Medicinal Chemistry Research最新文献_第6页

Redefining the significance of quinoline containing compounds as potent VEGFR-2 inhibitors for cancer therapy 重新定义含喹啉化合物作为强效 VEGFR-2 抑制剂在癌症治疗中的意义

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-27 DOI: 10.1007/s00044-024-03252-w

Jurnal Reang, Vinita Sharma, Vivek Yadav, Rajiv K. Tonk, Jaseela Majeed, Archana Sharma, Prabodh C. Sharma

{"title":"Redefining the significance of quinoline containing compounds as potent VEGFR-2 inhibitors for cancer therapy","authors":"Jurnal Reang, Vinita Sharma, Vivek Yadav, Rajiv K. Tonk, Jaseela Majeed, Archana Sharma, Prabodh C. Sharma","doi":"10.1007/s00044-024-03252-w","DOIUrl":"10.1007/s00044-024-03252-w","url":null,"abstract":"<div><p>Vascular endothelial growth factor receptor-2 (VEGFR-2), a tyrosine kinase receptor (TKR) is frequently overexpressed in most of the cancers. It plays a crucial part in tumor angiogenesis through mediating vital angiogenic cellular signals, including endothelial cell survival, proliferation, migration and vascular permeability. Due to the key importance in facilitated tumor vasculature, VEGFR-2 has emerged as a legit therapeutic target against cancer. Quinoline a fused heterocyclic scaffold with weak basicity can deliver a diverse degree of activity upon chemical substitution and attract considerable scientific attention. Quinoline containing compounds namely lenvatinib and cabozantinib have been approved as VEGFR-2 inhibitors for the management of various categories of cancer, while some drugs such as lucitanib and foretanib are currently under clinical evaluation. Some recently synthesized quinoline-(1H)-4 one derivative substituted at 3<sup>rd</sup>, and 6<sup>th</sup> position, and another compound substituted at 4<sup>th</sup> position with 2-(3,4-dichlorophenyl)-1<i>H</i>-benzo[<i>d</i>]imidazol-6-amine have showed VEGFR-2 inhibition better than the standard drugs sorafenib and sunitinib, respectively (45 nM, and 40 nM, respectively). The quinoline analogs hold promise as VEGFR-2 inhibitors for future cancer treatment, with ongoing research addressing the structural refinement, potential toxicity and combination therapies. This review summarizes the role of VEGFR-2 in cancer progression, and quinoline containing compounds as VEGFR-2 inhibitors for cancer therapy.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 7","pages":"1079 - 1099"},"PeriodicalIF":2.6,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141517703","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}

引用次数: 0

Targeting cAMP signaling and phosphodiesterase 4 for liver disease treatment 靶向 cAMP 信号和磷酸二酯酶 4 治疗肝病

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-26 DOI: 10.1007/s00044-024-03267-3

Jingyi Ma, Dalton W. Staler, Ram I. Mahato

{"title":"Targeting cAMP signaling and phosphodiesterase 4 for liver disease treatment","authors":"Jingyi Ma, Dalton W. Staler, Ram I. Mahato","doi":"10.1007/s00044-024-03267-3","DOIUrl":"https://doi.org/10.1007/s00044-024-03267-3","url":null,"abstract":"<p>Liver disease is a significant health burden globally and accounts for 4% of total deaths annually. Alcoholic liver disease (ALD) and metabolism-associated fatty liver disease (MAFLD) are the leading causes of cirrhosis. Extensive studies have investigated the pathogenesis and molecular mechanisms underlying the diseases. However, there remains an urgent need for effective therapeutics. Cyclic adenosine monophosphate (cAMP) is the most studied intracellular second messenger, and its level is directly regulated by phosphodiesterase 4 (PDE4). PDE4 inhibitors are developed and marketed as a large category of drugs. Recent studies have revealed the significant role of cAMP in liver disease progression and evaluated the therapeutic efficacy of PDE4 inhibitors. PDE4 inhibitors exhibited efficacy in ameliorating ALD by reducing inflammation and mediating lipid metabolism. MAFLD, which shares similar disease features to ALD, was attenuated by PDE4 inhibitors due to improved homeostasis of fatty acid metabolism and insulin resistance. Fibrosis, which indicates the late stage of ALD and MAFLD progression, has been shown to improve with PDE4 inhibitors by inhibiting hepatic stellate cell (HSC) activation. However, the results from clinical trials evaluating PDE4 inhibitors for MAFLD management have been conflicting, highlighting the need for further validation and translation of preclinical findings to clinical settings.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"25 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505801","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}

