European Journal of Medicinal Chemistry最新文献

{"title":"Harnessing the bishomolithocholic acid scaffold for selective sialyltransferase inhibition: A targeted approach to suppress breast cancer metastasis","authors":"Ser John Lynon P. Perez ,&nbsp;Zih-Fan Hsu ,&nbsp;Tzu-Ting Chang ,&nbsp;Chia-Ling Chen ,&nbsp;Wen-Shan Li","doi":"10.1016/j.ejmech.2025.117674","DOIUrl":"10.1016/j.ejmech.2025.117674","url":null,"abstract":"<div><div>ST6GAL1 plays a crucial role in the progression of triple-negative breast cancer (TNBC), highlighting its potential as a therapeutic target for this aggressive cancer subtype. Due to the high metastatic potential of TNBC and the limitations of current therapies, selective and potent ST6GAL1 inhibitors are urgently needed. In this study, a scaffold-hopping approach from lithocholic acid to bishomolithocholic acid successfully led to the discovery of novel ST6GAL1 inhibitors, <strong>SPP-037</strong> and <strong>HZF01</strong>, with enhanced biological activity and selectivity. Both compounds significantly inhibited MDA-MB-231 cell migration, HUVEC tube formation, tumor growth, and metastasis in vitro and in vivo. Molecular docking studies revealed key interactions between the ST inhibitors and ST6GAL1, supporting their enhanced selectivity and binding affinity. Additionally, <strong>SPP-037</strong> and <strong>HZF01</strong> were found to block integrin α2,6-sialylation, disrupting integrin activation and downstream signaling pathways involving the phosphorylation of focal adhesion kinase (FAK) and paxillin, which are critical for cell migration. These results underscore the potential of targeting ST6GAL1 to suppress tumor progression and metastasis, offering a promising avenue for treating aggressive breast cancer.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117674"},"PeriodicalIF":6.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872487","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":"Molecular and supramolecular routes to enhance Gadolinium-based contrast agents relaxivity: How far are we from the theoretical optimal value?","authors":"Lorenzo Palagi ,&nbsp;Dario Livio Longo ,&nbsp;Éva Tóth ,&nbsp;Carlo C. Quattrocchi ,&nbsp;Aart J. van der Molen ,&nbsp;Silvio Aime ,&nbsp;Eliana Gianolio","doi":"10.1016/j.ejmech.2025.117668","DOIUrl":"10.1016/j.ejmech.2025.117668","url":null,"abstract":"<div><div>Gadolinium Based Contrast Agents (GBCAs) are routinely used in the clinical practice to enhance the diagnostic potential of MRI. Their contrast enhancing capabilities rely on their ability to increase the relaxation rate of tissue water protons. This property is expressed by the relaxivity, whose value is determined by structural, electronic and dynamic characteristics of the GBCA. Based on extensive experimental work over the past four decades and the well-established theory of paramagnetic relaxation, it is usually possible to correlate observed relaxivity values to specific molecular properties. Key determinants include the number of water molecules and/or exchangeable protons in the first and second coordination spheres, their distance from the paramagnetic Gd³⁺ ion, the ion's electronic relaxation time, molecular reorientation time, and the exchange rate of the coordinated water molecules. Understanding the key factors that affect relaxivity has enabled the design of systems with optimized structural and dynamic properties. However, some examples demonstrate exceptional relaxivity which cannot be fully explained by the established theory. In particular, GBCAs within confined environments show significant promise for developing high-relaxivity agents. Overall, one may state that nowadays it is possible to attain highly efficient GBCAs thanks to the in-depth understanding of the structural and dynamic determinants of their relaxivity, together with the optimization of their <em>in vivo</em> stability and biodistribution/excretion properties. This knowledge is crucial for the rational design of the next generation of MRI CAs. The domain of Molecular Imaging will also largely benefit from these efforts.