A series of novel Triclosan–Isatin–Isoniazid triads were synthesized and evaluated for antitubercular activity. These hybrids showed potent efficacy against Mycobacterium tuberculosis with low minimum inhibitory concentrations (MICs) ranging from 0.78 to 1.56 μg/mL, along with high selectivity indices, indicating strong activity with minimal cytotoxicity in human macrophages. Time-kill assays revealed bactericidal effects, with some hybrids achieving sustained bacterial growth suppression comparable to INH at equivalent MICs. At higher doses, a 3-log reduction in bacterial viability was achieved within three days, with one triad showing an additional 1-log reduction by day six. Mechanistic evaluation using INH-resistant katG mutant strains revealed reduction in activity, indicating KatG-dependent bioactivation. Cytotoxicity assays confirmed low toxicity (IC50 > 100 μg/mL), underscoring their potential as safe and effective anti-TB agents.
{"title":"TCS-isatin-INH triads as potent and selective anti-mycobacterial with high efficacy against Mycobacterium tuberculosis","authors":"Shekhar , Francoise Roquet-Banères , Laurent Kremer , Vipan Kumar","doi":"10.1016/j.ejmcr.2025.100307","DOIUrl":"10.1016/j.ejmcr.2025.100307","url":null,"abstract":"<div><div>A series of novel Triclosan–Isatin–Isoniazid triads were synthesized and evaluated for antitubercular activity. These hybrids showed potent efficacy against <em>Mycobacterium tuberculosis</em> with low minimum inhibitory concentrations (MICs) ranging from 0.78 to 1.56 μg/mL, along with high selectivity indices, indicating strong activity with minimal cytotoxicity in human macrophages. Time-kill assays revealed bactericidal effects, with some hybrids achieving sustained bacterial growth suppression comparable to INH at equivalent MICs. At higher doses, a 3-log reduction in bacterial viability was achieved within three days, with one triad showing an additional 1-log reduction by day six. Mechanistic evaluation using INH-resistant <em>katG</em> mutant strains revealed reduction in activity, indicating KatG-dependent bioactivation. Cytotoxicity assays confirmed low toxicity (IC<sub>50</sub> > 100 μg/mL), underscoring their potential as safe and effective anti-TB agents.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100307"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The global emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2019 resulted in widespread consequences for human health, with an ongoing situation six years later. Despite extensive efforts, the virus continues to circulate, resulting in a persistent rate of new diagnoses and fatalities. The potential for future outbreaks is heightened by the emergence of new mutations, underscoring the need for effective additional treatment options, such as antiviral drugs, to prevent the difficulties experienced during the COVID-19 pandemic. In this study, a structure-guided ligand design strategy was applied to optimize the SARS-CoV-2 papain-like protease (PLpro) inhibitor GRL0617 and enhance its potency. A series of covalent inhibitors was synthesized, and their inhibition potential, target-specificity, binding mode, and selectivity against several human proteases were evaluated. Two compounds, LS 22–5 and AZ 23–6, demonstrating the nanomolar inhibition potential of PLpro, were identified as lead compounds for antiviral drug design.
