European Journal of Medicinal Chemistry Reports最新文献

{"title":"Glaucumolides C-P, cembrane-type diterpenoids from the marine soft coral Sarcophyton glaucum with potential attenuating activities against IgAN nephropathy","authors":"Kang Zhou ,&nbsp;Jian Huang ,&nbsp;Hongli Jia ,&nbsp;Pianpian Wang ,&nbsp;Bin Wang ,&nbsp;Wei Cheng ,&nbsp;Wenhan Lin","doi":"10.1016/j.ejmcr.2025.100287","DOIUrl":"10.1016/j.ejmcr.2025.100287","url":null,"abstract":"<div><div>Cembranoids represent a class of diterpenes, featuring a cyclotetradecadiene backbone substituted by an isopropyl residue and three methyl groups with diverse subtypes and a panel of bioactivities. In this study, molecular networking-based metabolomic analysis revealed the soft coral <em>Sarcophyton glaucum</em> containing a chemical profile of cembrane-type diterpenes. Targeted isolation of the diterpene-enriched fractions resulted in the isolation of 14 undescribed cembranoids, namely glaucumolides C-P (<strong>1</strong>–<strong>14</strong>). Their structures were determined by extensive spectroscopic data in association with the X-ray diffraction and electronic circular dichroism (ECD) data for configurational assignments. All analogs featured an unsaturated γ-lactone in the backbone. Glaucumolide M and metabolite-A exhibited significant inhibition against the proliferation of lipopolysaccharide (LPS)-induced DAKIKI cells, and upregulated the expression of mRNA of C1GalT1 and its chaperone Cosmc in DAKIKI cells dose-dependently. Those findings suggest glaucumolides to be potential to prevent imunoglobulin A (IgA) nephropathy.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100287"},"PeriodicalIF":0.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722338","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}

{"title":"Triazenes as inhibitors of HIV-1 and HCoV-OC43: A structure-activity relationship study","authors":"Natacha Mérindol ,&nbsp;Seyedeh Mahsa Hashemian ,&nbsp;Seynabou Sokhna ,&nbsp;Marie-Pierre Girard ,&nbsp;Marc Presset ,&nbsp;Insa Seck ,&nbsp;Lalla Aïcha Ba ,&nbsp;Seydou Ka ,&nbsp;Samba Fama Ndoye ,&nbsp;Issa Samb ,&nbsp;Erwan Le Gall ,&nbsp;Lionel Berthoux ,&nbsp;Matar Seck ,&nbsp;Isabel Desgagné-Penix","doi":"10.1016/j.ejmcr.2025.100288","DOIUrl":"10.1016/j.ejmcr.2025.100288","url":null,"abstract":"<div><div>Triazenes, or amino-substituted diazenes, are organic compounds containing three contiguous nitrogen atoms, that have potent biological activities. We previously demonstrated that triazenes, particularly those substituted with a phenyl or 3-pyridyl ring at the 1-position and a 2-pyridyl ring at the 3-position, exhibit anti-DENV properties. Here, we evaluated the antiviral activity against a betacoronavirus (HCoV-OC43) and a lentivirus (HIV-1). 1-(4-trifluoromethylphenyl)-2-imidazole-1-yldiazene (<strong>21</strong>) exhibited broad-spectrum activity (EC₅₀ = 6.6–6.8 μM) but was cytotoxic to THP-1 cells. Pyridyl triazenes (<strong>14, 15</strong>) were the most potent against HCoV-OC43, while 1-(4-methoxyphenyl)-2-morpholin-4-yldiazene (<strong>6</strong>) and 1-(4-methoxyphenyl)3-(-6-methylpyridin-2-yl)triazene (<strong>10</strong>) inhibited HIV-1 the most. Structure–activity relationship analysis, supported by molecular docking, indicated that <em>para</em>-methoxy groups favored interactions with viral enzyme binding pockets, enhancing antiviral potency, while <em>meta</em> and <em>para</em>-trifluoromethyl groups were associated with reduced activity and increased cytotoxicity. These findings support the further development of triazenes as antiviral scaffolds.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100288"},"PeriodicalIF":0.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686407","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}

