21-1 and MNAzyme-155-1) were obtained. With fluorescence signaling method, the limit of detection for miR-21 and miR-155 could be improved for about 4.9 and 12-fold, respectively. With this critical element, the modified MNAzyme could be further adapted for other analytes and combined with other detection methods for better performance, due to the programmability of MNAzyme components.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130325"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558667","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}

{"title":"Discovery of novel fusidic acid derivatives in mitigating LPS-induced acute liver injury by modulating RIPK1","authors":"Jing Gao ,&nbsp;Zhiyuan Geng ,&nbsp;Hui Yang ,&nbsp;Yan Wei ,&nbsp;Zhuoxi Chen ,&nbsp;Qian Jiang ,&nbsp;Yutong Chen ,&nbsp;Yi Bi ,&nbsp;Leiming Zhang","doi":"10.1016/j.bmcl.2025.130322","DOIUrl":"10.1016/j.bmcl.2025.130322","url":null,"abstract":"<div><div>Inflammation plays a crucial role in the onset and progression of sepsis, affecting the overall trajectory of the condition. Additionally, sepsis can result in acute liver injury, which in turn may cause damage to multiple organ systems. Fusidic acid (<strong>FA</strong>) is a natural product with a steroidal structure and has good anti-inflammatory activity without the hormonal side effects of steroidal anti-inflammatory drugs, so it has potential applications in the development of anti-inflammatory drugs. In the present study, a series of novel <strong>FA</strong> derivatives were designed and synthesized by structural modification of <strong>FA</strong> C-3, C-16 and C-21, among which, compound <strong>12</strong> exhibited the strongest anti-inflammatory activity. Compound <strong>12</strong> inhibited nitric oxide (NO) release with an IC₅₀ of 3.26 ± 0.12 μM. Assessments conducted in both in vivo and in vitro settings indicated that compound <strong>12</strong> can reduce the levels of inflammatory factors, inhibit the activation of inflammatory pathways and improve liver pathological damage. Cellular thermal shift assay showed that compound <strong>12</strong> had binding ability with receptor interaction protein kinase 1 (RIPK1). Furthermore, through the western blotting experiment, this study found that compound <strong>12</strong> inhibited proteins such as RIPK1, p-IκB, p-p65, p-p38, p-JNK and p-ERK within the RIPK1/nuclear factor-κB (NF-κB)/mitogen-activated protein kinases (MAPK) signaling pathway. Concurrently, ELISA experiments indicated that compound <strong>12</strong> could dose-dependently reduce the levels of IL-6 and TNF-α. These results imply that compound <strong>12</strong> can protect the liver from inflammatory invasion by suppressing RIPK1 expression, which subsequently results in decreased activation of the NF-κB and MAPK signaling pathways. In this study, we creatively modified the structure of fusidic acid and obtained a new type of fusidic acid derivative <strong>12</strong>. Compared with the glucocorticoids currently used for glucocorticoid receptors, compound <strong>12</strong> is novel in terms of structure and mechanism of action in alleviating sepsis. Our research indicates that compound <strong>12</strong> represents a promising candidate for the design and development of anti-sepsis therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130322"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558666","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}

{"title":"Biotinylated Hsp90β-selective inhibitors","authors":"Chaitanya Kondam ,&nbsp;Nitin Sharma ,&nbsp;Gaya K. Amarasinge ,&nbsp;Brian S.J. Blagg","doi":"10.1016/j.bmcl.2025.130323","DOIUrl":"10.1016/j.bmcl.2025.130323","url":null,"abstract":"<div><div>Heat shock protein 90 (Hsp90) has emerged as an attractive target for the development of therapeutics against cancer due to its crucial role in the folding and stabilization of client proteins associated with oncogenesis. Hsp90 pan inhibitors entered clinical trials for the treatment of cancer and showed detrimental adverse effects. Hsp90α isoform inhibition has been attributed to on-target toxicities such as cardio- and ocular-toxicity. To determine whether off-target toxicities caused by the interaction of Hsp90β inhibitors with other cellular proteins, biotinylated Hsp90β-selective inhibitors with various tether lengths were synthesized and validated in vitro to be used in affinity purification experiments to identify proteins that interact with Hsp90β-selective inhibitors. These studies will lead to the development of Hsp90β-selective inhibitors with reduced toxicities.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130323"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558665","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}

