Bioorganic & Medicinal Chemistry最新文献_第6页

Chemical dissection of bacterial virulence 细菌毒力的化学解剖。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-12-20 DOI: 10.1016/j.bmc.2024.118047

Xinglin Yang , Howard C. Hang

{"title":"Chemical dissection of bacterial virulence","authors":"Xinglin Yang , Howard C. Hang","doi":"10.1016/j.bmc.2024.118047","DOIUrl":"10.1016/j.bmc.2024.118047","url":null,"abstract":"<div><div>The emergence of antibiotic-resistant bacteria has intensified the need for novel therapeutic strategies targeting bacterial virulence rather than growth or survival. Bacterial virulence involves complex processes that enable pathogens to invade and survive within host cells. Chemical biology has become a powerful tool for dissecting these virulence mechanisms at the molecular level. This review highlights key chemical biology approaches for studying bacterial virulence, focusing on four areas: 1) regulation of virulence, where chemoproteomics has identified small molecule-protein interactions that modulate virulence gene expression; 2) identification of virulence proteins, using techniques like unnatural amino acid incorporation and activity-based protein profiling (ABPP) to uncover proteins involved in infection; 3) post-translational modifications of host proteins, where chemical probes have revealed how bacterial effectors alter host cell processes; and 4) effector-host protein interactions, with methods such as bifunctional unnatural amino acid incorporation facilitating the discovery of key host targets manipulated by bacterial effectors. Collectively, these chemical tools are providing new insights into pathogen-host interactions, offering potential therapeutic avenues that aim to disarm pathogens and combat antibiotic resistance.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118047"},"PeriodicalIF":3.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity 利奈唑胺减轻骨髓抑制和血清素能毒性的结构毒性关系

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-29 DOI: 10.1016/j.bmc.2024.118025

Matin Shaikh , Harun Patel

{"title":"Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity","authors":"Matin Shaikh , Harun Patel","doi":"10.1016/j.bmc.2024.118025","DOIUrl":"10.1016/j.bmc.2024.118025","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a significant global health challenge, with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains posing severe threats to treatment efficacy. Linezolid, a key component of the BPaL (Bedaquiline, Pretomanid and Linezolid) regimen, has demonstrated substantial efficacy against MDR-TB and XDR-TB. However, its clinical utility is often limited by side effects such as myelosuppression and monoamine oxidase (MAO) inhibition, linked to its mechanism of action. This perspective centres on the structural toxicity relationship (STR) of Linezolid and its analogues, exploring modifications to the C-ring and C-5 position that aim to reduce these toxicities while maintaining or enhancing antibacterial activity. Several promising analogues have been identified that exhibit reduced myelosuppression and MAO inhibition, highlighting the potential for developing safer Linezolid derivatives. The findings underscore the importance of continued research into the structure toxicity relationships of oxazolidinones to improve the therapeutic profiles of these essential drugs in combating drug-resistant TB.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118025"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758891","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}

引用次数: 0

Synthesis and anti-tumor activity of menthylamine derivatives: Focusing on the potent inhibitory effect of compound W8 on glioma growth 甲胺衍生物的合成及抗肿瘤活性：重点研究化合物W8对胶质瘤生长的抑制作用

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-28 DOI: 10.1016/j.bmc.2024.118024

Xiaoran Wu , Yanhang Zhuo , Jiangjian Liu , Ziming He , Meiling Wang , Wenjun Lei , Qiong Liang , Aidong Wang , Zhiyi Shen , Sunhui Chen , Shihao Zheng , Huihui Huang

{"title":"Synthesis and anti-tumor activity of menthylamine derivatives: Focusing on the potent inhibitory effect of compound W8 on glioma growth","authors":"Xiaoran Wu , Yanhang Zhuo , Jiangjian Liu , Ziming He , Meiling Wang , Wenjun Lei , Qiong Liang , Aidong Wang , Zhiyi Shen , Sunhui Chen , Shihao Zheng , Huihui Huang","doi":"10.1016/j.bmc.2024.118024","DOIUrl":"10.1016/j.bmc.2024.118024","url":null,"abstract":"<div><div>In this work, we successfully synthesized eight distinct compounds, comprising four chiral menthylamines and related derivatives. We evaluated their cytotoxic potential against a panel of human cancer cell lines, including human colon cancer HCT-116 cells, human esophageal squamous KYSE-150 cells, human breast cancer MCF-7 cells, and human glioma U87 cells. The U87 cells were chosen for a more in-depth investigation of their anti-tumor efficacy. Further exploration of the cytotoxicity mechanisms was conducted, complemented by in vivo studies using mice bearing tumors. These analyses unveiled the possible mechanisms by which menthylamide derivatives exert their anti-tumor effects. Notably, compound W8 demonstrated a potent inhibitory action against the proliferation of brain glioma cells. The findings from this research provide valuable insights that pave the way for the future application of menthylamides in cancer therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118024"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142757395","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}