{"title":"New cytotoxic dolabellane and dolastane diterpenes from Brown seaweed Dictyota dichotoma","authors":"Kolukula Ashwini ,&nbsp;Bandi Siva ,&nbsp;Penta Poornima ,&nbsp;Solipeta Divya Reddy ,&nbsp;Hashnu Dutta ,&nbsp;Vedula Girija Sastry ,&nbsp;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 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 <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":"2025-07-17","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}

{"title":"Naphthalimide-polyamine conjugates: a promising avenue for targeted anticancer therapy","authors":"Zhiyong Tian ,&nbsp;Luyao Tian ,&nbsp;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., &gt;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. <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 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.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100285"},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","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}

{"title":"Structure-activity study of oncocins modified with cationic polar moieties at the termini","authors":"Johan Storm Jørgensen ,&nbsp;Anita Wester ,&nbsp;Carina Sofia Silva Matias ,&nbsp;Lina Maria Cavaco ,&nbsp;Carina Vingsbo Lundberg ,&nbsp;Camilla Brolin ,&nbsp;Elnaz Harifi Mood ,&nbsp;Dorota Żabicka ,&nbsp;Magdalena Tomczak ,&nbsp;Malgorzata Urbas ,&nbsp;Fredrik Björkling ,&nbsp;Peter E. Nielsen ,&nbsp;Henrik Franzyk","doi":"10.1016/j.ejmcr.2025.100284","DOIUrl":"10.1016/j.ejmcr.2025.100284","url":null,"abstract":"<div><div>The critical emergence of antimicrobial resistance is aggravated by a pipeline deficient in novel antibiotic classes against Gram-negative pathogens. Proline-rich antimicrobial peptides (PrAMPs) are attractive starting points for novel antibiotics, capable of targeting Gram-negative pathogens. Here, we explored a series of oncocin analogs, which were modified with bacteria-penetrating moieties to promote transporter-independent antibacterial activity. Elongation with arginine-rich motifs conferred 2- to 8-fold improved potency against the Gram-negative <em>Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa</em> and <em>Acinetobacter baumannii</em>. The highest degree of enhancement was seen for <em>K. pneumoniae</em>, in which the most active analogs had minimal inhibitory concentrations of 0.25 μg/mL (∼0.05 μM).</div><div>Notably, antibacterial activity proved considerably less dependent on the inner-membrane peptide transporter SbmA, being the main transporter involved in internalization of PrAMPs. Permeabilization experiments showed that these cationic modifications did not alter the original intracellular mode of action of oncocin itself towards a membrane-disruptive mechanism for these analogs. Importantly, their effect on human cell viability remained low for the best analogs (i.e., below 5 % hemolysis at 400 μg/mL and IC₅₀ values ≥ 1280 μg/mL in HepG2 cells). Moreover, the frequencies of existing resistance of best analogs in <em>E. coli</em> and <em>K. pneumoniae</em> were low (i.e., 1-5 × 10⁻¹⁰). Finally, two analogs were tested in a mouse peritonitis model with <em>E. coli</em>, while one analog was tested in a model with <em>K. pneumoniae</em>. This showed efficacy comparable to that of colistin in the <em>E. coli</em> model, while a lower efficacy than that of colistin was seen in the <em>K. pneumoniae</em> model.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100284"},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563102","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}

