Medicinal Chemistry Research最新文献

{"title":"Naphthoquinones and tricyclic derivatives: in vitro evaluation as xanthine oxidase inhibitors","authors":"Stephanus J. Cloete,&nbsp;Roslyn Lefin,&nbsp;Jacobus P. Petzer,&nbsp;Anél Petzer","doi":"10.1007/s00044-025-03395-4","DOIUrl":"10.1007/s00044-025-03395-4","url":null,"abstract":"<div><p>The enzyme, xanthine oxidase (XO), is a complex flavoprotein that catalyzes the sequential oxidation of hypoxanthine and xanthine to ultimately yield uric acid as the final steps in the catabolism of adenine nucleotides. In this process molecular oxygen is reduced to yield the superoxide anion radical and hydrogen peroxide. The overproduction of uric acid could lead to hyperuricemia and the deposition of urate crystals in joints and surrounding tissues. This condition is known as gout and is the most common cause of inflammatory arthritis. XO inhibitors are well-known treatment for the prevention of hyperuricemia and gout, and may find application in various other disease states that are associated with XO-induced production of reactive oxygen species. To discover new inhibitors of XO, the present study investigated 55 diverse compounds from an in-house library. The results showed that seven compounds inhibited bovine milk XO with IC₅₀ &lt; 10 µM: juglone (IC₅₀ = 2.45 µM); menadione (IC₅₀ = 4.38 µM); benz(<i>g</i>)isoquinoline-5,10-dione (IC₅₀ = 2.07 µM); 2-chloro-7-methoxy-10<i>H</i>-phenothiazine (IC₅₀ = 2.17 µM); cinnabarinic acid (IC₅₀ = 3.41 µM); 9,10-phenanthrenequinone (IC₅₀ = 0.726 µM); quinalizarin (IC₅₀ = 8.54 µM). These potencies were comparable to that recorded for the reference inhibitor, chrysin (IC₅₀ = 13.6 µM). This study therefore discovered naphthoquinone and tricyclic derivatives as small molecule XO inhibitors for the development of treatments for hyperuricemia and other disorders that are associated with the overactivity of XO.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 5","pages":"1014 - 1024"},"PeriodicalIF":2.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03395-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919080","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":"Discovery of structurally novel tetrahydroisoquinoline derivatives bearing NO donor as potential anti-cancer therapeutics","authors":"Hao Chen,&nbsp;Xin Gao,&nbsp;Siqi Fan,&nbsp;Xiaodong Ma,&nbsp;Fang Fang","doi":"10.1007/s00044-025-03396-3","DOIUrl":"10.1007/s00044-025-03396-3","url":null,"abstract":"<div><p>In this study, 20 tetrahydroisoquinoline (THIQ)-NO donor hybrids, derived from our in-house trans-<i>β</i>-arylacryl-THIQ-based scaffold, were designed, synthesized, and in vitro biologically evaluated as potential anti-cancer therapeutics. Among them, compounds <b>13h</b>, <b>j</b> and <b>20b</b> exerted anti-proliferative activities at single-digit micromolar level against A549, HepG2, HCT-116, and HL-60 cell lines, which are superior to those of the parent compound <b>7</b>. The anti-proliferative potency of <b>13j</b> and <b>20g</b> against HL-60 cells were comparable to that of gefitinib. In addition, <b>13j</b> induced the release of NO in HepG2 cells in a dose-dependent manner. The western blot analysis illustrated that <b>13j</b> also dose-dependently ablated the phosphorylation of AKT and ERK1/2 in this cell line. With the aforementioned attractive performance, compound <b>13j</b> deserves further functional investigation.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 5","pages":"966 - 972"},"PeriodicalIF":2.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919298","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":"New amidrazone analogs as multi-kinase inhibitors: in-silico and biological investigation as an anticancer agent","authors":"Almeqdad Y. Habashneh,&nbsp;Mahmoud A. Al-Sha’er,&nbsp;Sanaa K. Bardaweel","doi":"10.1007/s00044-025-03397-2","DOIUrl":"10.1007/s00044-025-03397-2","url":null,"abstract":"<div><p>A series of novel biphenyl- and naphthyl-based amidrazone derivatives was synthesized and evaluated for anticancer activity against breast (MDA-MB-231) and colon (HL-60) cancer cell lines. Seven piperazine-containing