引用次数: 0

De novo discovery of cyclic peptide inhibitors of IL-11 signaling IL-11信号通路环肽抑制剂的新发现。

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-27 DOI: 10.1016/j.bmc.2024.118017

Sam Lear , Rosalba Tafi , Valentina A. Di Biasio , Petro Halkowycz , Ruhi Kamran , Joanne Miura , Tony S. Gibson , Jing Li , Bertram Bleck , Claudia Dall’Armi , Anna Demartis , Antoine Henninot

{"title":"De novo discovery of cyclic peptide inhibitors of IL-11 signaling","authors":"Sam Lear , Rosalba Tafi , Valentina A. Di Biasio , Petro Halkowycz , Ruhi Kamran , Joanne Miura , Tony S. Gibson , Jing Li , Bertram Bleck , Claudia Dall’Armi , Anna Demartis , Antoine Henninot","doi":"10.1016/j.bmc.2024.118017","DOIUrl":"10.1016/j.bmc.2024.118017","url":null,"abstract":"<div><div>Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited. In this work, a series of cyclic peptides derived from phage display biopanning campaigns against both IL-11 and its cognate receptor IL-11Rα are presented. The most active IL-11 binder (peptide <strong>4</strong>, <em>K</em><sub>D</sub> 140 nM) exhibited inhibition of IL-11/IL-11Rα dimerization in a biochemical AlphaLISA assay (<em>K</em><sub>i</sub> 300 nM), and alanine scanning was carried out on this sequence to identify residues important for target binding and inhibitory activity. Further structural optimization yielded lead peptide <strong>15</strong> (<em>K</em><sub>i</sub> 180 nM), which exhibited at least 70-fold greater activity than IL-11 inhibitors previously reported in the literature. The <em>de novo</em> peptide macrocycles presented serve as a robust starting point for development of therapeutic inhibitors of the IL-11/IL-11Rα interaction.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"119 ","pages":"Article 118017"},"PeriodicalIF":3.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a potent and selective TRPC3 antagonist with neuroprotective effects 发现具有神经保护作用的强效选择性 TRPC3 拮抗剂

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-26 DOI: 10.1016/j.bmc.2024.118021

Jiaxing Wang , Sicheng Zhang , Vijay K. Boda , Hao Chen , Hyunseo Park , Keyur Parmar , Dejian Ma , Duane D. Miller , Bernd Meibohm , Jianyang Du , Francesca-Fang Liao , Zhongzhi Wu , Wei Li

{"title":"Discovery of a potent and selective TRPC3 antagonist with neuroprotective effects","authors":"Jiaxing Wang , Sicheng Zhang , Vijay K. Boda , Hao Chen , Hyunseo Park , Keyur Parmar , Dejian Ma , Duane D. Miller , Bernd Meibohm , Jianyang Du , Francesca-Fang Liao , Zhongzhi Wu , Wei Li","doi":"10.1016/j.bmc.2024.118021","DOIUrl":"10.1016/j.bmc.2024.118021","url":null,"abstract":"<div><div>The TRPC3 protein plays a pivotal role in calcium signaling, influencing cell function. Aberrant TRPC3 expression is implicated in various pathologies, including cardiovascular diseases, tumors, and neurodegeneration. Despite its functional similarities with TRPC6 and TRPC7, TRPC3 exhibits distinct roles in disease contexts. Therefore, it is of paramount importance to develop a potent and selective TRPC3 antagonist with favorable drug-like properties. We employed extensive medicinal chemistry synthesis and structure–activity relationships (SARs) study. Thirty-one novel TRPC3 antagonists were designed and synthesized using the lead compound <strong>JW-65</strong> as the scaffold. Compound <strong>60a</strong> exhibits a 4-fold improvement in potency and displays exceptional selectivity. With favorable drug-like properties, this compound shows a heightened <em>in vitro</em> neuronal protective effect. Molecular modeling suggests possible modes of action between the TRPC3 protein and its antagonists. In summary, <strong>60a</strong> holds significant promise for clinical development in conditions associated with TRPC3 dysregulation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118021"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719916","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}

引用次数: 0

Synthesis of aromatic glycoconjugates as anti-fungal agents against Candida spp. and assessment of their covalent crosslinking capabilities 芳香糖缀合物抗念珠菌的合成及其共价交联性能的评价

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-26 DOI: 10.1016/j.bmc.2024.118020

Kyle Doherty , Keela Kessie , Harlei Martin , Jordan Loughlin , Oliwier Dulawa , Kaja Kasements , Trinidad Velasco-Torrijos

