European Journal of Medicinal Chemistry最新文献

{"title":"Discovery of a novel and potent antiplatelet thiol prodrug CG-0255","authors":"Hao Wu,&nbsp;Kai Hou,&nbsp;Xiaowu Chen,&nbsp;Xiubo Tang,&nbsp;Wenyuan Fan,&nbsp;Changliang Lu,&nbsp;Yuanchao Zhang,&nbsp;Ziqiang Gu,&nbsp;Gongxin He","doi":"10.1016/j.ejmech.2025.117973","DOIUrl":"10.1016/j.ejmech.2025.117973","url":null,"abstract":"<div><div>A series of novel thiol prodrugs based on clopidogrel active metabolite <strong>H4</strong> were conceived and synthesized as a new generation of antiplatelet agents. The prodrugs are capable of being rapidly converted to <strong>H4</strong> through fast one-step hydrolysis catalyzed by carboxylesterases, thus potentially overcoming clopidogrel resistance and many other issues caused by the reliance of clopidogrel on cytochrome P-450 (CYP)-mediated oxidative bioactivation. One of the thiol prodrugs, <strong>CG-0255</strong>, was selected for further development. <strong>CG-0255</strong> exhibited excellent pharmacokinetic and pharmacodynamic properties suitable for being developed as a once daily oral antiplatelet drug. In addition, <strong>CG-0255</strong> possessed adequate solubility and chemical stability capable of being formulated as an intravenous formulation, expanding its uses into surgical or emergency settings where intravenous administration is more desired. <strong>CG-0255</strong> is the first P2Y₁₂ inhibitor available in both intravenous and oral formulation, showing several advantages, such as rapid onset of action, low risk of drug-drug interaction, and an expected reduction in individual variation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117973"},"PeriodicalIF":6.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the multifaceted phytochemical: an updated review on therapeutic potential, pharmaceutical formulations, pre-clinical studies, and clinical trials of Zingerone","authors":"Simran Rashpa,&nbsp;Jatin Chadha ,&nbsp;Lavanya Khullar ,&nbsp;Bharti Sharma,&nbsp;Kusum Harjai","doi":"10.1016/j.ejmech.2025.117971","DOIUrl":"10.1016/j.ejmech.2025.117971","url":null,"abstract":"<div><div>Zingerone (ZiN), a polyphenolic alkanone derived from ginger (<em>Zingiber officinale</em>), is a natural bioactive compound with a broad spectrum of pharmacological properties. This review explores its multifaceted therapeutic applications, including antivirulence, antioxidative, anti-inflammatory, anticancer, and various other biological properties, as well as its potential application in diverse avenues. We provide an extensive overview of ZiN's phytochemistry, safety, metabolism, toxicity, bioavailability, and its potential as a promising candidate for drug development. Further, we shed light on the recent advancements made towards formulating different drug delivery systems, including nanoparticles and liposomal formulations, that have significantly improved the therapeutic efficacy and pharmacokinetics of ZiN. Moreover, we present findings from preclinical studies (<em>in vitro</em> and <em>in vivo</em>), that establish and validate its protective efficacy against human disorders/diseases like diabetes, chronic inflammation, acute diarrhoea, malignant cancers, radiation- and chemical-induced oxidative stress, and bacterial infections by enlisting the currently-known biomolecular targets of ZiN. Besides, this review outlines clinical trials conducted with ZiN and its derivatives, discussing the primary obstacles that have limited its application in mainstream medicine and providing future perspectives. Overall, this review presents an updated insight into the biological attributes and pharmacological prospects of ZiN, comprehensively establishing its multifarious nature as a potent drug.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117971"},"PeriodicalIF":6.