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117668"},"PeriodicalIF":6.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872210","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, biophysical and biological evaluation of original condensed pyrrolopyrimidine and pyrrolopyridine ligands as anti-SARS-CoV-2 agents targeting G4","authors":"Jean Guillon ,&nbsp;Solène Savrimoutou ,&nbsp;Nicolas Da Rocha ,&nbsp;Sandra Albenque-Rubio ,&nbsp;Olivier Helynck ,&nbsp;Cyrielle Durand ,&nbsp;Jeanne Chiaravalli ,&nbsp;Noël Pinaud ,&nbsp;Luisa Ronga ,&nbsp;Stéphane Moreau ,&nbsp;Simon Chirold ,&nbsp;Tshering Zangmo ,&nbsp;Melika Arab ,&nbsp;Lindita Lari ,&nbsp;Jean-Louis Mergny ,&nbsp;Hélène Munier-Lehmann ,&nbsp;Marc Lavigne","doi":"10.1016/j.ejmech.2025.117655","DOIUrl":"10.1016/j.ejmech.2025.117655","url":null,"abstract":"<div><div>The design and synthesis of novel bis[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines, pyrrolopyridines, pyrazolopyrimidines, imidazopyrimidines, and tris[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines are reported here. These original G-quadruplex (G4) ligands have been then subjected to a screening on SARS-CoV-2 using a competition HTRF assay by targeting the SUD-NM/TRF2 RNA G4 interaction. The more promising derivatives have been evaluated <em>in vitro</em> to determine their potential antiviral effect on two different cell lines infected by two SARS-CoV-2 strains. This study revealed a clear correlation between their antiviral property and their efficacy to prevent the SUD/G4 interaction. This correlation supports the choice of SUD/RNA G4 complexes formed during SARS-CoV-2 infection as new antiviral targets.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117655"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862741","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":"Aromatic group-induced self-assembly of short antimicrobial peptides: unveiling exceptionally potent antimicrobial efficacy","authors":"Yao Liu ,&nbsp;Tingting Yang ,&nbsp;Beibei Li ,&nbsp;Yu Wang ,&nbsp;Xu Ouyang ,&nbsp;Zufang Ba ,&nbsp;Yuhuan Zhao ,&nbsp;Zhongwei Yu ,&nbsp;Bingqian Ren ,&nbsp;Pengyi Yan ,&nbsp;Xueting Liu ,&nbsp;Liru Yuan ,&nbsp;Qingyang Xu ,&nbsp;Chao Zhong ,&nbsp;Hui Liu ,&nbsp;Yun Zhang ,&nbsp;Sanhu Gou ,&nbsp;Jingman Ni","doi":"10.1016/j.ejmech.2025.117659","DOIUrl":"10.1016/j.ejmech.2025.117659","url":null,"abstract":"<div><div>Self-assembled antimicrobial peptides (AMPs) have superior antimicrobial properties from their supramolecular nanostructures. A systematic study is needed to determine which AMPs can generate more significant self-assembled structures for antimicrobial activity. In this study, thirty-six self-assembled AMPs were systematically designed by combining six hexapeptide sequences with five aromatic groups, exploring the contributions of different sequences and groups to self-assembly and antimicrobial properties. Most peptides had broad-spectrum antimicrobial and self-assembly capabilities. Moderate self-assembly can endow these new AMPs with excellent antimicrobial properties. Candidate peptides Nap-f5f6 and Npx-f5f6 had outstanding antimicrobial activity, low toxicity, and high selectivity. This may be due to their self-assembly into nanofibers and nanospheres via <em>π-π</em> stacking provided by C- and N-terminal aromatic groups. Their membrane-disrupting bactericidal mechanism gives a rapid effect and prevents antibiotic resistance. Also, in infected mouse skin wounds, Nap-f5f6 and Npx-f5f6 had low toxicity, reduced bacterial load, and accelerated wound healing.