Medicinal Chemistry Research最新文献

{"title":"A multi enzyme study reviewing the role of target enzymes in Alzheimer’s disease and unveiling potential inhibitors with insights on their present and future assessment","authors":"Syed Bassam Zaki,&nbsp;Sahar Afzal Khan,&nbsp;Ruhi Ali","doi":"10.1007/s00044-025-03373-w","DOIUrl":"10.1007/s00044-025-03373-w","url":null,"abstract":"<div><p>One of the most common types of Dementia mostly affecting people over the age of 65 is Alzheimer’s Disease. Characterized by various Neuropsychiatric Symptoms such as, memory loss, cognitive impairment, mood and behavioral disturbances leading to a poor life style. WHO 2021 Global status report states that the cases of dementia will drastically increase from 55 million in 2019 to 139 million in 2050 and the total amount paid for health care, long-term care and hospice services by dementia patients is $360 billion (estimated) in 2024. This is alarming and requires serious attention. To do so, first and foremost, identification of the targets involved in the pathogenesis of the disease is necessary. In Alzheimer’s disease, there are two highly accepted hypothesis, Tau and Amyloid beta (Aβ). Extensive research on these Hypothesis has revealed some potential target enzymes such as, Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), Monoamine oxidases (MAO), GSK-3 (Glycogen synthase kinase-3) and Cholinesterases. Scientists tried to leverage, enzyme inhibition as a way to modulate the activity of these enzymes and modulation of enzymes was perceived to be affecting the progression and symptoms of the disease significantly. From there, enzyme inhibition has been thought to therapeutically affect the pathogenesis of disease. Some drugs which have undergone clinical trials but were not able to complete them due to side effects and lack of efficacy are Crenezumab (targeting Aβ), LMTM (TRx0237) (targeting Tau) and verubecestat (BACE-1 inhibitor) were terminated in clinical trials. In this review we have inquired the role of BACE-1, MAO, GSK-3 and Cholinesterases in Alzheimer’s Disease and unveiled Potential Inhibitors, which may fulfill the demand of a novel drug.</p><div><figure><div><div><picture><source><img></source></picture></div><div><p>Target Enzymes involved in the pathogenesis of Alzheimer’s Disease and Therapeutic approach.</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"549 - 570"},"PeriodicalIF":2.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481195","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, optimization and biological evaluation of chromone derivatives as novel BRD4 inhibitors","authors":"Zhao-Tong Jia,&nbsp;You Li,&nbsp;Wei Shi,&nbsp;Jian-Qiang Qian,&nbsp;Ya-Yu Xu,&nbsp;Hai-Ran Fan,&nbsp;Xiao-Long Hu,&nbsp;Hao Wang","doi":"10.1007/s00044-025-03380-x","DOIUrl":"10.1007/s00044-025-03380-x","url":null,"abstract":"<div><p>Bromodomain-containing protein 4 (BRD4), as the reader of epigenetics, could regulate gene transcription by recognizing acetylated lysine of histones. In recent years, researchers have found that dysregulation of BRD4 leads to the occurrence and development of various cancers, making BRD4 a promising target for cancer therapy. To identify novel BRD4 inhibitors from natural products, a hierarchical virtual screening method including pharmacophore modeling, molecular docking, and molecular dynamic simulation was performed to obtain five hit compounds with potential BRD4 inhibitory activity. Subsequently, structural optimization of the hit compound (ZINC2648030) with chromone structure was conducted to afford a series of derivatives (<b>8a</b>–<b>13e</b>), and their BRD4 inhibitory activities were evaluated. Among them, <b>13b</b> showed remarkable BRD4 inhibitory activity (IC₅₀ = 0.60 μM). Moreover, <b>13b</b> displayed a potent inhibitory effect on A549 cells with an IC₅₀ value of 0.79 μM, and further investigations demonstrated that it has the potential to induce apoptosis, inhibit colony formation, and suppress cell invasion. These findings indicated that <b>13b</b> might be a candidate for cancer treatment.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"720 - 744"},"PeriodicalIF":2.