{"title":"Design, synthesis, and binding analysis of target-specific covalent inhibitors of SARS-CoV-2 papain-like protease","authors":"Martynas Bagdonas , Laimonas Stančaitis , Ernestas Urniežius , Audrius Zakšauskas , Aurelija Mickevičiūtė , Rūta Kananavičiūtė , Audronė Rukšėnaitė , Vaida Juozapaitienė , Jurgita Matulienė , Visvaldas Kairys , Franz-Josef Meyer-Almes , Asta Zubrienė , Daumantas Matulis","doi":"10.1016/j.ejmcr.2025.100306","DOIUrl":"10.1016/j.ejmcr.2025.100306","url":null,"abstract":"<div><div>The global emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2019 resulted in widespread consequences for human health, with an ongoing situation six years later. Despite extensive efforts, the virus continues to circulate, resulting in a persistent rate of new diagnoses and fatalities. The potential for future outbreaks is heightened by the emergence of new mutations, underscoring the need for effective additional treatment options, such as antiviral drugs, to prevent the difficulties experienced during the COVID-19 pandemic. In this study, a structure-guided ligand design strategy was applied to optimize the SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) inhibitor GRL0617 and enhance its potency. A series of covalent inhibitors was synthesized, and their inhibition potential, target-specificity, binding mode, and selectivity against several human proteases were evaluated. Two compounds, <strong>LS 22</strong>–<strong>5</strong> and <strong>AZ 23</strong>–<strong>6</strong>, demonstrating the nanomolar inhibition potential of PL<sup>pro</sup>, were identified as lead compounds for antiviral drug design.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100306"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-06-19DOI: 10.1016/j.ejmcr.2025.100282
Vid Kavaš , Philip Hinchliffe , Maša Zorman , Alen Krajnc , Matic Proj , Majda Golob , Martina Hrast Rambaher , James Spencer , Stanislav Gobec
Antimicrobial resistance has emerged as a critical global public health threat, impacting human, animal and environmental health. An important mechanism of resistance is the production of β-lactamases, enzymes that hydrolyze the β-lactam ring, rendering β-lactam antibiotics ineffective. Metallo-β-lactamases (MBLs), which contain zinc ions in their active sites, are particularly challenging to counter as there are currently no inhibitors targeting these enzymes available on the market. Therefore, there is an urgent need for innovative drug discovery strategies to develop MBL-targeted therapies. New Delhi Metallo-β-Lactamase 1 (NDM-1) is the most widely disseminated MBL, with a global distribution in Enterobacterales. In this study, we used our library of fragment-sized chloroacetamides as a starting point to synthesize mercaptoacetamides as potential NDM-1 inhibitors. This resulted in a compound (14a) with an IC50 of 20 μM, which crystallography shows binds to NDM-1 in two different poses. Using this structure as a starting point for in silico design, we developed a series of larger thiol-based compounds designed to occupy more space in the active site and to utilize other novel zinc-binding groups. Although some showed minimal inhibition (which makes them valuable as decoys for metalloenzyme studies) one compound exhibited an IC50 of 14 μM, with crystallography indicating that an additional aromatic group, compared to 14a, interacts with hydrophobic residues on an NDM-1 active site loop. These data identify promising scaffolds for the further development of potent MBL inhibitors and show the utility of repurposing chemical libraries to target clinically important enzymes.
{"title":"Repurposing of compound libraries yields new inhibitors of NDM-1 metallo-β-lactamase with diverse zinc-binding moieties","authors":"Vid Kavaš , Philip Hinchliffe , Maša Zorman , Alen Krajnc , Matic Proj , Majda Golob , Martina Hrast Rambaher , James Spencer , Stanislav Gobec","doi":"10.1016/j.ejmcr.2025.100282","DOIUrl":"10.1016/j.ejmcr.2025.100282","url":null,"abstract":"<div><div>Antimicrobial resistance has emerged as a critical global public health threat, impacting human, animal and environmental health. An important mechanism of resistance is the production of β-lactamases, enzymes that hydrolyze the β-lactam ring, rendering β-lactam antibiotics ineffective. Metallo-β-lactamases (MBLs), which contain zinc ions in their active sites, are particularly challenging to counter as there are currently no inhibitors targeting these enzymes available on the market. Therefore, there is an urgent need for innovative drug discovery strategies to develop MBL-targeted therapies. New Delhi Metallo-β-Lactamase 1 (NDM-1) is the most widely disseminated MBL, with a global distribution in <em>Enterobacterales</em>. In this study, we used our library of fragment-sized chloroacetamides as a starting point to synthesize mercaptoacetamides as potential NDM-1 inhibitors. This resulted in a compound (<strong>14a</strong>) with an IC<sub>50</sub> of 20 μM, which crystallography shows binds to NDM-1 in two different poses. Using this structure as a starting point for <em>in silico</em> design, we developed a series of larger thiol-based compounds designed to occupy more space in the active site and to utilize other novel zinc-binding groups. Although some showed minimal inhibition (which makes them valuable as decoys for metalloenzyme studies) one compound exhibited an IC<sub>50</sub> of 14 μM, with crystallography indicating that an additional aromatic group, compared to <strong>14a</strong>, interacts with hydrophobic residues on an NDM-1 active site loop. These data identify promising scaffolds for the further development of potent MBL inhibitors and show the utility of repurposing chemical libraries to target clinically important enzymes.