引用次数: 0

Design and synthesis of diphenyl-1H-imidazole analogs targeting Mpro/3CLpro enzyme of SARS-CoV-2 针对 SARS-CoV-2 的 Mpro/3CLpro 酶的二苯基-1H-咪唑类似物的设计与合成

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-26 DOI: 10.1007/s00044-024-03263-7

Ashish M. Kanhed, Amisha Vora, Ami Thakkar, Gudepalya Renukaiah Rudramurthy, Radha Krishan Shandil, Rajappa Harisha, Mayas Singh, Shridhar Narayanan

{"title":"Design and synthesis of diphenyl-1H-imidazole analogs targeting Mpro/3CLpro enzyme of SARS-CoV-2","authors":"Ashish M. Kanhed, Amisha Vora, Ami Thakkar, Gudepalya Renukaiah Rudramurthy, Radha Krishan Shandil, Rajappa Harisha, Mayas Singh, Shridhar Narayanan","doi":"10.1007/s00044-024-03263-7","DOIUrl":"10.1007/s00044-024-03263-7","url":null,"abstract":"<div><p>The prevailing COVID-19 pandemic, triggered by the novel coronavirus SARS-CoV-2, stands as the predominant global health crisis of the decade, claiming millions of lives and causing profound disruptions to society. Despite the rapid development of vaccines against COVID-19, the situation remains challenging, necessitating the exploration of new antiviral drugs. In this study, we present the design and synthesis of diphenyl-1H-imidazole derivatives as a potential lead series for inhibiting the SARS-CoV-2 3CL<sup>pro</sup> enzyme. The synthesized molecules underwent screening for inhibiting the SARS-CoV-2 3CL<sup>pro</sup> enzyme at a concentration of 20 µM. Compounds 6–14 exhibited inhibition ranging from 88 to 99%. Further assessments were conducted to evaluate the anti-SARS-CoV-2 activity of these compounds against both the ancestral SARS-CoV-2 strain and the Delta variant in virus-infected cells. Compounds such as 4-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-<i>1H</i>-imidazole <b>(9)</b>, 4-(2,4-dichlorophenyl)-2-(3,4-dimethoxyphenyl)-<i>1H</i>-imidazole <b>(10)</b>, and 4-(4-(2,4-dichlorophenyl)-<i>1H</i>-imidazol-2-yl)benzene-1,2-diol <b>(14)</b> exhibited promising activity against both the SARS-CoV-2 strain (with IC<sub>50</sub> values of 7.7 µM, 12.6 µM, and 11.8 µM, respectively) and the Delta variant (with IC<sub>50</sub> values of 7.4 µM, 13.8 µM, and 12.1 µM, respectively). Moreover, the 3CL<sup>pro</sup> inhibition IC<sub>50</sub> values for these compounds correlated well with the observed antiviral activity, measuring at 5.1 µM <b>(9)</b>, 10.9 µM <b>(10)</b>, and 7.3 µM <b>(14)</b>. These findings underscore the efficacy of diphenyl-<i>1H</i>-imidazole derivatives as promising candidates for further development and optimization in the fight against COVID-19.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1568 - 1577"},"PeriodicalIF":2.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505802","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}

引用次数: 0

Gallic acid derived diarylpropanones exhibit synergistic antibacterial activities 从没食子酸中提取的二元丙酮具有协同抗菌活性

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-20 DOI: 10.1007/s00044-024-03254-8

Sneha Singh, Sana Khan, Alka Kurmi, Ranjana Das, Barsha Thapa, Poonam Rani, Feroz Khan, Dharmendra Saikia, Debabrata Chanda, Arvind Singh Negi