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4′,3′:4,5] thieno[2,3-d] pyrimidine derivatives as Arf1-GEFs inhibitors for the treatment of colon cancer","authors":"Ning Li ,&nbsp;Chenfei Luo ,&nbsp;Yufan Liu ,&nbsp;Shaoliang Duan ,&nbsp;Xuan Wang ,&nbsp;Hua Cheng ,&nbsp;Dengqi Xue ,&nbsp;Yuetong Wang ,&nbsp;Wei Li ,&nbsp;Steven X. Hou ,&nbsp;Liming Shao","doi":"10.1016/j.ejmech.2025.117962","DOIUrl":"10.1016/j.ejmech.2025.117962","url":null,"abstract":"<div><div>Arf1, a member of the Ras superfamily of small GTPases, plays a crucial role in lipid metabolism, tumor progression, and immune suppression, making Arf1-GEFs inhibitors attractive targets for cancer immunotherapy. However, current Arf1 inhibitors face challenges such as high toxicity and poor solubility. In this study, we report the design, synthesis, and biological evaluation of a series of (<em>E)</em>-4-(2-((1<em>H</em>-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4′,3':4,5] thieno[2,3-<em>d</em>] pyrimidine derivatives, derived from the lead compound <strong>Du102</strong>. Rational structural modifications significantly enhanced aqueous solubility while retaining strong Arf1 inhibitory activity. Among these, <strong>18a</strong> emerged as a potent Arf1-GEFs inhibitor, effectively promoting CCL5 expression, exhibiting improved <em>in vitro</em> pharmacokinetic properties and demonstrating robust antitumor efficacy in CT26 colon cancer xenograft models. This study identifies <strong>18a</strong> as a promising candidate for colon cancer immunotherapy and provides a solid foundation for the development of novel Arf1-GEFs inhibitors with superior pharmacological properties.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117962"},"PeriodicalIF":6.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly effective Ru(II) and Os(II) half-sandwich complexes induce cytotoxicity in cancer cells through combined mitochondrial and endoplasmic reticulum stress","authors":"Jan Hošek ,&nbsp;Kamila Petrželová ,&nbsp;Renata Héžová ,&nbsp;Nicol Straková ,&nbsp;Simona Kajabová ,&nbsp;Ivan Nemec ,&nbsp;Pavlína Šimečková ,&nbsp;Kateřina Pěnčíková ,&nbsp;Josef Mašek ,&nbsp;Ján Moncoľ ,&nbsp;Pavel Štarha","doi":"10.1016/j.ejmech.2025.117970","DOIUrl":"10.1016/j.ejmech.2025.117970","url":null,"abstract":"<div><div>A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)-substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η⁶-pcym)Cl(L)]PF₆ (<strong>1</strong>–<strong>4</strong>) and [Os(η⁶-pcym)Cl(L)]PF₆ (<strong>5</strong>–<strong>8</strong>) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (<strong>9</strong>–<strong>12</strong>) and iridium(III) (<strong>13</strong>–<strong>16</strong>) [M(η⁵-Cp∗)Cl(L)]PF₆ complexes; L = ethane-1,2-diamine-based Schiff bases (L1–L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (<em>p</em>-cymene), Cp∗ = pentamethylcyclopentadienyl. Biological testing demonstrated that <strong>1</strong>–<strong>8</strong> possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex <strong>5</strong> showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117970"},"PeriodicalIF":6.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide inhibitors: Breaking cancer code","authors":"Fleur Coburn ,&nbsp;Yanyamba Nsereko ,&nbsp;Amy Armstrong ,&nbsp;Othman Al Musaimi","doi":"10.1016/j.ejmech.2025.117961","DOIUrl":"10.1016/j.ejmech.2025.117961","url":null,"abstract":"<div><div>Tumour signalling pathways play a pivotal role in tumorigenesis by controlling key cellular processes, including growth, proliferation, metastasis, and survival. Conventional treatments like chemotherapy often face limitations such as non-specific toxicity and drug resistance. Peptide inhibitors have gained attention as a promising therapeutic alternative due to their high selectivity in disrupting oncogenic pathways via protein-protein interactions (PPIs) and ligand binding. Currently, two out of 31 peptide-based cancer