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100282"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Five new dolabellane (1–5), three dolastane (6–8) type diterpenes together with five previously identified congeners (9–13), were isolated from the organic extracts of the brown seaweed Dictyota dichotoma, collected in the Mandapam coast, Tamil Nadu. The structures and relative stereochemistry of the new isolates 1–8 were determined on the basis of extensive spectroscopic (NMR and Mass spec) data, whereas the structures of 10 and 12 were verified by X-ray diffraction analysis. A plausible biogenetic relationship between undescribed compounds 1–8 were also proposed. The in vitro anti-cancer activity of the isolates was examined against a panel of cancer cell lines, including DU145 (prostate), B16F10 (melanoma), HeLa (cervical), and MDA-MB231 (breast) using MTT assay. The screening results showed that majority of the isolated compounds exhibited moderate to potent activities against tested cell lines. Among the tested, compounds 4 and 7 manifested potent activities with an IC50 value of 3.53 ± 0.05 and 2.18 ± 0.06 μM respectively, against B16F10 and DU145 cells. Further, detailed fluorescence assays, scratch assay and flow cytometry analysis revealed that the compounds 4 and 7 diminished proliferation and arrested cell cycle in the G0 phase and G0/G1 phase, which induced cell death by apoptosis. Overall, this study provided that compounds 4 and 7 could serve as lead molecules for the development of potent anti-cancer agents.
{"title":"New cytotoxic dolabellane and dolastane diterpenes from Brown seaweed Dictyota dichotoma","authors":"Kolukula Ashwini , Bandi Siva , Penta Poornima , Solipeta Divya Reddy , Hashnu Dutta , Vedula Girija Sastry , Katragadda Suresh Babu","doi":"10.1016/j.ejmcr.2025.100286","DOIUrl":"10.1016/j.ejmcr.2025.100286","url":null,"abstract":"<div><div>Five new dolabellane (<strong>1</strong>–<strong>5</strong>), three dolastane (<strong>6</strong>–<strong>8</strong>) type diterpenes together with five previously identified congeners (<strong>9</strong>–<strong>13</strong>), were isolated from the organic extracts of the brown seaweed <em>Dictyota dichotoma,</em> collected in the Mandapam coast, Tamil Nadu. The structures and relative stereochemistry of the new isolates <strong>1</strong>–<strong>8</strong> were determined on the basis of extensive spectroscopic (NMR and Mass spec) data, whereas the structures of <strong>10</strong> and <strong>12</strong> were verified by X-ray diffraction analysis. A plausible biogenetic relationship between undescribed compounds <strong>1</strong>–<strong>8</strong> were also proposed. The <em>in vitro</em> anti-cancer activity of the isolates was examined against a panel of cancer cell lines, including DU145 (prostate), B16F10 (melanoma), HeLa (cervical), and MDA-MB231 (breast) using MTT assay. The screening results showed that majority of the isolated compounds exhibited moderate to potent activities against tested cell lines. Among the tested, compounds <strong>4</strong> and <strong>7</strong> manifested potent activities with an IC<sub>50</sub> value of 3.53 ± 0.05 and 2.18 ± 0.06 μM respectively, against B16F10 and DU145 cells. Further, detailed fluorescence assays, scratch assay and flow cytometry analysis revealed that the compounds <strong>4</strong> and <strong>7</strong> diminished proliferation and arrested cell cycle in the G0 phase and G0/G1 phase, which induced cell death by apoptosis. Overall, this study provided that compounds <strong>4</strong> and <strong>7</strong> could serve as lead molecules for the development of potent anti-cancer agents.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100286"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-14DOI: 10.1016/j.ejmcr.2025.100303
Christian Bailly
Marine-derived bioactive natural products are an essential resource for drug discovery. In particular, marine sponges and associated symbionts can be exploited to discover innovative compounds and new drug candidates. The sponge Hyrtios erectus which is largely distributed in Asian tropical areas, has been extensively investigated as a source of bioactive natural products. A detailed analysis of the natural products isolated from this sponge and their pharmacological properties has been performed. The study led to the identification of over 160 natural products, including over 50 alkaloids, 100 terpenoids and a few other compounds like phenolic alkenes (erectuseneols), chromanones (hyrtiosones) and cyclic peptides (spongitatin-1). The survey introduces multiple series of products, such as the hyrtiosins, hyrtiosulawesine, hyrtiazepine, hyrtioerectines, hyrtioreticulins, hyrtimomines, hyrtinadines, and hainanerectamines among the alkaloids. A large range of sesterterpenes and sesquiterpenes have been isolated, in particular scalarane-type sesterterpenoids such as erectascalaranes A-B, hyrtioscalaranes A-B and hyrtiosins A-F, in addition to a panoply of scalarin and scalaradial derivatives. All these compounds are presented together with their pharmacological properties. Synthetic procedures leading to some of these natural products and analogues are described, notably for hyrtiozulawesine, hyrtinadine A, hytiosine B, and salmahyrtisol A. At the pharmacological level, the most interesting products and associated molecular targets are discussed, such as the targeting of the orphan nuclear receptor Nur77 with 12-epi-scalaradial derivatives. An updated view of the chemical and pharmacological diversity associated with Hyrtios erectus is provided with the goal to promote further researches with this sponge erected as an emblematic figure of the marine natural product chemistry.
