Bioorganic & Medicinal Chemistry最新文献

{"title":"Synthesis and evaluation of phenylimidazole FabK inhibitors as new Anti-C. Difficile agents","authors":"Krissada Norseeda ,&nbsp;Fahad Bin Aziz Pavel ,&nbsp;Jacob T. Rutherford ,&nbsp;Humna N. Meer ,&nbsp;Chetna Dureja ,&nbsp;Julian G. Hurdle ,&nbsp;Kirk E. Hevener ,&nbsp;Dianqing Sun","doi":"10.1016/j.bmc.2023.117330","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117330","url":null,"abstract":"<div><p>Previously, 1-((4-(4-bromophenyl)-1<em>H</em>-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea bearing a <em>p</em>-bromine substitution was shown to possess selective inhibitory activity against the <em>Clostridioides difficile</em><span> enoyl-acyl carrier protein (ACP) reductase<span> II enzyme, FabK. Inhibition of </span></span><em>Cd</em><span>FabK by this compound translated to promising antibacterial activity<span> in the low micromolar range. In these studies, we sought to expand our knowledge of the SAR of the phenylimidazole </span></span><em>Cd</em><span>FabK inhibitor series while improving the potency of the compounds. Three main series of compounds were synthesized and evaluated based on: 1) pyridine head group modifications including the replacement with a benzothiazole moiety, 2) linker explorations, and 3) phenylimidazole tail group modifications. Overall, improvement in the </span><em>Cd</em>FabK inhibition was achieved, while maintaining the whole cell antibacterial activity. Specifically, compounds 1-((4-(4-bromophenyl)-1<em>H</em>-imidazol-2-yl)methyl)-3-(5-((3-(trifluoromethyl)pyridin-2-yl)thio)thiazol-2-yl)urea, 1-((4-(4-bromophenyl)-1<em>H</em>-imidazol-2-yl)methyl)-3-(6-(trifluoromethyl)benzo[<em>d</em>]thiazol-2-yl)urea, and 1-((4-(4-bromophenyl)-1<em>H</em>-imidazol-2-yl)methyl)-3-(6-chlorobenzo[<em>d</em>]thiazol-2-yl)urea showed <em>Cd</em>FabK inhibition (IC₅₀<span> = 0.10 to 0.24 μM), a 5 to 10-fold improvement in biochemical activity relative to 1-((4-(4-bromophenyl)-1</span><em>H</em>-imidazol-2-yl)methyl)-3-(5-(pyridin-2-ylthio)thiazol-2-yl)urea, with anti-<em>C. difficile</em> activity ranging from 1.56 to 6.25 μg/mL. Detailed analysis of the expanded SAR, supported by computational analysis, is presented.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117330"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3269661","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":"Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists","authors":"Teppo O. Leino ,&nbsp;Ainoleena Turku ,&nbsp;Lauri Urvas ,&nbsp;Karuna Adhikari ,&nbsp;Jouni Oksanen ,&nbsp;Yana Steynen ,&nbsp;Jari Yli-Kauhaluoma ,&nbsp;Henri Xhaard ,&nbsp;Jyrki P. Kukkonen ,&nbsp;Erik A.A. Wallén","doi":"10.1016/j.bmc.2023.117325","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117325","url":null,"abstract":"<div><p>Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist <strong>Nag 26</strong>, which is binding to both orexin receptors OX₁ and OX₂ with preference towards OX₂. The most potent azulene-based compound was identified as an OX₁ orexin receptor agonist (pEC₅₀ = 5.79 ± 0.07, maximum response = 81 ± 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca²⁺ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117325"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1695618","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 pyridachlometyl: A new class of pyridazine fungicides","authors":"Akio Manabe,&nbsp;Hiroshi Ikegami,&nbsp;Hiroshi Morishita,&nbsp;Yuichi Matsuzaki","doi":"10.1016/j.bmc.2023.117332","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117332","url":null,"abstract":"<div><p>Pyridachlometyl is a unique pyridazine fungicide with a novel mode of action. Herein, we describe the pathway for the invention of pyridachlometyl. First, we identified a diphenyl-imidazo[1,2-<em>a</em>]pyrimidine as our proprietary lead with potent fungicidal activity. Then, aiming to simplify the chemical structure, we applied judicious estimations to explore monocyclic heterocycles as pharmacophores. This enabled the identification of a novel class of tetrasubstituted pyridazine compounds with potent fungicidal activity, likely retaining the same mode of action as the aforementioned compounds. The findings indicated bioisosteric similarity between diphenyl-imidazo[1,2-<em>a</em>]pyrimidine and pyridazine. Further structure–activity and mammalian safety investigations of pyridazine compounds resulted in the discovery of pyridachlometyl as a candidate for commercial development.