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481091","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":"Olaparib research update: mechanism, structure and clinical trials","authors":"Hao Che,&nbsp;Li-Wei Wang,&nbsp;Xiang-Yang Ye,&nbsp;Xingrui He","doi":"10.1007/s00044-025-03375-8","DOIUrl":"10.1007/s00044-025-03375-8","url":null,"abstract":"<div><p>Current cancer treatments are known for their low selectivity, and life-threatening toxicity. To solve these issue, various innovative approaches were applied. One of them is the inhibition of DNA repair mechanisms, which have been developed as a new hotspot for its selective inhibition and low toxicity. Notably, PARP inhibition has shown potential for effective targeted cancer therapy. Olaparib, the first FDA-approved PARP inhibitor, has been available for nearly a decade, demonstrating superior efficacy in treating breast and ovarian cancers. This article reviews the latest mechanistic studies, structural modifications, and clinical trials of Olaparib.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"535 - 548"},"PeriodicalIF":2.6,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480955","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":"Uncaria-derived compounds for cancer treatment: mechanistic insights and therapeutic potential","authors":"Zhichao Wang,&nbsp;Shi Xiang,&nbsp;Wenwen Zhang,&nbsp;Hui Chen,&nbsp;Chao Yang","doi":"10.1007/s00044-025-03370-z","DOIUrl":"10.1007/s00044-025-03370-z","url":null,"abstract":"<div><p>Uncaria is a traditional medicinal plant belonging to the Rubiaceae family, with a particularly strong presence in Asia, Central America, and South America. Recent studies have indicated the potential of Uncaria-derived compounds, particularly alkaloids such as rhynchophylline and mitraphylline, as a means of cancer therapy. The objective of this review is to provide a comprehensive overview of the mechanistic insights into how these compounds exert anticancer effects, including their roles in apoptosis induction, cell cycle regulation, and modulation of key signaling pathways such as NF-κB and MAPK. Furthermore, we examine the capacity of Uncaria-derived compounds to augment the efficacy of conventional chemotherapeutics and their potential to mitigate adverse effects. Preclinical and clinical studies highlight the potential of Uncaria-derived compounds as a multifaceted approach to cancer treatment. Despite promising findings, further investigations are required to elucidate the full spectrum of their pharmacological activities, optimize dosage regimens, and assess long-term safety. This review emphasises the significance of Uncaria-derived compounds as a promising avenue for adjunctive cancer therapy, paving the way for future research and clinical applications.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"517 - 534"},"PeriodicalIF":2.6,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03370-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and antifungal study of novel 2-aryl-3,4-dihydroisoquinolin-2-ium salts containing benzoate moieties","authors":"Wei Chen,&nbsp;Yanxi Jin,&nbsp;Luyao Wang","doi":"10.1007/s00044-025-03372-x","DOIUrl":"10.1007/s00044-025-03372-x","url":null,"abstract":"<div><p>To discover natural-derived fungicides, three series of 2-aryl-3,4-dihydroisoquinolinium salts (<b>6</b>–<b>8</b>) containing benzoate moieties were designed and synthesized based-on quaternary isoquinoline alkaloids. Their structures were confirmed by spectroscopic analysis. Antifungal activities against 10 phytopathogenic fungi were evaluated in vitro at 50 mg/L. Most of the title compounds exhibited moderate to excellent fungicidal activities, which were as active as the positive controls (chlorothalonil, carbendazim) and better than the reference model <b>9</b>. Furthermore, for <i>R. solani</i> and <i>R. cerealis</i> <b>8c</b> presented EC₅₀ values of 5.03 and 7.41 mg/L, respectively, equal to or <span>superior</span> than chlorothalonil (4.63 mg/L, 15.0313 mg/L). The SARs studies indicated that introduce the benzoate moieties had significant effect on the antifungal activity, in which the presence of 3′-CO₂Me (<b>7</b>) and 4′-CO₂Me (<b>8</b>) derivatives were more active than 2′-CO₂Me ones (<b>6</b>). Further mechanism studies on <i>R. solani</i> elucidated that compound <b>8c</b> could increase the permeability of the cell membrane, dramatically induce the accumulation of ROS. These results revealed that compound <b>8c</b> could represent as a potential lead for the development of antifungal agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"709 - 719"},"PeriodicalIF":2.