{"title":"Pharmacognosy and natural product chemistry of the marine sponge Hyrtios erectus","authors":"Christian Bailly","doi":"10.1016/j.ejmcr.2025.100303","DOIUrl":"10.1016/j.ejmcr.2025.100303","url":null,"abstract":"<div><div>Marine-derived bioactive natural products are an essential resource for drug discovery. In particular, marine sponges and associated symbionts can be exploited to discover innovative compounds and new drug candidates. The sponge <em>Hyrtios erectus</em> which is largely distributed in Asian tropical areas, has been extensively investigated as a source of bioactive natural products. A detailed analysis of the natural products isolated from this sponge and their pharmacological properties has been performed. The study led to the identification of over 160 natural products, including over 50 alkaloids, 100 terpenoids and a few other compounds like phenolic alkenes (erectuseneols), chromanones (hyrtiosones) and cyclic peptides (spongitatin-1). The survey introduces multiple series of products, such as the hyrtiosins, hyrtiosulawesine, hyrtiazepine, hyrtioerectines, hyrtioreticulins, hyrtimomines, hyrtinadines, and hainanerectamines among the alkaloids. A large range of sesterterpenes and sesquiterpenes have been isolated, in particular scalarane-type sesterterpenoids such as erectascalaranes A-B, hyrtioscalaranes A-B and hyrtiosins A-F, in addition to a panoply of scalarin and scalaradial derivatives. All these compounds are presented together with their pharmacological properties. Synthetic procedures leading to some of these natural products and analogues are described, notably for hyrtiozulawesine, hyrtinadine A, hytiosine B, and salmahyrtisol A. At the pharmacological level, the most interesting products and associated molecular targets are discussed, such as the targeting of the orphan nuclear receptor Nur77 with 12-<em>epi</em>-scalaradial derivatives. An updated view of the chemical and pharmacological diversity associated with <em>Hyrtios erectus</em> is provided with the goal to promote further researches with this sponge erected as an emblematic figure of the marine natural product chemistry.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100303"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145320176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-07-26DOI: 10.1016/j.ejmcr.2025.100290
Fathimath Henna , G. Arun Kumar , Amritha Thaikkad , T.K. Varun , E. Jayadevi Variyar , Rajesh Raju , J. Abhithaj
Chronic inflammation underlies various diseases, including cardiovascular disorders, cancer, and autoimmune conditions. Phospholipase A2 (PLA2) plays a central role in the inflammatory response by hydrolyzing membrane phospholipids to release arachidonic acid, a precursor for pro-inflammatory eicosanoids via the COX and LOX pathways. Due to its upstream regulatory function, PLA2 presents a strategic target for inflammation control. However, developing safe and effective PLA2 inhibitors remains challenging due to limitations in efficacy and side effects.