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117332"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1888931","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 beginner’s guide to current synthetic linker strategies towards VHL-recruiting PROTACs","authors":"Nikol A. Zografou-Barredo,&nbsp;Alex J. Hallatt,&nbsp;Jennyfer Goujon-Ricci,&nbsp;Céline Cano","doi":"10.1016/j.bmc.2023.117334","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117334","url":null,"abstract":"<div><p>Over the last two decades, proteolysis targeting chimeras (PROTACs) have been revolutionary in drug development rendering targeted protein degradation (TPD) as an emerging therapeutic modality. These heterobifunctional molecules are comprised of three units: a ligand for the protein of interest (POI), a ligand for an E3 ubiquitin ligase, and a linker that tethers the two motifs together. Von Hippel-Lindau (VHL) is one of the most widely employed E3 ligases in PROTACs development due to its prevalent expression across tissue types and well-characterised ligands. Linker composition and length has proven to play an important role in determining the physicochemical properties and spatial orientation of the POI-PROTAC-E3 ternary complex, thus influencing the bioactivity of degraders. Numerous articles and reports have been published showcasing the medicinal chemistry aspects of the linker design, but few have focused on the chemistry around tethering linkers to E3 ligase ligands. In this review, we focus on the current synthetic linker strategies employed in the assembly of VHL-recruiting PROTACs. We aim to cover a range of fundamental chemistries used to incorporate linkers of varying length, composition and functionality.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117334"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3202824","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":"Novel drug-like fluorenyl derivatives as selective butyrylcholinesterase and β-amyloid inhibitors for the treatment of Alzheimer’s disease","authors":"Anna Pasieka ,&nbsp;Dawid Panek ,&nbsp;Paula Zaręba ,&nbsp;Emilia Sługocka ,&nbsp;Natalia Gucwa ,&nbsp;Alba Espargaró ,&nbsp;Gniewomir Latacz ,&nbsp;Nadia Khan ,&nbsp;Adam Bucki ,&nbsp;Raimon Sabaté ,&nbsp;Anna Więckowska ,&nbsp;Barbara Malawska","doi":"10.1016/j.bmc.2023.117333","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117333","url":null,"abstract":"<div><p>Butyrylcholinesterase (BuChE) and amyloid β (Aβ) aggregation remain important biological target and mechanism in the search for effective treatment of Alzheimer’s disease. Simultaneous inhibition thereof by the application of multifunctional agents may lead to improvement in terms of symptoms and causes of the disease. Here, we present the rational design, synthesis, biological evaluation and molecular modelling studies of novel series of fluorene-based BuChE and Aβ inhibitors with drug-like characteristics and advantageous Central Nervous System Multiparameter Optimization scores. Among 17 synthesized and tested compounds, we identified <strong>22</strong> as the most potent <em>eq</em>BuChE inhibitor with IC₅₀ of 38 nM and 37.4% of Aβ aggregation inhibition at 10 μM. Based on molecular modelling studies, including molecular dynamics, we determined the binding mode of the compounds within BuChE and explained the differences in the activity of the two enantiomers of compound <strong>22</strong>. A novel series of fluorenyl compounds meeting the drug-likeness criteria seems to be a promising starting point for further development as anti-Alzheimer agents.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117333"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3453400","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, synthesis and biological evaluation of novel lipophilic 2, 5-disubstituted tetrazole analogues of muramyl dipeptide as NOD2 agonists","authors":"Tukaram B. Mhamane ,&nbsp;Shainy Sambyal ,&nbsp;Sravanthi Vemireddy ,&nbsp;Rama Subba Reddy Paturu ,&nbsp;Suresh Babu Katragadda ,&nbsp;Shafi Syed ,&nbsp;Arif Khan ,&nbsp;Sampath Kumar Halmuthur M.","doi":"10.1016/j.bmc.2023.117296","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117296","url":null,"abstract":"<div><p>A focused library of six new 2, 5-disubstituted tetrazole (2, 5-DST) analogues of <em>N</em><span>-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) as potential immunomodulators were synthesized by the bioisosteric replacement of α-amide of d-isoglutamine with 5-substituted tetrazole (5-ST). Another parameter ‘lipophilicity’ was also considered to improve the pharmacological properties of MDP through the alkylation of 5-substituted tetrazole during synthesis. In total, six 2, 5-DST analogues of MDP were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, among the varied lengths of the alkyl chain in 2, 5-disubstituted tetrazole derivatives, the tetrazole analogues </span><strong>12b</strong> bearing the -Butyl (C4) and <strong>12c</strong> having -Octyl (C8) chain showed the best NOD2 stimulation potency equivalent with reference compound MDP. These analogues were evaluated for their adjuvanticity against dengue antigen and analogues <strong>12b</strong> and <strong>12c</strong> have elicited a potent humoral and cell mediated response.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117296"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2614631","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":"Non-fused imidazole-biphenyl analogs repress triple-negative breast cancer growth by mainly stabilizing the c-MYC G-quadruplex via a multi-site binding mode","authors":"Xiao-Dong Wang,&nbsp;Jia-Xin Wang,&nbsp;Bing-Ying Yu,&nbsp;Shu-Quan Zhang,&nbsp;Ming-Hao Hu","doi":"10.1016/j.bmc.2023.117336","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117336","url":null,"abstract":"<div><p>As oncogene <em>c-MYC</em> is abnormally expressed during TNBC pathogenesis, stabilizing its promoter G-quadruplex (G4), which may thus inhibit <em>c-MYC</em> expression and promote DNA damage, may be a potential anti-TNBC strategy. However, large quantities of potential G4-forming sites exist in the human genome, which represents a potential drug selectivity problem. In order to achieve better recognition for <em>c-MYC</em> G4, we herein presented a new approach of designing small-molecule ligands by linking tandem aromatic rings with the <em>c-MYC</em> G4 selective binding motifs. Thus, a series of non-fused, conformation-tunable imidazole-biphenyl analogs were designed and synthesized. Among them, the optimal ligand appeared more effective on stabilizing <em>c-MYC</em> G4 than other types of G4s possibly through an adaptive, multi-site binding mode involved of end-stacking, groove-binding and loop-interacting. Then, the optimal ligand exerted good inhibitory activity on <em>c-MYC</em> expression and induced remarkable DNA damage, leading to the occurrence of G2/M phase arrest, apoptosis and autophagy. Furthermore, the optimal ligand exhibited potent antitumor effects in a TNBC xenograft tumor model. To sum up, this work offers new insights for the development of selective <em>c-MYC</em> G4 ligands against TNBC.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117336"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2614632","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":"Recent developments in antimalarial drug discovery","authors":"Théoneste Umumararungu ,&nbsp;Jean Bosco Nkuranga ,&nbsp;Gratien Habarurema ,&nbsp;Jean Baptiste Nyandwi ,&nbsp;Marie Jeanne Mukazayire ,&nbsp;Janvier Mukiza ,&nbsp;Raymond Muganga ,&nbsp;Innocent Hahirwa ,&nbsp;Matabishi Mpenda ,&nbsp;Alain Nyirimigabo Katembezi ,&nbsp;Emmanuel Oladayo Olawode ,&nbsp;Egide Kayitare ,&nbsp;Pierre Claver Kayumba","doi":"10.1016/j.bmc.2023.117339","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117339","url":null,"abstract":"<div><p><span><span>Although malaria remains a big burden to many countries that it threatens their socio-economic stability, particularly in the countries where malaria is endemic, there have been great efforts to eradicate this disease with both successes and failures. For example, there has been a great improvement in malaria prevention and </span>treatment methods with a net reduction in infection and mortality rates. However, the disease remains a global threat in terms of the number of people affected because it is one of the infectious diseases that has the highest prevalence rate, especially in Africa where the deadly </span><span><em>Plasmodium falciparum</em></span><span> is still widely spread. Methods to fight malaria are being diversified, including the use of mosquito nets, the target candidate profiles (TCPs) and target product profiles (TPPs) of medicine for malarial venture (MMV) strategy, the search for newer and potent drugs<span> that could reverse chloroquine<span> resistance, and the use of adjuvants such as rosiglitazone<span> and sevuparin. Although these adjuvants have no antiplasmodial activity<span>, they can help to alleviate the effects which result from plasmodium invasion such as cytoadherence<span>. The list of new antimalarial drugs under development is long, including the out of ordinary new drugs MMV048, CDRI-97/78 and INE963 from South Africa, India and Novartis, respectively.