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480928","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":"Design, synthesis and insecticidal activities of novel m-diamide compounds containing n-propyl group","authors":"Daoxin Wu,&nbsp;Bingqing Li,&nbsp;Jiyong Liu,&nbsp;Tingting Zhao,&nbsp;Juncheng Xiang,&nbsp;Kangming Li","doi":"10.1007/s00044-025-03374-9","DOIUrl":"10.1007/s00044-025-03374-9","url":null,"abstract":"<div><p>To develop a structurally novel and efficient insecticide, a series of meta-diamide compounds incorporating <i>n</i>-propyl groups were designed and synthesized through active substructure splicing. This was achieved by using cyproflanilide as the lead compound while maintaining its fundamental active skeleton. All compounds were characterized by ¹H NMR, ¹³C NMR, and HRMS. Preliminary bioassay results showed that some target compounds exhibited strong insecticidal activity against <i>Plutella xylostella</i>, <i>Mythimna separata</i>, and <i>Tetranychus cinnabarinus</i>. Notably, compound <b>7i</b> exhibited 100% lethality at a concentration of 1 mg/L against both <i>Plutella xylostella</i> and <i>Mythimna separata</i>; meanwhile, compound 7f achieved complete lethality against <i>Tetranychus cinnabarinus</i> at a concentration of 100 mg/L. These findings may provide valuable insights for developing novel, highly efficient meta-diamide compounds.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"700 - 708"},"PeriodicalIF":2.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481116","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":"Synthesis and antibacterial activity of environmentally friendly sulfonium compounds","authors":"Jing Li,&nbsp;Wenyang Chen,&nbsp;Xinrui Bi,&nbsp;Yue Lin,&nbsp;Chengcai Liu,&nbsp;Yan Sun,&nbsp;Guinan Shen","doi":"10.1007/s00044-024-03341-w","DOIUrl":"10.1007/s00044-024-03341-w","url":null,"abstract":"<div><p>The abuse and overuse of antibacterial drugs have caused the increasing drug resistance of pathogenic bacteria, which threats human health and environmental health. Therefore the development of new environmentally friendly antibacterial drugs is of great urgency. The purpose of this study is to develop novel sulfonium compounds and evaluate their antibacterial activities. The sulfonium compounds were obtained by substitution reactions of methionine. The antimicrobial activities of the compounds were evaluated by measurement of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against <i>S. aureus</i> and <i>E. coli</i>. A total of fifteen sulfonium compounds were synthesized and all of them showed antibacterial activity that varied with the substitution chain length. These compounds were highly sensitive to <i>S. aureus</i> with the lowest MIC and MBC at 0.39 μmol/L and 1.56 μmol/L, respectively, which are lower than that of commercial quaternary ammonium compounds. An extra group of eight sulfonium compounds were also constructed to study the relationship between compound structures and their antibacterial abilities. A preferred structure with one longer hydrophobic alkyl chain at the amine position has been demonstrated for better antibacterial activity.</p><div><figure><div><div><picture><source><img></source></picture></div><div><p>Methionine based sulfonium compound as environmentally friendly antibacterial agent.</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"690 - 699"},"PeriodicalIF":2.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480910","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":"Pancreatic lipase inhibitors as anti-obesity agents: a review of recent chemical scaffolds and their pancreatic lipase inhibitory potential","authors":"Noor ul Amin Mohsin,&nbsp;Matloob Ahmad,&nbsp;Maryam Farrukh,&nbsp;Sidra Rafique","doi":"10.1007/s00044-025-03371-y","DOIUrl":"10.1007/s00044-025-03371-y","url":null,"abstract":"<div><p>Obesity is an excessive accumulation of fat in the body. The disease of obesity is increasing all over the world. At present, only a few drugs are available for the treatment of obesity. Various strategies have been explored for the management of obesity. The inhibition of fat metabolizing enzyme, pancreatic lipase (PL) is one of the best strategies for its treatment. In recent years, many organic compounds, heterocyclic and phytochemicals have been evaluated as PL inhibitors. The nitrogen-containing heterocyclic compounds have acquired great consideration due to their significant biological activities. Most of the compounds have been evaluated by in vitro and in silico experiments. The review highlights the PL inhibitory effects of different chemical scaffolds.