{"title":"Synthesis of aromatic glycoconjugates as anti-fungal agents against Candida spp. and assessment of their covalent crosslinking capabilities","authors":"Kyle Doherty , Keela Kessie , Harlei Martin , Jordan Loughlin , Oliwier Dulawa , Kaja Kasements , Trinidad Velasco-Torrijos","doi":"10.1016/j.bmc.2024.118020","DOIUrl":"10.1016/j.bmc.2024.118020","url":null,"abstract":"<div><div>Covalent drugs are becoming increasingly attractive in drug discovery, as they can enhance potency and selectivity for their molecular targets. Covalent inhibitors have been investigated for several therapeutic applications, including anti-cancer and anti-infection agents. However, there are only a few examples of covalent inhibitors targeting fungal pathogens. We have previously reported aromatic glycoconjugates (AGCs) capable of inhibiting the adhesion of <em>Candida albicans</em> to buccal epithelial cells. In this work, we synthesize novel derivatives of the AGCs to which we have added reactive functional groups, such as acryloyl and vinyl sulfones, and investigated their antifungal efficacy against <em>Candida</em> spp<em>.</em> Although the compounds were ineffective at clinically relevant concentrations, we found that some of the galactose derivatives featuring reactive groups were amongst the most active, so their ability to crosslink nucleophilic side chains was assessed in model reactions.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118020"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743644","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}

引用次数: 0

A bleomycin-mimicking manganese-porphyrin-conjugated mitochondria-targeting peptoid for cancer therapy 一种用于癌症治疗的博莱霉素模拟锰卟啉共轭线粒体靶向蛋白胨

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-24 DOI: 10.1016/j.bmc.2024.118023

Minjae Jun , Veena Vijayan , Seungheon Shin , Ho Yeon Nam , Dasom Song , Jieun Choi , Shyam Vasvani , Steve K. Cho , In-Kyu Park , Jiwon Seo

{"title":"A bleomycin-mimicking manganese-porphyrin-conjugated mitochondria-targeting peptoid for cancer therapy","authors":"Minjae Jun , Veena Vijayan , Seungheon Shin , Ho Yeon Nam , Dasom Song , Jieun Choi , Shyam Vasvani , Steve K. Cho , In-Kyu Park , Jiwon Seo","doi":"10.1016/j.bmc.2024.118023","DOIUrl":"10.1016/j.bmc.2024.118023","url":null,"abstract":"<div><div>Bleomycin (BLM) is a natural product with established anticancer activity, attributed to its ability to cleave intracellular DNA. BLM complexes with iron (BLM-Fe<sup>3+</sup>) exhibit peroxidase-like activity, generate reactive oxygen species (ROS), and cause DNA cleavage. Inspired by the mechanism of BLM, we synthesized a novel conjugate of manganese tetraphenylporphyrin (MnTPP) with a biomimetic peptoid (i.e., oligo-<em>N</em>-substituted glycines); this conjugate harnesses the oxidative capabilities of manganese porphyrins combined with the cell-penetrating ability of a previously reported mitochondria-targeting peptoid (MTP). UV–vis spectroscopy showed the formation of Mn(V)-oxo porphyrin, a potent oxidative species, in the presence of hydrogen peroxide, simulating metallobleomycin reactivity. Biological assays demonstrated that MnTPP-MTP significantly boosted ROS production and induced cytotoxicity toward cancer cells, while sparing normal fibroblasts. Tetramethylrhodamine ethyl ester (TMRE) assay revealed reversible, dose-dependent impairment of the mitochondrial membrane potential by MnTPP-MTP treatment. DNA cleavage assays showed that MnTPP-MTP, specifically in the presence of hydrogen peroxide, could elicit substantial DNA damage, in a similar way to BLM. In vivo studies using liposome-encapsulated MnTPP-MTP (lipo-peptoid) indicated superior tumor suppression, without systemic toxicity, when administered locally. Immunofluorescence staining for Ki67 and TUNEL confirmed reduced cell proliferation and increased apoptosis, respectively, validating the anticancer efficacy of lipo-peptoid. These results suggest that MnTPP-MTP, particularly in a liposomal formulation, is a promising new chemotherapeutic agent with robust oxidative mechanisms, poised for further development and application against diverse cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118023"},"PeriodicalIF":3.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719915","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}

引用次数: 0

Stereoisomers of cannabidiols and their pharmacological activities – A potentially novel direction for cannabinoids 大麻二酚的立体异构体及其药理活性--大麻素的潜在新方向

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-23 DOI: 10.1016/j.bmc.2024.118019

Vajja Krishna Rao , Melissa M. Lewis-Bakker , Ewa Wasilewski , Hance A. Clarke , Lakshmi P. Kotra