</span></span></span></span></span></span></p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"88 ","pages":"Article 117339"},"PeriodicalIF":3.5,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1888930","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, synthesis, and biological evaluation of acyl sulfonamide derivatives with spiro cycles as NaV1.7 inhibitors for antinociception","authors":"Xiangshuo Ouyang ,&nbsp;Min Su ,&nbsp;Dengqi Xue ,&nbsp;Liying Dong ,&nbsp;Heling Niu ,&nbsp;Wei Li ,&nbsp;Yani Liu ,&nbsp;KeWei Wang ,&nbsp;Liming Shao","doi":"10.1016/j.bmc.2023.117290","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117290","url":null,"abstract":"<div><p><span>Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel Na</span>_V<span><span>1.7 preferentially expressed in sensory neurons of </span>dorsal root<span><span> ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl </span>sulfonamide derivatives<span> targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound </span></span></span><strong>36c</strong> was identified as a selective and potent Na_V1.7 inhibitor <em>in vitro</em> and exhibited antinociceptive effects <em>in vivo</em>. The identification of <strong>36c</strong> not only provides a new insight into the discovery of selective Na_V1.7 inhibitors, but also may hold premise for pain therapy.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"86 ","pages":"Article 117290"},"PeriodicalIF":3.5,"publicationDate":"2023-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1888108","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-Activity relationships of replacements for the triazolopyridazine of Anti-Cryptosporidium lead SLU-2633","authors":"Edmund Oboh ,&nbsp;José E. Teixeira ,&nbsp;Tanner J. Schubert ,&nbsp;Adriana S. Maribona ,&nbsp;Brylon N. Denman ,&nbsp;Radhika Patel ,&nbsp;Christopher D. Huston ,&nbsp;Marvin J. Meyers","doi":"10.1016/j.bmc.2023.117295","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117295","url":null,"abstract":"<div><p><span><span>Cryptosporidiosis is a diarrheal disease particularly harmful to children and immunocompromised people. Infection is caused by the </span>parasite </span><span><em>Cryptosporidium</em></span><span> and leads to dehydration, malnutrition, and death in severe cases. Nitazoxanide<span><span> is the only FDA approved drug but is only modestly effective in children and ineffective in </span>immunocompromised patients<span>. To address this unmet medical need, we previously identified triazolopyridazine SLU-2633 as potent against </span></span></span><span><em>Cryptosporidium parvum</em></span>, with an EC₅₀<span> of 0.17 µM. In the present study, we develop structure–activity relationships (SAR) for the replacement of the triazolopyridazine head group by exploring different heteroaryl groups with the aim of maintaining potency while reducing affinity for the hERG channel. 64 new analogs of SLU-2633 were synthesized and assayed for potency versus </span><em>C. parvum</em>. The most potent compound, 7,8-dihydro-[1,2,4]triazolo[4,3-<em>b</em>]pyridazine <strong>17a</strong>, was found to have a <em>Cp</em> EC₅₀<span> of 1.2 µM, 7-fold less potent than SLU-2633 but has an improved lipophilic efficiency (LipE) score. </span><strong>17a</strong><span> was found to decrease inhibition in an hERG patch-clamp assay by about two-fold relative to SLU-2633 at 10 µM despite having similar inhibition in a [</span>³<span>H]-dofetilide competitive binding assay. While most other heterocycles were significantly less potent than the lead, some analogs such as azabenzothiazole </span><strong>31b</strong>, have promising potency in the low micromolar range, similar to the drug nitazoxanide, and represent potential new leads for optimization. Overall, this work highlights the important role of the terminal heterocyclic head group and represents a significant extension of the understanding of the SAR for this class of anti-<em>Cryptosporidium</em> compounds.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"86 ","pages":"Article 117295"},"PeriodicalIF":3.5,"publicationDate":"2023-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10201403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1795690","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}