{"title":"Key determinants of the chemo-sensitizing activity of novel Telmisartan derivatives","authors":"Maximilian Gebhart ,&nbsp;Christian A. Elvert ,&nbsp;Anna M. Schoepf ,&nbsp;Alexandra Scheiber ,&nbsp;Stefan Schwaiger ,&nbsp;Cornelia A. Karg ,&nbsp;Ronald Gust ,&nbsp;Stefan Salcher","doi":"10.1016/j.ejmcr.2025.100281","DOIUrl":"10.1016/j.ejmcr.2025.100281","url":null,"abstract":"<div><div>Despite the success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), resistance remains a major challenge due to target mutations and drug efflux. To counter this, chemo-sensitizers - non-cytotoxic agents that restore drug sensitivity - are being explored. A promising approach involves Telmisartan (<strong>1</strong>)-based cell death modulators, which may help overcome TKI resistance. Modification of the 2-COOH group of Telmisartan to a carboxamide (2-CONH₂, Telmiamide (<strong>2</strong>)) or methyl ester (2-CO₂CH₃, Telmiester (<strong>3</strong>)) transformed these derivatives into potent inhibitors of the efflux transporter ABCB1 and the STAT5 protein - two critical mediators of CML persistence during TKI therapy. Both compounds successfully restored Imatinib (<strong>Im</strong>) sensitivity in TKI-resistant CML cells. The present structure-activity relationship (SAR) analysis demonstrated that substituent modifications at 2-CONH₂ and 2-CO₂CH₃ significantly influenced biological efficacy, stability in cell culture medium, cellular uptake in CML cells, and inhibition of ABCB1 and STAT5. Among the tested compounds, propyl-, butyl-, phenyl-, and 4-phenoxyphenyl-substituted Telmiamides (<strong>2a-d</strong>) and Telmiesters (<strong>3a-d</strong>) exhibited strong chemo-sensitizing potential <em>in vitro</em>, with a half-maximal sensitizing concentration (SC₅₀) &lt; 0.5 μM. Additionally, most derivatives showed improved stability in cell culture, enhancing their suitability for future <em>in vivo</em> studies. When considering cellular uptake in CML cells, these compounds displayed ABCB1 inhibition comparable to the efflux transporter inhibitor Elacridar (<strong>E</strong>). Notably, their dual mode of action, combining potent ABCB1 and STAT5 inhibition with low cytotoxicity, offers a distinct advantage over Elacridar (<strong>E</strong>). ADME (absorption, distribution, metabolism, and excretion) studies identified significant limitations in the phenyl carboxamide derivative (<strong>2c</strong>), revealing low permeability and high metabolism due to the bound phenyl ring. These findings indicate that aromatic residues at the 2-CONH-R group may compromise bioavailability, highlighting a key structural constraint to address in the future optimization of Telmisartan derivatives for therapeutic development. Overall, the study highlights Telmisartan-based derivatives as promising candidates for overcoming TKI resistance in CML and warrants further optimization for clinical translation.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100281"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563101","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}

{"title":"Anti-scarring drug discovery: potential targets and therapeutic opportunities","authors":"Meiling Feng ,&nbsp;Xiaotian Niu ,&nbsp;Shan Wang ,&nbsp;Liuxin Lu ,&nbsp;Xilong Feng ,&nbsp;Xiaoying Jiang ,&nbsp;Wenchao Chen ,&nbsp;Renren Bai","doi":"10.1016/j.ejmcr.2025.100283","DOIUrl":"10.1016/j.ejmcr.2025.100283","url":null,"abstract":"<div><div>Scar formation is a ubiquitous pathological response during the skin wound healing process. While physical therapy can effectively mitigate scar development, it is often accompanied by issues such as poor patient compliance and a range of side effects. Consequently, there is an urgent clinical need for the discovery of effective anti-scarring drugs. However, this need has not been fully addressed to date. This review delves systematically and comprehensively into the characteristics of scars, the underlying mechanisms of their formation, and potential therapeutic targets. Additionally, it reviews drug repurposing efforts, natural products and small molecule compounds in the drug discovery stage with anti-scarring effects. The information presented herein will offer valuable insights and enlightenment for exploring potential targets and pathways, as well as viable lead compounds for the discovery and development of novel anti-scarring drugs.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100283"},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490946","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}