Natural compounds, particularly phytochemicals with anti-inflammatory potential, are gaining attention as alternative therapeutics. This study investigated Lariciresinol, a phenolic lignan from Zingiber officinale (ginger), for its inhibitory activity against PLA2. Selected through in silico screening, Lariciresinol was evaluated using molecular docking, molecular dynamics (MD) simulations, and in vitro enzyme inhibition assays. The compound showed competitive inhibition with an IC50 of 57.6μM. The binding energy of Lariciresinol improved from −24.71kcal/mol to −34.38kcal/mol after MD simulations. The results from the binding energy analysis and MD simulations revealed stable interactions with key catalytic residues, supporting its proposed mechanism of action.
Further in silico analysis of Root Mean Square Deviation, Root Mean Square Fluctuation, Radius of Gyration, H-bonds, Solvent Accessible Surface Area, and Free Energy Landscape validated the results. These results highlight Lariciresinol a promising scaffold for developing novel PLA2-targeted anti-inflammatory agents, warranting further in vitro and in vivo validation for clinical application.
{"title":"In silico and In vitro profiling of lariciresinol against PLA2: A molecular approach to regulate inflammation","authors":"Fathimath Henna , G. Arun Kumar , Amritha Thaikkad , T.K. Varun , E. Jayadevi Variyar , Rajesh Raju , J. Abhithaj","doi":"10.1016/j.ejmcr.2025.100290","DOIUrl":"10.1016/j.ejmcr.2025.100290","url":null,"abstract":"<div><div>Chronic inflammation underlies various diseases, including cardiovascular disorders, cancer, and autoimmune conditions. Phospholipase A2 (PLA2) plays a central role in the inflammatory response by hydrolyzing membrane phospholipids to release arachidonic acid, a precursor for pro-inflammatory eicosanoids via the COX and LOX pathways. Due to its upstream regulatory function, PLA2 presents a strategic target for inflammation control. However, developing safe and effective PLA2 inhibitors remains challenging due to limitations in efficacy and side effects.</div><div>Natural compounds, particularly phytochemicals with anti-inflammatory potential, are gaining attention as alternative therapeutics. This study investigated Lariciresinol, a phenolic lignan from Zingiber officinale (ginger), for its inhibitory activity against PLA2. Selected through <em>in silico</em> screening, Lariciresinol was evaluated using molecular docking, molecular dynamics (MD) simulations, and <em>in vitro</em> enzyme inhibition assays. The compound showed competitive inhibition with an IC50 of 57.6μM. The binding energy of Lariciresinol improved from −24.71kcal/mol to −34.38kcal/mol after MD simulations. The results from the binding energy analysis and MD simulations revealed stable interactions with key catalytic residues, supporting its proposed mechanism of action.</div><div>Further <em>in silico</em> analysis of Root Mean Square Deviation, Root Mean Square Fluctuation, Radius of Gyration, H-bonds, Solvent Accessible Surface Area, and Free Energy Landscape validated the results. These results highlight Lariciresinol a promising scaffold for developing novel PLA2-targeted anti-inflammatory agents, warranting further <em>in vitro</em> and <em>in vivo</em> validation for clinical application.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100290"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-09-27DOI: 10.1016/j.ejmcr.2025.100300
Ruirong Peng , Yu Zhang , Zhenyu He , Yueling Pang , Huanhuan Ma , Ming Fang , Xiaoshan Ding , Yanan Wang , Zhihong Du , Fanming Kong , Liping Chen , Yongqi Liu , Ling Li , Jiawei Li
Systemic diseases are conditions caused by multiple factors (such as immune disorders, inflammation, tumors, etc.) that affect multiple organs, tissues, or systems throughout the body. These diseases are typically characterized by complex pathological states and diverse clinical symptoms. Vascular cell adhesion molecule-1 (VCAM-1) is a multifunctional transmembrane protein that plays a key role in various pathological processes, including inflammation, immune responses, and tumor progression, by mediating immune cell adhesion, regulating the tumor microenvironment, and facilitating signal transduction. This article aims to review the mechanistic roles of VCAM-1 in systemic diseases affecting the circulatory, respiratory, and digestive systems, as well as the association between VCAM-1 and tumor characteristics. Additionally, it discusses targeted therapeutic drugs (including traditional Chinese medicine and Western medicine) that regulate VCAM-1 for disease treatment, providing a theoretical basis for clinical research.