{"title":"Gallic acid derived diarylpropanones exhibit synergistic antibacterial activities","authors":"Sneha Singh, Sana Khan, Alka Kurmi, Ranjana Das, Barsha Thapa, Poonam Rani, Feroz Khan, Dharmendra Saikia, Debabrata Chanda, Arvind Singh Negi","doi":"10.1007/s00044-024-03254-8","DOIUrl":"10.1007/s00044-024-03254-8","url":null,"abstract":"<div><p>Development of resistance against most of the clinical antibiotics is a menace to mankind for their use in future. Present study aimed at design and synthesis of some microtubule dynamics modulators as antibacterial and anticancer agents. Eight diverse Aza Michael adducts were prepared at diarylpropenone core possessing desired motifs in 38–57% yields. Compound <b>6b</b> showed significant antiproliferative activity against K562, leukemic cell line. While compound <b>6</b><b>h</b> exhibited potent antibacterial activity against methicillin resistant <i>Staphylococcus aureus</i> and methicillin resistant <i>S. epidermidis</i>. In the checkerboard experiment, <b>6</b><b>h</b> showed synergistic effect in combination of penicillin and also with norfloxacin, up to four-fold reduction in quantity of the antibiotic drug. Its effect was bacteriostatic as evident from time kill assay. The 3,4,5-trimethoxyphenyl motif induces antitubulin effect in Aza Michael adduct <b>6b</b> for anticancer activity. Both the leads can further be optimized for better efficacy in future.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 7","pages":"1218 - 1228"},"PeriodicalIF":2.6,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505872","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}

引用次数: 0

Amyloid-independent pathogenesis for Alzheimer’s disease: implications for drug design 阿尔茨海默病的淀粉样蛋白依赖性发病机制：对药物设计的影响

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-18 DOI: 10.1007/s00044-024-03261-9

Michael S. Wolfe

{"title":"Amyloid-independent pathogenesis for Alzheimer’s disease: implications for drug design","authors":"Michael S. Wolfe","doi":"10.1007/s00044-024-03261-9","DOIUrl":"https://doi.org/10.1007/s00044-024-03261-9","url":null,"abstract":"<p>Alzheimer’s disease (AD) is characterized pathologically by cerebral deposits of the amyloid β-peptide (Aβ), particularly the aggregation prone 42-residue variant Aβ42. The amyloid hypothesis of AD pathogenesis, which has dominated the field for over 30 years, posits that Aβ42 aggregation triggers a cascade of events culminating in neurodegeneration. Strong support of the amyloid hypothesis includes genetic mutations that cause early-onset familial AD (FAD), which are found in the amyloid precursor protein (APP) and in presenilin and alter Aβ production or properties. Presenilin is the catalytic component of γ-secretase, which cleaves APP substrate to produce Aβ peptides; thus, all FAD mutations are in the substrate and enzyme that generates Aβ. Nevertheless, how Aβ42 triggers neurodegeneration remains unclear, and recently approved therapeutics targeting Aβ are modestly effective at best, suggesting Aβ may not be the primary disease driver. Recent studies suggest that FAD mutations result in stalled γ-secretase enzyme-substrate (E-S) and that these stalled complexes can trigger synaptic degeneration in the absence of Aβ production. These findings suggest that drug discovery efforts should focus on rescuing stalled γ-secretase E-S complexes and deficient enzyme activity.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"38 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141517705","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}

引用次数: 0

Sulfur (VI) fluoride exchange (SuFEx): a versatile tool to profile protein-biomolecule interactions for therapeutic development 氟化硫（VI）交换（SuFEx）：分析蛋白质-生物大分子相互作用以促进治疗开发的多功能工具

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-18 DOI: 10.1007/s00044-024-03255-7