derivatives exhibited significant anticancer effects with IC₅₀ values ranging from 7 to 30 μM while showing low toxicity toward fibroblasts (IC₅₀ &gt; 300 μM). Molecular docking studies revealed that the most active compounds, <b>10a</b> and <b>10e</b>, bind strongly within the ATP-binding site of c-Abl kinase (PDB: 1IEP, resolution: 2.10 Å), achieving LibDock scores of 64.26 and 87.68, respectively, and enzyme inhibition IC₅₀ values of 18.29 μM and 10.28 μM. Compounds <b>12b, 12c, 12e</b>, and <b>15b</b> significantly inhibited PKN2 activity, while <b>12d</b> and <b>16d</b> showed enhanced potency against IKKβ despite lower c-Abl inhibition. These findings indicate that the anticancer effects of the synthesized derivatives are likely mediated by multitarget kinase inhibition, underscoring their promise as candidates for developing multi-kinase-targeting anticancer 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 5","pages":"996 - 1013"},"PeriodicalIF":2.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919299","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, hydrolysis, and COX-2/15-LOX inhibitory evaluation of 4-Acetamidophenyl 4-Bromobenzoates","authors":"Uzma Afzal,&nbsp;Abid Mahmood,&nbsp;Muhammad Zubair,&nbsp;Nasir Rasool,&nbsp;Aqsa Kanwal,&nbsp;Maria Sohail,&nbsp;Gulraiz Ahmad","doi":"10.1007/s00044-025-03393-6","DOIUrl":"10.1007/s00044-025-03393-6","url":null,"abstract":"<div><p>The enzymes cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) metabolize arachidonic acid and have been associated with the onset and progression of several disorders, including various inflammatory diseases. Dual COX-2/15-LOX inhibition is a useful approach to develop drugs with enhanced biological activities and reduced off-target drug actions, with a wider range of anti-inflammatory properties as compared to traditional NSAIDs. In the current work, we designed and developed a number of arylated carboxylate acetaminophen analogues as COX-2/15-LOX dual inhibitors. Compounds <b>5b</b>, <b>5d</b>, and <b>5e</b> exhibited moderate COX-2 inhibitory activity (IC₅₀ = 1.44 ± 0.10, 1.80 ± 0.14, &amp; 2.39 ± 0.11 µM) in vitro assay. Compound <b>5c</b> had higher COX-2 selectivity (IC₅₀ = 0.18 ± 0.05 µM) than celecoxib (IC₅₀ = 0.33 ± 011 µM). Compared to the quercetin (standard inhibitor), with an IC₅₀ = 15.8 ± 0.61 µM that all synthesized analogues exhibited significantly improved inhibitory activity towards 15-LOX and compound <b>5c</b> was found to be the most effective 15-LOX inhibitor (IC₅₀ = 0.14 ± 0.18 µM). Moreover, molecular docking closely aligns with in vitro studies, revealing the specific interactions towards synthesized derivatives (<b>5a</b>–<b>5f</b>) and target proteins.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 5","pages":"982 - 995"},"PeriodicalIF":2.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919148","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":"Identification of the chemical composition of blue honeyberry leaves (Lonicera caerulea L. var. edulis) and their anti-inflammatory activity","authors":"Zhenji Rong,&nbsp;Chunping Yu,&nbsp;Xin Wang,&nbsp;Ruyue Wang,&nbsp;Yang Gao,&nbsp;Hailong Zhang","doi":"10.1007/s00044-025-03391-8","DOIUrl":"10.1007/s00044-025-03391-8","url":null,"abstract":"<div><p>Blue honeyberry is a well-known nutritious fruit. Meanwhile, it is also an Oroqen herb in China. However, the chemical constituent of the leaves of the plant is little known, despite having better anti-inflammatory activity. In this study, we investigated the chemical constituents of blue honeyberry leaves and screened their anti-inflammatory effects in RAW264.7 cells. Thirty-nine compounds including a new fernane-type triterpenoid were isolated and identified using various chromatographic approaches and spectroscopic techniques. The new compound and some other components showed a significant anti-inflammatory effect by inhibiting nitric oxide production in RAW264.7 cells, in which compounds <b>6</b> and <b>38</b> exhibited the inhibition of 40.6 ± 4.8% and 46.0 ± 1.4% at the concentration of 100 μM, respectively, without inducing any cytotoxicity.