{"title":"Targeted regulatory strategies for VCAM-1 in multisystem diseases","authors":"Ruirong Peng , Yu Zhang , Zhenyu He , Yueling Pang , Huanhuan Ma , Ming Fang , Xiaoshan Ding , Yanan Wang , Zhihong Du , Fanming Kong , Liping Chen , Yongqi Liu , Ling Li , Jiawei Li","doi":"10.1016/j.ejmcr.2025.100300","DOIUrl":"10.1016/j.ejmcr.2025.100300","url":null,"abstract":"<div><div>Systemic diseases are conditions caused by multiple factors (such as immune disorders, inflammation, tumors, etc.) that affect multiple organs, tissues, or systems throughout the body. These diseases are typically characterized by complex pathological states and diverse clinical symptoms. Vascular cell adhesion molecule-1 (VCAM-1) is a multifunctional transmembrane protein that plays a key role in various pathological processes, including inflammation, immune responses, and tumor progression, by mediating immune cell adhesion, regulating the tumor microenvironment, and facilitating signal transduction. This article aims to review the mechanistic roles of VCAM-1 in systemic diseases affecting the circulatory, respiratory, and digestive systems, as well as the association between VCAM-1 and tumor characteristics. Additionally, it discusses targeted therapeutic drugs (including traditional Chinese medicine and Western medicine) that regulate VCAM-1 for disease treatment, providing a theoretical basis for clinical research.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100300"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-08-07DOI: 10.1016/j.ejmcr.2025.100293
Valentina Arciuolo , Simona Marzano , Rossella Buono, Nicola Grasso, Anna Di Porzio, Antonio Randazzo, Bruno Pagano, Jussara Amato
G-quadruplexes (G4s) are noncanonical DNA/RNA structures involved in key cellular processes, and their interactions with proteins are emerging as therapeutic targets. However, strategies to identify ligands that bind G4s and potentially modulate these interactions remain limited. Here, we describe a fluorescence-based assay for rapid, quantitative evaluation of small molecules that bind G4s and potentially interfere with protein recognition. The method employs a fluorophore-labeled peptide derived from a conserved G4-binding protein motif, and a G4-forming sequence labeled with a fluorescence acceptor. Ligand-induced peptide displacement is detected via fluorescence increase. A panel of known G4 ligands was tested, and results correlated with binding affinities. A duplex DNA competition assay further assessed ligand selectivity. This method provides a scalable tool for screening G4 ligands with ability to compete with G4-recognition motifs, supporting drug discovery efforts.
g -四plex （G4s）是参与关键细胞过程的非规范DNA/RNA结构，它们与蛋白质的相互作用正成为治疗靶点。然而，鉴定结合G4s并可能调节这些相互作用的配体的策略仍然有限。在这里，我们描述了一种基于荧光的检测方法，用于快速定量评估结合G4s并可能干扰蛋白质识别的小分子。该方法采用从保守的g4结合蛋白基序衍生的荧光团标记肽，以及用荧光受体标记的g4形成序列。通过荧光增加检测配体诱导的肽位移。对一组已知的G4配体进行了测试，结果与结合亲和力相关。双链DNA竞争分析进一步评估了配体的选择性。该方法提供了一种可扩展的工具，用于筛选具有与G4识别基序竞争能力的G4配体，支持药物发现工作。
{"title":"Screening of G-quadruplex DNA ligands by fluorescence detection of peptide displacement","authors":"Valentina Arciuolo , Simona Marzano , Rossella Buono, Nicola Grasso, Anna Di Porzio, Antonio Randazzo, Bruno Pagano, Jussara Amato","doi":"10.1016/j.ejmcr.2025.100293","DOIUrl":"10.1016/j.ejmcr.2025.100293","url":null,"abstract":"<div><div>G-quadruplexes (G4s) are noncanonical DNA/RNA structures involved in key cellular processes, and their interactions with proteins are emerging as therapeutic targets. However, strategies to identify ligands that