Lingyun Yang, Zhengnan Yuan, Yongkuan Li, Shuyue Yang, Bingchen Yu

{"title":"Sulfur (VI) fluoride exchange (SuFEx): a versatile tool to profile protein-biomolecule interactions for therapeutic development","authors":"Lingyun Yang, Zhengnan Yuan, Yongkuan Li, Shuyue Yang, Bingchen Yu","doi":"10.1007/s00044-024-03255-7","DOIUrl":"https://doi.org/10.1007/s00044-024-03255-7","url":null,"abstract":"<p>Sulfur (VI) fluoride exchange (SuFEx), a new generation of click chemistry, enables the creation of a stable covalent linkage between a protein and its interacting biomolecule. This transformative process converts the transient and reversible protein-biomolecule interaction into a stable binding complex, which allows the subsequent pull-down assay to identify unknown interactors. Therefore, SuFEx has emerged as a versatile tool to investigate protein-biomolecule interactions and facilitate new therapeutic development. SuFEx warheads such as aryl fluorosulfates and aryl sulfonyl fluorides can be appended to small molecules to investigate protein-ligand interactions. Furthermore, they can be incorporated into proteins site-specifically to probe protein-protein interactions (PPIs) and protein-RNA interactions with pinpoint accuracy. Here, we describe the principles of SuFEx, summarize its application in profiling protein-biomolecule interactions, and delve into the kinetics of SuFEx. This overview can serve as a roadmap to understanding the application of SuFEx in biomedical research.</p>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"168 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505876","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}

引用次数: 0

Docking-guided exploration of the anti-flt3 potential of isoindigo derivatives towards potential treatments of acute myeloid leukemia 以对接为指导，探索异靛蓝衍生物在治疗急性髓性白血病方面的抗 Flt3 潜力

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-17 DOI: 10.1007/s00044-024-03259-3

Mazen Al Sulaibi, Jalal Zahra, Sanaa Bardaweel, Mustafa El Abadleh, Mutasem O. Taha

{"title":"Docking-guided exploration of the anti-flt3 potential of isoindigo derivatives towards potential treatments of acute myeloid leukemia","authors":"Mazen Al Sulaibi, Jalal Zahra, Sanaa Bardaweel, Mustafa El Abadleh, Mutasem O. Taha","doi":"10.1007/s00044-024-03259-3","DOIUrl":"10.1007/s00044-024-03259-3","url":null,"abstract":"<div><p>FMS-like tyrosine kinase 3 (Flt3) is an oncogenic kinase implicated in leukemia, with its primary association being acute myeloid leukemia (AML). Flt3-specific inhibitors have demonstrated promising outcomes in disrupting AML progression. While isoindigo derivatives, e.g., meisoindigo, have proven effective against chronic myeloid leukemia, their structural resemblance to indirubin derivatives, known for potent anti-Flt3 bioactivities, does not guarantee similar effects. In fact, meisoindigo and other related derivatives have been reported to exhibit limited or no anti-Flt3 bioactivities. This observation prompted us to explore the anti-Flt3 profile of novel isoindigo derivatives. Employing docking studies on both wild-type and mutated active Flt3, we synthesized a series of isoindigo derivatives and assessed their Flt3 inhibitions. Nine derivatives displayed low micromolar and submicromolar IC<sub>50</sub> values. The most potent derivative achieved an IC<sub>50</sub> of 88 nM against the mutant Flt3D835Y. Intriguingly, the same compound showed an anti-RET kinase IC<sub>50</sub> of 57 nM, reminiscent of the dual Flt3/RET inhibitory profiles of indirubin derivatives. Cell-based bioassays further revealed that these derivatives exhibited submicromolar selective toxicities against HL-60 human leukemia cells, which overexpress Flt3. In contrast, no cytotoxic effects were observed on HCT-116 colon cancer cells, MCF-7 breast cancer cells, or normal fibroblasts, all known to lack Flt3 expression.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 7","pages":"1242 - 1266"},"PeriodicalIF":2.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141505873","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}

引用次数: 0

Reversible in-situ assembly of PROTACs using iminoboronate conjugation 利用亚氨基硼酸酯共轭在原位可逆组装 PROTAC

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-15 DOI: 10.1007/s00044-024-03258-4

Ce Yang, Yayun Xie, Xiaoxiao Yang, Jun Yin, Binghe Wang

引用次数: 0

In silico drug discovery: a machine learning-driven systematic review 硅学药物发现：机器学习驱动的系统综述

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-15 DOI: 10.1007/s00044-024-03260-w