drugs have demonstrated signalling inhibition, with several others under investigation. However, challenges related to stability, delivery, and resistance persist, prompting innovations in peptide design, such as cyclisation and nanoparticle-based delivery systems. This review examines strategies to enhance peptide drug efficacy, explores the mechanisms by which peptide inhibitors target key pathways like the rat sarcoma protein (RAS) and mammalian target of rapamycin (mTOR) pathways, and highlights ongoing research on peptide-based interventions. Key examples include RAS-targeting peptides such as KRpep-2D, cyclo-CRVLIR, L5UR, RAS-binding peptide (RBP), the mutant <em>KRAS</em> peptide vaccine combined with Nivolumab and Ipilimumab, cyclorasin B4-27, and LUNA18, as well as mTOR-targeting peptides like P1_WT, PDHK1-241aa, TRIM1-269aa, and the micropeptide human small regulatory polypeptide of amino acid response (hSPAR). Among these, the mutant <em>KRAS</em> peptide vaccine (with Nivolumab and Ipilimumab) and LUNA18 demonstrate promising clinical potential and are currently undergoing trials.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117961"},"PeriodicalIF":6.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive sesquiterpene lactones from Elephantopus scaber: semi-synthesis, target fishing, anti-malignant glioma efficacy in vitro and in vivo","authors":"Hui Ren ,&nbsp;Kun Tao ,&nbsp;Jun Liu ,&nbsp;Lin Zu ,&nbsp;Yuyang Liu ,&nbsp;Yaodong Hu ,&nbsp;Bensong Xin ,&nbsp;Li Ye ,&nbsp;Ming Bai ,&nbsp;Guo-Dong Yao ,&nbsp;Qingbo Liu ,&nbsp;Wei Cui ,&nbsp;Shao-Jiang Song","doi":"10.1016/j.ejmech.2025.117954","DOIUrl":"10.1016/j.ejmech.2025.117954","url":null,"abstract":"<div><div>Traditional Chinese Medicine (TCM) offers distinct advantages in the treatment of tumors, since it serves dually as both a medicinal treatment and a dietary therapy. <em>Elephantopus scaber</em> (<em>E. scaber</em>), with a plethora of folk medicinal usage for treating pneumonia and hepatitis, contains sesquiterpene lactone (SL) as the primary component for therapeutic efficacy. The orphan drug ACT001, as the SL derivative, has been used in the treatment of glioma, which demonstrated significant potential for the development of such compounds. In this work, two series of plant-derived SL derivatives were synthesized and their efficacy against malignant glioma (MG) was evaluated. Among them, compound <strong>1e</strong> exhibited the most potent inhibitory effects with IC₅₀ values of 3.95 and 3.43 μM against U87 and T98G cells, respectively. Preliminary mechanism investigations suggested that <strong>1e</strong> induced the cell-cycle arrest at S phase and inhibited the tube formation to the anti-angiogenesis. Meanwhile, <strong>1e</strong> enhanced E-cadherin protein level while decreased the levels of Vimentin, MMP-2 and MMP9, thereby suppressing MG cells migration and invasion. Furthermore, the orthotopic glioma model using live animal fluorescence imaging demonstrated the therapeutic effect of <strong>1e</strong> on MG <em>in vivo</em> and pharmacokinetic studies indicated <strong>1e</strong> with a favorable pharmacokinetic profile. Moreover, we performed competitive activity-based protein profiling (ABPP) to explore the potential targets of SL derivatives in U87 cells, providing a basis for the follow-up studies of MG.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117954"},"PeriodicalIF":6.