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 5","pages":"973 - 981"},"PeriodicalIF":2.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919199","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":"A glance into Schiff-based α-glucosidase inhibitors in medicinal chemistry","authors":"Sakineh Dadashpour","doi":"10.1007/s00044-025-03390-9","DOIUrl":"10.1007/s00044-025-03390-9","url":null,"abstract":"<div><p>Diabetes mellitus is a chronic disorder characterized by hyperglycemia and is caused by metabolic dysregulation. According to a report from the World Health Organization (WHO), in 2014, more than 422 million people in the world were diagnosed with diabetes. In the small intestine, α-glucosidase mediates the hydrolysis of polysaccharides into monosaccharides which cause a spike in blood glucose levels. Therefore, inhibitors of α-glucosidase can reduce the rate of polysaccharides breakdown, reduce of glucose absorption, and provide antidiabetic effects. Schiff bases derived from a primary amine and carbonyl compound involving an aldehyde or a ketone, are a well-known group of organic compounds with a broad range of biological activities including antidiabetic activity. The current study emphasizes the molecular structure of various synthesized Schiff base-containing compounds and the structure-activity relationship of the most active compounds that serve as α-glucosidase inhibitors. We believe this review will provide valuable information for those developing Schiff base compounds with antidiabetic activity.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 5","pages":"945 - 965"},"PeriodicalIF":2.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel benzbromarone derivatives via the closed metabolic site as potent human uric acid transporter 1 (URAT1) inhibitors","authors":"Wenfeng Ye,&nbsp;Mingchao He,&nbsp;Gaofeng Lin,&nbsp;Li Shao,&nbsp;Jiajia Mo,&nbsp;Yan Zhao,&nbsp;Xiaodong Ma,&nbsp;Qinlong Xu,&nbsp;Zhaoxing Chu","doi":"10.1007/s00044-025-03389-2","DOIUrl":"10.1007/s00044-025-03389-2","url":null,"abstract":"<div><p>Although benzbromarone is a highly potent inhibitor of URAT1, the toxicity of its metabolite has led to the restricted use. In this study, to decrease its toxicity, thirteen benzbromarone derivatives were designed and synthesized via blocking metabolic site. Among them, most of the compounds had moderate to strong inhibitory activity against URAT1, with IC₅₀ values ranging from 0.041 ± 0.010 μM to 3.208 ± 0.458 μM. In particular, compound <b>30</b> demonstrated the most potent URAT1-inhibitory activity (IC₅₀ = 0.041 ± 0.010 μM), which is nearly seven-fold enhanced over BBR (IC₅₀ = 0.278 ± 0.053 μM). Importantly, it displayed a favorable bioavailability of 75.2%. As demonstrated by the in vitro and in vivo experiments, no reported toxic metabolites were found and the risk of potential liver toxicity was low.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 4","pages":"929 - 943"},"PeriodicalIF":2.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622132","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":"Correction: Anticancer therapeutic potential of silibinin: current trends, scope and relevance","authors":"Anupam Sharma,&nbsp;Sunil Kumar,&nbsp;Virender Pahil,&nbsp;Babli Mamoria,&nbsp;Mukesh Yadav,&nbsp;Nirmala Sehrawat,&nbsp;Manoj Singh,&nbsp;Anil Kumar Sharma","doi":"10.1007/s00044-025-03388-3","DOIUrl":"10.1007/s00044-025-03388-3","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 4","pages":"825 - 826"},"PeriodicalIF":2.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622273","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, biological evaluation, and in silico studies of imidazo[2,1-b][1,3,4]thiadiazole derivatives as cholinesterase inhibitors","authors":"Wen-Rong Du,&nbsp;Yi-Xuan Wang,&nbsp;Xue-Wei Zhou,&nbsp;Yong Lan,&nbsp;Ben-Ben Wei,&nbsp;Xin-Yuan Guo,&nbsp;Xiao-Ke Wang,&nbsp;Zheng-Yue Ma","doi":"10.1007/s00044-025-03387-4","DOIUrl":"10.1007/s00044-025-03387-4","url":null,"abstract":"<div><p>In this study, a series of imidazo[2,1-<i>b</i>][1,3,4]thiadiazole derivatives were designed, synthesized, and evaluated as potential cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Furthermore, the antioxidant activities of these compounds were examined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The inhibition assay against cholinesterase (ChE) revealed that these synthesized compounds exhibited moderate inhibitory activities against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Notably, some of the tested compounds had varying antioxidant activities. Specifically, compound <b>20aa</b> (eeAChE, IC₅₀ = 0.75 μM; eqBChE, IC₅₀ = 4.11 μM; SI = 5.48) was found to be the most effective ChEI, exhibiting approximately 5-fold greater activity against AChE and 4-fold greater activity against BChE compared to galantamine. Additionally, compound <b>20aa</b> also possessed antioxidant activity, with IC₅₀ value of 442.87 µM. To understand the binding mode of compound <b>20aa</b>, molecular docking studies were performed, and the results indicated that compound <b>20aa</b> could interact with amino acid residues in the catalytic active site (CAS) of both BChE and AChE, as well as with the peripheral anionic site (PAS) of AChE. Among them, compound <b>20aa</b> showed a mixed inhibition pattern with AChE, which aligned with the results of the enzyme kinetics studies. Molecular dynamics (MD) simulation studies demonstrated the stability of the <b>20aa</b>-AChE/BChE complexes. Considering its biological activity and molecular properties, compound <b>20aa</b> could be a promising lead compound for the development of AD drugs.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 4","pages":"910 - 928"},"PeriodicalIF":2.6,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622263","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":"An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 interaction: synthesis, biological evaluation and computational analysis","authors":"Albert Enama Ehinak,&nbsp;Maloba M. M. Lobe,&nbsp;Donatus B. Eni,&nbsp;Conrad V. Simoben,&nbsp;Ian Tietjen,&nbsp;Mathieu J. Mbenga Tjegbe,&nbsp;Joel Cassel,&nbsp;Joseph M. Salvino,&nbsp;Luis J. Montaner,&nbsp;Wolfgang Sippl,&nbsp;Simon M. N. Efange,&nbsp;Fidele Ntie-Kang","doi":"10.1007/s00044-025-03386-5","DOIUrl":"10.1007/s00044-025-03386-5","url":null,"abstract":"<div><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained significant public health attention owing to its devastating effects on lives and livelihoods worldwide. Due to difficult access to vaccines in many developing countries and the inefficiency of vaccines in providing complete protection even with fully vaccinated persons, there remains the need for the development of novel drugs to combat the disease. This study describes the in vitro activity of a library of fifty-five spiro-fused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) as potential blocking agents of the interaction between the SARS-CoV-2 viral spike and the human angiotensin-converting enzyme 2 (ACE2) receptor, essential for viral transmission. The synthesis was conducted by the Pictet-Spengler condensation of phenethylamine and isatin derivatives, while the screening against spike-ACE2 interaction was done using our previously described AlphaScreen fluorescent assay. The in vitro screening identified compound (<b>11j</b>) as the most active, showing a 50% inhibitory concentration (IC₅₀) of 3.6 μM against SARS-CoV-2 spike/ACE2 interaction. Structure-activity relationships explained via molecular docking studies and the computation of binding free energy of each compound with respect to the spike/ACE2 protein-protein interaction showed that the most active compound possesses a bulky naphthyl group, which addresses voluminous hydrophobic regions of the ACE2 binding site and interacts with the hydrophobic residues of the target. Therefore, these compounds could be potentially useful in searching for SARS-CoV-2 spike/ACE2 interaction blocking 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 4","pages":"895 - 909"},"PeriodicalIF":2.6,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-025-03386-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621949","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}