{"title":"Genipin derivative induced the apoptosis and inhibited the invasion and migration of A549 cancer cells via regulation of EGFR/JAK1/STAT3 signaling","authors":"Do Hyeon Kim ,&nbsp;Hyun-Ha Hwang ,&nbsp;Jinwon Hong ,&nbsp;Kobeom Seo ,&nbsp;Jung Hwan Choi ,&nbsp;Jeong-Hui Je ,&nbsp;Hyeong-Chan Lee ,&nbsp;Ji-Sung Yoo ,&nbsp;Seong-Gyu Ko ,&nbsp;Jae Yeol Lee","doi":"10.1016/j.bmcl.2025.130320","DOIUrl":"10.1016/j.bmcl.2025.130320","url":null,"abstract":"<div><div>Genipin, a natural compound derived from the fruit of <em>Gardenia jasminoides</em>, has demonstrated anticancer effects in various malignancies, including gastric, cervical, breast, and lung cancers. In this study, a series of genipin derivatives was designed, synthesized, and evaluated for their anticancer activity against A549 non-small-cell lung cancer (NSCLC) cells to identify more potent analogs and elucidate their mechanisms of action. Several derivatives exhibited stronger antiproliferative effects than genipin, with compound <strong>2b</strong> showing the most potent activity (IC₅₀ = 117 μM) and effectively suppressing colony formation. Further investigations revealed that <strong>2b</strong> induced cell cycle arrest and apoptotic cell death. Mechanistically, <strong>2b</strong> inhibited the phosphorylation of EGFR, JAK1, and STAT3, and modulated epithelial–mesenchymal transition (EMT)-related protein expression, thereby attenuating cell migration and invasion. Notably, although <strong>2b</strong> did not inhibit ATP-dependent EGFR kinase activity in vitro, molecular docking simulations indicated its binding to the EGFR extracellular domain (domain III), suggesting an alternative, ATP-independent mechanism—likely via interference with EGF binding. Collectively, these results highlight <strong>2b</strong> (MRC-G-001) as a promising lead-like compound for further optimization and preclinical development targeting EGFR-driven A549 cancer cells.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130320"},"PeriodicalIF":2.5,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524019","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}

{"title":"Desulfonylative halogenation of arene sulfonyl chlorides using N-halosuccinimides: Synthesis, molecular docking, and anti-Alzheimer activity","authors":"Vikas Yadav ,&nbsp;Rohit Kumar ,&nbsp;Saripella Srikrishna ,&nbsp;Virendra Prasad","doi":"10.1016/j.bmcl.2025.130321","DOIUrl":"10.1016/j.bmcl.2025.130321","url":null,"abstract":"<div><div>Considering the significant biological potential of halogenated arenes, we developed a novel and eco-friendly method for accessing dihalogenated arenes <em>via</em> <em>N</em>-halosuccinimide-promoted desulfonylative halogenation of arenesulfonyl chlorides under metal-free conditions. <em>In silico</em> evaluations of selected compounds for amyloid-beta (Aβ) protein interactions identified compounds 1d and 2d as promising candidates, exhibiting strong binding potential and low toxicity in wild-type <em>Oregon R</em> flies. Furthermore, these compounds demonstrated significant neuroprotective activity in an Aβ-induced Alzheimer's disease model in <em>Drosophila</em>, emphasizing the need for further studies in higher organisms and detailed mechanistic investigations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130321"},"PeriodicalIF":2.5,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525762","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}

{"title":"Natural products targeting the NF-κB signaling pathway:Potential therapeutic drug candidates","authors":"Hai-Yang Li ,&nbsp;Lu Tong ,&nbsp;Qunfei Zhao,&nbsp;Qing-Li He","doi":"10.1016/j.bmcl.2025.130319","DOIUrl":"10.1016/j.bmcl.2025.130319","url":null,"abstract":"<div><div>The NF-κB signaling pathway plays a critical role in regulating cell growth, immune responses, and inflammation. Aberrant activation of this pathway is closely associated with various diseases, including cancers, autoimmune disorders, inflammatory diseases, and neurodegenerative diseases. Consequently, therapeutic strategies targeting the NF-κB pathway, particularly these natural products derived from plants or microorganisms, have attracted significant attention. This review commences with an introduction to the key components and functions of the NF-κB signaling pathway, and mainly focuses on natural products and their analogs targeting different stages of this pathway, especially membrane receptors, kinases, and p65/50 subunits, as well as other signaling pathways that regulate the NF-κB pathway, aiming to provide substantial guidance for the design and development of new NF-κB inhibitors and the clinical treatment of NF-κB-related diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130319"},"PeriodicalIF":2.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524257","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}

{"title":"Histone deacetylase 6 inhibitors in Alzheimer's disease therapy: structure design and challenges","authors":"Baiyun Dang ,&nbsp;Hou Chen ,&nbsp;Shiru Liu ,&nbsp;Haijuan Liu ,&nbsp;Zhiwen Kang ,&nbsp;Zhen Yang ,&nbsp;Weixia Yang ,&nbsp;Jiadong Hu ,&nbsp;Xin Chen","doi":"10.1016/j.bmcl.2025.130318","DOIUrl":"10.1016/j.bmcl.2025.130318","url":null,"abstract":"<div><div>Recently, histone deacetylases 6 (HDAC6) has been extensively studied for involvement in pathogenesis of central nervous system (CNS) diseases, especially for Alzheimer's disease (AD). A lot of literatures have disclosed that HDAC6 inhibitors (HDAC6is) are effective and promising in AD treatment. Though many HDAC6is were reported, only a handful of them displayed appropriate in vivo activities in models of neurological diseases. BBB permeability and off-target toxicity are the major obstacle and challenge for the development of available HDAC6is. In this review, we summarized recent brain-permeable HDAC6is from drug design perspective, and discussed the challenges and structural modification attempts in developing HDAC6is with better blood-brain barrier (BBB) permeability.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130318"},"PeriodicalIF":2.5,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511001","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}