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylenedioxy open-loop and closed-loop aporphines designed for the evaluation of potential antidepressants","authors":"Yili Wan ,&nbsp;Chunyu Wu ,&nbsp;Benqin Tang ,&nbsp;Li Chen ,&nbsp;Jianbo Sun","doi":"10.1016/j.ejmech.2025.117969","DOIUrl":"10.1016/j.ejmech.2025.117969","url":null,"abstract":"<div><div>A series of methylenedioxy open-loop and closed-loop aporphine derivatives were designed and synthesized to systematically compare their antidepressant effects and addiction potential. The methylenedioxy open-loop derivatives showed slightly superior antidepressant activity compared with their closed-loop counterparts. Notably, the open-loop derivative <strong>Ie</strong> demonstrated significantly lower addictive potential than the closed-loop derivative <strong>IIe</strong>, suggesting that the open-loop methylenedioxy moiety may attenuate the addiction liability of related synthetic antidepressants. Further investigations revealed a significant increase in brain 5-hydroxytryptamine (5-HT) levels following treatment with <strong>Ie</strong>, which may be attributed to its synergistic effect on downregulating the expression of 5-HT_2A receptors (5-HT_2AR) and serotonin transporters (SERT). Collectively, the results indicate that <strong>Ie</strong> possesses the most potent and rapid antidepressant activity among the synthesized compounds, outperforming fluoxetine (Flu) in both efficacy and onset of action. These findings suggest that methylenedioxy open-loop aporphines—particularly <strong>Ie</strong>—hold strong promise as drug candidates for central nervous system modulation.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117969"},"PeriodicalIF":6.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hunting for lubeluzole analogues as antimyotonic agents with reduced cardiac liability","authors":"Maria Maddalena Cavalluzzi ,&nbsp;Roberta Gualdani ,&nbsp;Alessandro Farinato ,&nbsp;Concetta Altamura ,&nbsp;Sabata Pierno ,&nbsp;Natalie Paola Rotondo ,&nbsp;Francesco Terlizzi ,&nbsp;Laura Beatrice Mattioli ,&nbsp;Maria Grazia Perrone ,&nbsp;Maria Cristina Lomuscio ,&nbsp;Giuseppe Felice Mangiatordi ,&nbsp;Nicola Antonio Colabufo ,&nbsp;Antonio Carrieri ,&nbsp;Roberta Budriesi ,&nbsp;Peter Gmeiner ,&nbsp;Harald Huebner ,&nbsp;Jean-François Desaphy ,&nbsp;Giovanni Lentini","doi":"10.1016/j.ejmech.2025.117964","DOIUrl":"10.1016/j.ejmech.2025.117964","url":null,"abstract":"<div><div>Lubeluzole is a neuroprotective agent displaying antimyotonic activity. Lubeluzole clinical development as an antiischemic drug was discontinued due to a lack of efficacy in human trials and possible cardiac toxicity. Since lubeluzole is a potent inhibitor of the hERG channel, involved in long QT syndromes and the potentially fatal cardiac arrhythmia Torsade de Pointes, a series of lubeluzole analogues were prepared to investigate the structural requirements to reduce the affinity for hERG channels to possibly obtain safe antimyotonic drugs. Compound <strong>16o</strong> was identified as the less potent hERG blocker possibly endowed with lower cardiac liability in comparison with the parent compound. Antimyotonic activity of <strong>16o</strong> was also investigated in vitro on hNav1.4 and higher use-dependence was observed in comparison to lubeluzole, thus suggesting greater selectivity toward highly excited tissues, such as the myotonic muscle. To further verify the cardiac safety of <strong>16o</strong>, patch-clamp experiments on hNav1.5 were also carried out and a 3-fold reduction of potency in comparison with hNav1.4 in phasic block was observed. In vivo evaluation of the antimyotonic activity showed unintended effects on rat motor performance. Ex vivo studies suggested calcium channel blocking activity as a possible off-target source of the <strong>16o</strong> unintended effects, also reinforced by possible interaction with β₂ receptors, as indicated by in vitro binding assays and in silico studies. In conclusion, we think our results may support the rational design of lubeluzole analogues endowed with both antimyotonic activity and lower hERG liability.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117964"},"PeriodicalIF":6.