{"title":"Stereoisomers of cannabidiols and their pharmacological activities – A potentially novel direction for cannabinoids","authors":"Vajja Krishna Rao , Melissa M. Lewis-Bakker , Ewa Wasilewski , Hance A. Clarke , Lakshmi P. Kotra","doi":"10.1016/j.bmc.2024.118019","DOIUrl":"10.1016/j.bmc.2024.118019","url":null,"abstract":"<div><div>Cannabidiol (CBD), a bicyclic non-psychoactive cannabinoid biosynthesized by <em>Cannabis</em> spp. of plants, has attracted significant interest in the past decade due to its therapeutic properties. In 2018, the US FDA approved Epidiolex®, a CBD<strong>-</strong>based drug for the treatment of two rare epileptic seizure disorders.</div><div>CBD possesses two chiral centers at C3 and C4 on its terpenoid moiety and exhibits <em>cis</em>–<em>trans</em> stereoisomerism along the C3–C4 bond axis. (−)<strong>-</strong><em>trans</em><strong>-</strong>(3<em>R</em>,4<em>R</em>)<strong>-</strong>CBD, the natural CBD, is biosynthesized by the cannabis plant, while the unnatural (+)<strong>-</strong><em>trans</em><strong>-</strong>(3<em>S</em>,4<em>S</em>)<strong>-</strong>CBD is obtained <em>via</em> chemical synthesis. Both <em>trans</em> isomers exhibit broad <em>in vitro</em> and <em>in vivo</em> biological activities; typically, the unnatural stereoisomer (+)<strong>-</strong><em>trans</em>-CBD and its derivatives exhibited more potent activities in comparison to the corresponding (−)<strong>-</strong><em>trans</em> isomers. On the other hand, <em>cis</em><strong>-</strong>CBD isomers have only been reported recently and can undergo epimerization into <em>trans</em> isomers.</div><div>There is a significant opportunity to explore unique synthetic methods and biological activities of stereoisomers of CBD that may pave the path for the development of novel therapeutics. Herein, as a novel direction in cannabinoids, we review the chemistry of CBD stereoisomers, their structure–activity relationships, target selectivity and efficacy in animal models.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118019"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview 来自麦金拉雅物种的生物碱和合成的麦金唑啉酮衍生物：概述

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-23 DOI: 10.1016/j.bmc.2024.118018

Julie Jaouen , Christian Bailly

{"title":"Alkaloids from Mackinlaya species and synthetic mackinazolinone derivatives: An overview","authors":"Julie Jaouen , Christian Bailly","doi":"10.1016/j.bmc.2024.118018","DOIUrl":"10.1016/j.bmc.2024.118018","url":null,"abstract":"<div><div>Mackinazolinone is the main alkaloid isolated from plants of the genus <em>Mackinlaya</em>, essentially distributed in tropical Asia and Australia. There are five <em>Mackinlaya</em> species all containing bioactive alkaloids with a tetrahydropyridoquinazolinone core such as mackinazoline (<strong>1</strong>) and mackinazolinone (<strong>2</strong>). The present review retraces the origin of mackinazolinone and compares the different chemical routes to synthesize the natural product, through different methods including classical batch synthesis, solid-phase supported synthesis, microwaved irradiation and photochemistry. A panel of about 70 mackinazolinone analogues and derivatives is presented to illustrate the diversity of chemical approaches and structures. The pharmacology of mackinazolinone has been little investigated but derivatives with antibacterial or anticancer properties have been identified. The molecular targets for these compounds are essentially unknown, but a few proteins of interest have been evoked occasionally, such as the EGFR kinase. The natural product mackinazolinone has largely inspired chemists to develop novel products and chemical processes. Hopefully, the review will now encourage pharmacologists to further explore the properties of these quinazolinones as potential anti-infectious, anticancer and/or neuroprotective agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118018"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model 天然提取的 Ar-turmerone 的结构优化，可作为新型神经炎症抑制剂在阿尔茨海默氏症小鼠模型中发挥作用

IF 3.3 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2024-11-22 DOI: 10.1016/j.bmc.2024.118014

Wei Zhou, Yuanyuan Chang, Qingwei Xiao, Zhujie Deng, Lanyue Zhang, Zhengqiang Yuan, Zhiyun Du

{"title":"Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model","authors":"Wei Zhou, Yuanyuan Chang, Qingwei Xiao, Zhujie Deng, Lanyue Zhang, Zhengqiang Yuan, Zhiyun Du","doi":"10.1016/j.bmc.2024.118014","DOIUrl":"10.1016/j.bmc.2024.118014","url":null,"abstract":"<div><div>Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant <em>Curcuma longa</em>, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure–activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (<strong>7c</strong>) and <em>N</em>-substituted amides (<strong>7a</strong>) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release <em>in vitro</em>. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer’s disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118014"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719919","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}

引用次数: 0