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"497 - 516"},"PeriodicalIF":2.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480911","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":"Design, synthesis, in vitro evaluation, and molecular dynamics simulation studies of novel coumarin-acetohydrazide Schiff base derivatives as urease enzyme inhibitors","authors":"Mohammad Azimi,&nbsp;Hassan Sepehrmansourie,&nbsp;Ahmad Ebadi,&nbsp;Gholamabbas Chehardoli,&nbsp;Mohammad Ali Zolfigol,&nbsp;Massoud Amanlou,&nbsp;Mohammad Nazari Montazer,&nbsp;Mohammad Mahdavi,&nbsp;Zahra Najafi","doi":"10.1007/s00044-024-03369-y","DOIUrl":"10.1007/s00044-024-03369-y","url":null,"abstract":"<div><p>Urease inhibition, a nickel-containing metalloenzyme, is a promising approach for treating Helicobacter pylori (H. pylori) infections as a critical virulence factor that allows the bacteria to colonize the gastric mucosa and survive the acidic environment of the stomach. In this context, we report the design, synthesis, in vitro evaluation, and molecular dynamics simulation (MD) studies of novel ((4,7-dimethyl-2-oxo-2<i>H</i>-chromen-5-yl)oxy)acetohydrazide derivatives as urease enzyme inhibitors. Notably, all compounds exhibited potent inhibitory activities, with IC₅₀ values ranging from 2.438 µM to 4.427 µM. Further kinetic studies revealed that compound <b>11g</b> as the most potent compound with IC₅₀ value of 2.438 ± 0.31 μM acts as a non-competitive inhibitor toward urease with an inhibition constant (Ki) of 2.33 μM. In silico studies elucidated the binding interactions of compound <b>11g</b>, revealing crucial hydrogen bonds with key amino acid residues as well as chelation with Ni ions within the active site of urease. Molecular dynamics (MD) simulations confirmed the stable ligand-urease complex maintains interactions with both the active site residues and the flap moiety of urease, acting as noncompetitive inhibitors. These findings demonstrate the potential of coumarin-acetohydrazide Schiff base derivatives as a new frontier in developing urease inhibitors.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"675 - 689"},"PeriodicalIF":2.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480997","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":"In vitro and in silico studies on α-glucosidase inhibitory properties of bioactive components from the rhizomes of Alpinia officinarum Hance","authors":"Zakhele Mphatsi Dlamini,&nbsp;Bongani Sicelo Dlamini,&nbsp;Shih-Han Fu,&nbsp;Ya-Lin Chang,&nbsp;Chi-Chien Lin,&nbsp;Yu-Kuo Chen,&nbsp;Kok-Tong Tan,&nbsp;Chi-I Chang","doi":"10.1007/s00044-024-03366-1","DOIUrl":"10.1007/s00044-024-03366-1","url":null,"abstract":"<div><p>Key digestive enzymes, <i>α</i>-glucosidase and <i>α</i>-amylase, are associated with the occurrence of type 2 diabetes mellitus (T2DM). Inhibition of these important enzymes is one of the important strategies for the treatment of T2DM. In the search for alternative <i>α</i>-glucosidase inhibitors, five compounds (<b>1–5</b>) were obtained from the rhizomes of <i>Alpinia officinarum</i> Hance by chromatographic methods. In vitro enzyme inhibition assays, kinetic analysis, and molecular docking studies were conducted to investigate the inhibition mechanism of the isolated compounds against <i>α</i>-glucosidase. Compounds <b>1</b>, <b>3</b>, <b>4</b>, and <b>5</b> showed comparable <i>α</i>-glucosidase inhibitory activities to quercetin (IC₅₀ value of 19.77 µM) with IC₅₀ values ranging from 37.48 to 89.08 µM. According to the findings of the kinetic analysis, compounds <b>1</b>, <b>2</b>, and <b>4</b> were uncompetitive inhibitors, while compound <b>3</b> was a competitive inhibitor and compound <b>5</b> was a mixed-type inhibitor of <i>α</i>-glucosidase. In the computational investigation, hydrogen bonds served as the primary bond between the compounds and the amino acid residues. The results showed that <i>A. officinarum</i> might be a viable source of <i>α</i>-glucosidase inhibitors and antidiabetic agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"664 - 674"},"PeriodicalIF":2.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480875","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}