bind G4s and potentially modulate these interactions remain limited. Here, we describe a fluorescence-based assay for rapid, quantitative evaluation of small molecules that bind G4s and potentially interfere with protein recognition. The method employs a fluorophore-labeled peptide derived from a conserved G4-binding protein motif, and a G4-forming sequence labeled with a fluorescence acceptor. Ligand-induced peptide displacement is detected via fluorescence increase. A panel of known G4 ligands was tested, and results correlated with binding affinities. A duplex DNA competition assay further assessed ligand selectivity. This method provides a scalable tool for screening G4 ligands with ability to compete with G4-recognition motifs, supporting drug discovery efforts.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100293"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-07-10DOI: 10.1016/j.ejmcr.2025.100285
Zhiyong Tian , Luyao Tian , Chaojie Wang
Although chemotherapy is fundamental in cancer therapy, its effectiveness is restricted by systemic toxicity and drug resistance. By combining DNA intercalation, topoisomerase inhibition, and tumor microenvironment modulation, naphthalimide-polyamine conjugates have emerged as promising agents targeting multiple pathways. This review explores how structural innovations in conjugates can overcome therapeutic resistance and minimize off-target effects. In the past, early derivatives such as amonafide encountered clinical challenges because of dose-limiting myelosuppression (e.g., >400 mg/m2). Nonetheless, recent progress in polyamine-mediated targeting and nanocarrier delivery has rejuvenated this class. We present a new Type I-VII classification approach that relates structural modifications—like heterocyclic fusion, polyamine chain adjustments, and substituent effects—to mechanistic outcomes. For example, compounds such as BND-12 inhibit metastasis in hepatocellular carcinoma by 61.8 % through ROS-induced mitochondrial dysfunction, whereas LU-79553 shows sub-micromolar effectiveness (IC50 ≤ 0.32 μM) in colorectal cancer with minimal hematotoxicity. Key advancements include: (1) Triple-action synergy, which simultaneously induces DNA damage through p53/PARP-1, disrupts autophagy regulation, and inhibits VEGF/MMP, thereby interfering with adaptive resistance mechanisms. (2) Targeted delivery: The use of polyamine transporters (PAT) and nanocarriers boosts tumor selectivity, as shown by compound 17, which reduces cisplatin resistance by 2–9 times by depleting lysosomal polyamines. (3) Structure-activity relationship (SAR) design: Adding a chlorine atom at the C4 position, such as in 4-ClNAHSPD, enhances DNA binding affinity (Kb = 1.7 × 104 M−1) and increases γ-H2AX foci formation by 1.8 times, while rigid cycloalkanediamine linkers improve cell cycle arrest. Preclinical success has been achieved, yet problems with metabolic stability and neurotoxicity persist. Future research focuses on AI-driven polyamine enhancement, nanoplatforms that can cross the blood-brain barrier (such as Angiopep-2-functionalized Ti@FeAu), and non-apoptotic cell death mechanisms like pyroptosis. Through the integration of structural innovation and multi-mechanistic synergy, this research sets up a design framework for precision oncology, illustrated by AI-optimized polyamine chains and nanoplatforms capable of crossing the blood-brain barrier. These methods provide a practical strategy for future cancer therapies aimed at overcoming adaptive resistance.