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analogues of gramicidin S: A promising direction for future antibacterial drug development?","authors":"Tatiana S. Shkuratova ,&nbsp;Daria V. Andreeva ,&nbsp;Alexander S. Tikhomirov ,&nbsp;Andrey E. Shchekotikhin","doi":"10.1016/j.ejmech.2025.117955","DOIUrl":"10.1016/j.ejmech.2025.117955","url":null,"abstract":"<div><div>Gramicidin S (GS) is a potent cyclic decapeptide antibiotic produced by <em>Bacillus brevis</em>, exhibiting strong activity against Gram-positive bacteria and remaining in clinical use for the topical treatment of skin and throat infections. Despite its efficacy, GS's clinical application is restricted due to significant hemolytic toxicity associated with its membranolytic mechanism of action. This review summarizes over 80 years of structure–activity relationship (SAR) studies on GS and its analogues, highlighting key strategies to enhance antibacterial activity while reducing cytotoxicity. Particular focus is given to the influence of amino acid substitutions, stereochemistry, sequence modifications, and the incorporation of peptidomimetic fragments. Additionally, we discuss GS-based oligo- and polymers, as well as analogues with expanded or contracted macrocycles, emphasizing their effects on biological activity and conformational stability. Collectively, these insights underscore the value of GS as a resilient scaffold for next-generation antimicrobial peptide design with improved therapeutic indices and potency towards resistant pathogens.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117955"},"PeriodicalIF":6.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting α4β1 integrin: from cyclic to linear ligands, effects of chemical modifications","authors":"Valentina Giraldi ,&nbsp;Andrea Maurizio ,&nbsp;Martina Cirillo ,&nbsp;Paolo Magnone ,&nbsp;Emanuela Fedele ,&nbsp;Andrea Bedini ,&nbsp;Monica Baiula ,&nbsp;Daria Giacomini","doi":"10.1016/j.ejmech.2025.117965","DOIUrl":"10.1016/j.ejmech.2025.117965","url":null,"abstract":"<div><div>The immune system depends on integrins for adhesion and migration during leukocyte trafficking and for intracellular signalling. There is a causal relationship between dysregulation of integrin expression and the onset of pathological conditions, such as autoimmune diseases, inflammation, cancer, and infections. Therefore, integrins, such as α₄β₁, are considered important therapeutic targets. In this study, a series of novel compounds were synthesized and evaluated for affinity and potency towards α₄β₁, and selectivity towards α₅β₁, and α_Mβ₂ integrins. Three compounds <strong>3</strong>, <strong>4</strong>, and <strong>8</strong> showed excellent binding affinities (K_i &lt; 10 nM) for α₄β₁. In cell adhesion assays these three ligands behaved as antagonists of α₄β₁, as confirmed by integrin-mediated intracellular signalling with a functional selectivity over ERK1/2 signalling pathway. Notably, compound <strong>4</strong>, a proline derivative, was an antagonist against α₄β₁ (IC₅₀ 15 ± 3 nM) and an agonist against α_Mβ₂ integrin (EC₅₀ 23 ± 5 nM). Compound <strong>2</strong>, a fluorinated β-lactam derivative, was a selective and potent agonist of α₅β₁ (EC₅₀ 45.98 ± 7.92 nM). Compound <strong>5</strong>, although it seems to bind to a different site compared to LDV in α₄β₁ integrin, showed an agonist behaviour in cell adhesion mediated by α₄β₁ and α₅β₁ integrin (EC₅₀ 25 ± 3 and 4.8 ± 3.4 nM, respectively) and in activating α₄β₁ integrin-mediated ERK1/2 and Akt phosphorylation. Compound <strong>8</strong> was the most potent agonist of the series against α_Mβ₂ (EC₅₀ 1.4 ± 0.2 nM). Overall, the present study provides new insights into the effects of new integrin ligands that could be considered as potential lead compounds for therapeutic applications in inflammatory diseases and cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117965"},"PeriodicalIF":6.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}