Sema Atasever

{"title":"In silico drug discovery: a machine learning-driven systematic review","authors":"Sema Atasever","doi":"10.1007/s00044-024-03260-w","DOIUrl":"10.1007/s00044-024-03260-w","url":null,"abstract":"<div><p>This systematic review, which was carried out between 2018 and 2022 in accordance with PRISMA principles, assesses how machine learning (ML) and other computational approaches are integrated into drug discovery, with a focus on virtual screening (VS). The main goals are to evaluate the state of in silico drug-target interaction prediction techniques, gather useful computational tools, and provide model building help. The study emphasizes the significance of ML, molecular docking, bioinformatics, and cheminformatics in improving drug development efficiency by assessing 201 papers, of which 119 met inclusion criteria. It serves as a methodological guide for researchers, emphasizing on the effective use of computational approaches and decision-making improvements. This study relates computational techniques to drug development, discusses present constraints, and recommends future research topics with the goal of accelerating and improving therapeutic agent discovery. In summary, this systematic review highlighted numerous major tools, databases, and techniques that are critical in computational drug discovery, including the ChEMBL Database, Random Forest (RF) Algorithm, Extended Connectivity Fingerprints (ECFP), and RDKit. These tools and techniques highlight the transforming power of computational methods in pharmaceutical development. They offer researchers the ability to develop new computational models and improve drug development processes, thereby enabling the rapid advancement for new therapeutic agents via robust platforms.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 9","pages":"1465 - 1490"},"PeriodicalIF":2.6,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141337589","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}

引用次数: 0

N-Benzyl, N-phenethyl and N-benzyloxybenzamide derivatives inhibit amyloid-beta (Aβ42) aggregation and mitigate Aβ42-induced neurotoxicity N-苄基、N-苯乙基和 N-苄氧基苯甲酰胺衍生物可抑制淀粉样蛋白-β（Aβ42）的聚集并减轻 Aβ42 诱导的神经毒性

IF 2.6 4区医学

Medicinal Chemistry Research Pub Date : 2024-06-15 DOI: 10.1007/s00044-024-03256-6

Yusheng Zhao, Arash Shakeri, Ahmed A. Hefny, Praveen P. N. Rao

{"title":"N-Benzyl, N-phenethyl and N-benzyloxybenzamide derivatives inhibit amyloid-beta (Aβ42) aggregation and mitigate Aβ42-induced neurotoxicity","authors":"Yusheng Zhao, Arash Shakeri, Ahmed A. Hefny, Praveen P. N. Rao","doi":"10.1007/s00044-024-03256-6","DOIUrl":"10.1007/s00044-024-03256-6","url":null,"abstract":"<div><p>A library of <i>N</i>-benzylbenzamide, <i>N</i>-phenethylbenzamide and <i>N</i>-benzyloxybenzamide derivatives were designed, synthesized and evaluated as amyloid beta (Aβ42) aggregation inhibitors. These compounds were designed by replacing the α,β-unsaturated linker region of chalcone with an amide bioisostere. The Aβ42 aggregation inhibition properties of these 27 benzamide derivatives were evaluated by the thioflavin T (ThT)-based fluorescence aggregation kinetics assay, transmission electron microscopy (TEM) studies, Aβ42-induced cytotoxicity assay in mouse hippocampal neuronal HT22 cell lines, fluorescence live cell imaging, and computational modelling studies using a pentamer model of Aβ42. These studies led to the identification of <i>N</i>-benzylbenzamides <b>3a</b> and <b>3f</b>, <i>N</i>-phenethylbenzamide <b>5a</b> and <i>N</i>-benzyloxybenzamide <b>7a</b> as promising compounds that were able to exhibit anti-aggregation properties in the ThT-based fluorescence experiments, TEM studies and more significantly were able to rescue the hippocampal neuronal HT22 cells from Aβ42-induced cytotoxicity (91–96% cell viability at 25 µM). These results demonstrate the usefulness of these benzamide-based templates in the design and development of novel small molecules as chemical tools and therapeutics to study and treat Alzheimer’s disease.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"33 7","pages":"1229 - 1241"},"PeriodicalIF":2.6,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141337091","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}

引用次数: 0