{"title":"Naphthalimide-polyamine conjugates: a promising avenue for targeted anticancer therapy","authors":"Zhiyong Tian , Luyao Tian , Chaojie Wang","doi":"10.1016/j.ejmcr.2025.100285","DOIUrl":"10.1016/j.ejmcr.2025.100285","url":null,"abstract":"<div><div>Although chemotherapy is fundamental in cancer therapy, its effectiveness is restricted by systemic toxicity and drug resistance. By combining DNA intercalation, topoisomerase inhibition, and tumor microenvironment modulation, naphthalimide-polyamine conjugates have emerged as promising agents targeting multiple pathways. This review explores how structural innovations in conjugates can overcome therapeutic resistance and minimize off-target effects. In the past, early derivatives such as amonafide encountered clinical challenges because of dose-limiting myelosuppression (e.g., >400 mg/m<sup>2</sup>). Nonetheless, recent progress in polyamine-mediated targeting and nanocarrier delivery has rejuvenated this class. We present a new Type I-VII classification approach that relates structural modifications—like heterocyclic fusion, polyamine chain adjustments, and substituent effects—to mechanistic outcomes. For example, compounds such as BND-12 inhibit metastasis in hepatocellular carcinoma by 61.8 % through ROS-induced mitochondrial dysfunction, whereas LU-79553 shows sub-micromolar effectiveness (IC<sub>50</sub> ≤ 0.32 μM) in colorectal cancer with minimal hematotoxicity. <strong>Key advancements include</strong>: (1) <strong>Triple-action synergy,</strong> which simultaneously induces DNA damage through p53/PARP-1, disrupts autophagy regulation, and inhibits VEGF/MMP, thereby interfering with adaptive resistance mechanisms. (2) <strong>Targeted delivery</strong>: The use of polyamine transporters (PAT) and nanocarriers boosts tumor selectivity, as shown by compound <strong>17</strong>, which reduces cisplatin resistance by 2–9 times by depleting lysosomal polyamines. (3) <strong>Structure-activity relationship (SAR) design:</strong> Adding a chlorine atom at the C<sub>4</sub> position, such as in 4-ClNAHSPD, enhances DNA binding affinity (Kb = 1.7 × 10<sup>4</sup> M<sup>−1</sup>) and increases γ-H<sub>2</sub>AX foci formation by 1.8 times, while rigid cycloalkanediamine linkers improve cell cycle arrest. Preclinical success has been achieved, yet problems with metabolic stability and neurotoxicity persist. Future research focuses on AI-driven polyamine enhancement, nanoplatforms that can cross the blood-brain barrier (such as Angiopep-2-functionalized Ti@FeAu), and non-apoptotic cell death mechanisms like pyroptosis. Through the integration of structural innovation and multi-mechanistic synergy, this research sets up a design framework for precision oncology, illustrated by AI-optimized polyamine chains and nanoplatforms capable of crossing the blood-brain barrier. These methods provide a practical strategy for future cancer therapies aimed at overcoming adaptive resistance.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100285"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-11DOI: 10.1016/j.ejmcr.2025.100311
Nicholas Schumann , Farah Shamma , Cory L. Brooks , Sean J. Johnson , Matthew K. Yim , Keith J. Olsen , Karla Peña , Petros C. Karakousis , Andrew Abell , Nathan E. Goldfarb
Mycobacterium tuberculosis (Mtb), the bacterium responsible for tuberculosis, is the leading cause of death due to a single infectious agent. Given the alarming increase in drug-resistant cases, therapeutic agents targeting novel Mtb drug targets are urgently needed. Hip1, a serine protease required for Mtb survival in macrophages and tolerance to various antibiotics, has been identified as an attractive therapeutic target. In the current study, we describe the design and synthesis of highly potent (pM range Ki) peptidomimetic α-keto ester inhibitors of Hip1. We also report the first two X-ray cocrystal structures of Hip1 bound to these compounds and describe the binding interactions in the active site of recombinant Hip1. Finally, we show that these compounds effectively reduce the intracellular bacillary burden in a macrophage model of Mtb infection.
{"title":"Discovery of highly potent α-keto ester-based peptidomimetic inhibitors of the Hip1 protease for the treatment of Mycobacterium tuberculosis","authors":"Nicholas Schumann , Farah Shamma , Cory L. Brooks , Sean J. Johnson , Matthew K. Yim , Keith J. Olsen , Karla Peña , Petros C. Karakousis , Andrew Abell , Nathan E. Goldfarb","doi":"10.1016/j.ejmcr.2025.100311","DOIUrl":"10.1016/j.ejmcr.2025.100311","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb), the bacterium responsible for tuberculosis, is the leading cause of death due to a single infectious agent. Given the alarming increase in drug-resistant cases, therapeutic agents targeting novel Mtb drug targets are urgently needed. Hip1, a serine protease required for Mtb survival in macrophages and tolerance to various antibiotics, has been identified as an attractive therapeutic target. In the current study, we describe the design and synthesis of highly potent (pM range <em>K</em><sub>i</sub><em>)</em> peptidomimetic α-keto ester inhibitors of Hip1. We also report the first two X-ray cocrystal structures of Hip1 bound to these compounds and describe the binding interactions in the active site of recombinant Hip1. Finally, we show that these compounds effectively reduce the intracellular bacillary burden in a macrophage model of Mtb infection.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100311"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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