{"title":"Repurposing of compound libraries yields new inhibitors of NDM-1 metallo-β-lactamase with diverse zinc-binding moieties","authors":"Vid Kavaš ,&nbsp;Philip Hinchliffe ,&nbsp;Maša Zorman ,&nbsp;Alen Krajnc ,&nbsp;Matic Proj ,&nbsp;Majda Golob ,&nbsp;Martina Hrast Rambaher ,&nbsp;James Spencer ,&nbsp;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 IC₅₀ 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 IC₅₀ 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":"2025-06-19","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}

{"title":"Aurones as versatile enzyme Inhibitors: Recent advancements, structural insights, mechanisms, and therapeutic potential","authors":"Bhavna Saroha ,&nbsp;Gourav Kumar ,&nbsp;Suresh Kumar","doi":"10.1016/j.ejmcr.2025.100280","DOIUrl":"10.1016/j.ejmcr.2025.100280","url":null,"abstract":"<div><div>Aurones belong to the flavonoid-based heterocyclic class of plant origin and are full of therapeutic potential. Characterized by their unique benzofuranone core structure and α,β unsaturated carbonyl group, aurones possess exceptional structural adaptability and electronic characteristics, making them excellent candidates for enzyme targeting and promising agents for drug development. Recent research has highlighted their ability to inhibit key enzymes, including cholinesterase, cathepsin B, monoamine oxidase, cyclooxygenase, and various digestive enzymes. This demonstrates their potential in treating cancer, neurodegenerative diseases, and metabolic disorders associated with the overexpression of these enzymes. The ability to functionalize the aurone scaffold further enhances its adaptability for selective and potent enzyme targeting. This review examines the structural features of aurones, their enzyme-inhibitory effects, an overview of their molecular mechanisms, and the structure-activity relationships (SAR) underlying their enzyme inhibition, supported by computational approaches. Although several review articles have addressed the synthetic and general biological profile of aurones, none have specifically focused on their enzyme inhibitory potential, which is the central theme of this review. This review offers a strong foundation and rationale for the design, synthesis, and optimization of novel aurone-based compounds aimed at achieving desirable therapeutic outcomes by targeting specific enzymes.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100280"},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330496","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}

{"title":"Structure optimization at position five of 4-thiazolidinone resulted in new potent PIM1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities for combating colorectal cancer","authors":"Ahmed K. Al-Kubeisi ,&nbsp;Saad R. El-Zemity ,&nbsp;Marwa M. Abu-Serie ,&nbsp;Aly A. Hazzaa ,&nbsp;Mostafa M.M. El-Miligy","doi":"10.1016/j.ejmcr.2025.100279","DOIUrl":"10.1016/j.ejmcr.2025.100279","url":null,"abstract":"<div><div>New thymol – 5-phenylthiazolidin-4-one hybrids were synthesized aiming to interact with the lipophilic flexible p-loop of PIM kinase active site via induced-fit binding mode to increase affinity hence anticancer activity against colorectal cancer (CRC). All target compounds were screened for their cytotoxicity against normal human lung fibroblasts and anticancer activity against CRC Caco-2 cell lines. <strong>6c</strong> and <strong>6e</strong> exhibited the highest anticancer activity at doses less than their EC₁₀₀ on normal human cells. In addition, <strong>6c</strong> and <strong>6e</strong> were further tested against liver cancer cell line (HepG-2) and breast cancer cell line (MCF-7) and proved their potent anticancer activities. Furthermore, both induced apoptosis in Caco-2 cell lines by 39 and 55 % and enhanced caspase 3/7 activation by 43 and 65 %, respectively. Besides, <strong>6c</strong> and <strong>6e</strong> revealed <em>in vitro</em> inhibitory activity against PIM1 kinase more than PIM2 kinase. Furthermore, induced fit docking and molecular dynamics simulation of <strong>6c</strong> and <strong>6e</strong> predicted enhanced PIM1 kinase activity via interaction to flexible p-loop. Moreover, both could act as PIM1 kinase competitive non-ATP mimetics as they interacted with Lys67.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100279"},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144231741","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}