European Journal of Medicinal Chemistry Reports最新文献

{"title":"Dual-target candidate compounds from a transformer chemical language model contain characteristic structural features","authors":"Sanjana Srinivasan ,&nbsp;Alec Lamens ,&nbsp;Jürgen Bajorath","doi":"10.1016/j.ejmcr.2025.100291","DOIUrl":"10.1016/j.ejmcr.2025.100291","url":null,"abstract":"<div><div>Chemical language models (CLMs) are increasingly used for generative design of candidate compounds for medicinal chemistry. However, their predictions are difficult to rationalize. Currently, detailed computational explanations of CLM-based compound generation are unavailable. Therefore, we have attempted to better understand from a medicinal chemistry perspective how CLMs learn and arrive at compound predictions. Therefore, we have subjected dual-target candidate compounds for polypharmacology generated with transformer CLMs to a series of analysis steps exploring structural features that are learned and compared them to known compounds with dual-target activity. Using machine learning combined with distinct chemical structure-oriented approaches from explainable artificial intelligence, we show that CLMs learn substructures characteristic of known dual-target compounds as a basis for generating new candidates with various chemical modifications.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100291"},"PeriodicalIF":0.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750759","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":"Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor","authors":"Naseer Ahmad Dar ,&nbsp;Owais Hassan Wani ,&nbsp;Yuanyuan Wang ,&nbsp;Faez Iqbal Khan ,&nbsp;Bilal A. Ganie ,&nbsp;Syed Wajaht A. Shah ,&nbsp;Tanveer Ali Dar ,&nbsp;Tabasum Ismail","doi":"10.1016/j.ejmcr.2025.100289","DOIUrl":"10.1016/j.ejmcr.2025.100289","url":null,"abstract":"<div><div>Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer's diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-linked 3-acetyl triazole-substituted coumarin derivatives as potential AChE inhibitors. The synthetic route involved 3-acetyl-7-hydroxycoumarin preparation through the reaction of 2,4-dihydoxybenzaldehyde with ethyl acetoacetate. Following alkylation at hydroxyl group, the acetylated 7-hydroxycoumarin underwent 1,3-dipolar cycloaddition i.e., Huisgen cycloaddition with various aromatic azides under sharpless click chemistry conditions, leading to the formation of a library of 16 novel coumarin tethered 1,2,3-triazole derivatives. Following synthesis and characterization using ¹H NMR, ¹³C NMR and IR spectroscopy, the AChE inhibitory potential of the coumarin derivatives was assessed, yielding IC₅₀ value in the range of 2.18 μM–67.89 μM. Among them, compound <strong>9</strong> exhibited the most potent inhibition (IC₅₀ = 2.18 μM), although lower than that of the standard inhibitor, eserine. Kinetic analysis indicated that compound <strong>9</strong> acted as a mixed-type inhibitor, with a K_i of 8.13 ± 0.18 μM. <em>In silico</em> simulation analysis elucidated the critical interactions between compound <strong>9</strong> and key AChE residues, including hydrogen bonding with Tyr121 and His444 and π-π stacking with Tyr334 and Trp283, supporting its strong binding affinity for the enzyme. Furthermore, the binding free energy calculations also confirmed the favourable thermodynamic interactions between the compound <strong>9</strong> and AChE. Collectively, the present findings highlight the therapeutic potential of compound <strong>9</strong> and establish this novel coumarin-triazole scaffold as a promising lead candidate for further optimization in development of AChE-targeted Alzheimer's therapeutics.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100289"},"PeriodicalIF":0.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750758","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":"In silico and In vitro profiling of lariciresinol against PLA2: A molecular approach to regulate inflammation","authors":"Fathimath Henna ,&nbsp;G. Arun Kumar ,&nbsp;Amritha Thaikkad ,&nbsp;T.K. Varun ,&nbsp;E. Jayadevi Variyar ,&nbsp;Rajesh Raju ,&nbsp;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":"2025-07-26","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}

{"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":"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}