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117659"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866588","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":"19F NMR in RNA structural biology: exploring structures, dynamics, and small molecule interactions","authors":"CongBao Kang","doi":"10.1016/j.ejmech.2025.117682","DOIUrl":"10.1016/j.ejmech.2025.117682","url":null,"abstract":"<div><div>RNA molecules play essential roles in numerous biological pathways, making them attractive targets for drug discovery. Despite the challenges in developing small molecules targeting RNA, the success in developing compounds that modulate RNA function underscores its therapeutic potential. ¹⁹F NMR spectroscopy has emerged as a powerful tool in structural biology and drug discovery, particularly for studying macromolecular structures and ligand interactions. As RNA continues to gain prominence as a drug target, ¹⁹F NMR is expected to play a pivotal role in advancing RNA-focused drug discovery. This review describes the diverse applications of ¹⁹F NMR in RNA biology, including its use in characterizing RNA structures, probing molecular dynamics, identifying small-molecule binders, and investigating interaction mechanisms of small-molecule ligands. By providing detailed structural and ligand binding insights, ¹⁹F NMR will facilitate the discovery of RNA-targeting therapeutics and deepen our understanding of RNA modulatory mechanisms.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117682"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866585","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":"4,5-Diazafluorene derivatives and their silver(I) complexes: Synthesis and biological evaluation as antiproliferative agents","authors":"Leonardo Sandin-Mazzondo ,&nbsp;Angela Trejo ,&nbsp;Mariachiara Mammone ,&nbsp;Maria Grazia Perrone ,&nbsp;Marialessandra Contino ,&nbsp;Sandra Rico-Martínez ,&nbsp;Concepción Alonso ,&nbsp;Camino Bartolomé","doi":"10.1016/j.ejmech.2025.117680","DOIUrl":"10.1016/j.ejmech.2025.117680","url":null,"abstract":"<div><div>This work is focused on the synthesis and biological evaluation of 4,5-diazafluorene bipyridines and their silver(I) complexes. These 4,5-diazafluorene derivatives have two aromatic R groups at the C9 position (R = 4-C₆H₄X, X = H, <strong>3</strong>; Me, <strong>4</strong>; NH₂, <strong>5</strong>; OH, <strong>6</strong>; OMe, <strong>7</strong>; Br, <strong>8</strong>; F, <strong>11</strong>; Cl, <strong>12</strong>; I, <strong>13</strong>; R = 3-Me-4-NH₂-C₆H₃, <strong>9</strong>; 3,5-Me₂-4-NH₂-C₆H₂, <strong>10</strong>). Their synthesis was carried out from a direct S_EAr from 4,5-diazafluoren-9-one and the corresponding aryl compound or <em>via</em> the diazonium salt strategy. These compounds were used as ligands to synthesize [Ag(N–N)₂]NO₃ complexes (<strong>3Ag</strong>–<strong>13Ag</strong>). The stability of these complexes in DMSO solution was studied showing that no dissociation was observed over 48 h. All compounds were characterized by NMR (¹H and ¹³C) and MS. The crystal structures of three complexes were determined by single-crystal X-ray diffraction revealing different coordination geometries in solid state. The cytotoxicity study of the compounds was analyzed in lung carcinoma (A-549), cervical carcinoma (HeLa), melanoma (HBT70) cancerous cell lines and in non-malignant lung fibroblasts (MRC-5) and normal human dermal fibroblasts (HDFn) cell lines. Only ligands <strong>3</strong>, <strong>7</strong>, <strong>11</strong>, and <strong>13</strong> exhibited antiproliferative activity. On the other hand, most of the complexes were active suggesting a positive impact when silver is incorporated into the molecule. The selectivity index towards cancerous cells was calculated. Values from 3 to more than 16 were obtained suggesting that these silver complexes are promising molecules for future anticancer treatments. Drug-likeness and ADME properties were <em>in silico</em> calculated for the ligands. The P-gp interaction and <em>P</em>_app were experimentally evaluated. Regarding their action, ROS production does not appear to be the main mechanism by which these complexes exert their cytotoxicity, nor do they appear to be DNA intercalators or DNA covalent binders.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117680"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866789","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":"Restyling an old scaffold: Ebsulfur analogs with improved activity and selectivity against the infective stage of trypanosomes","authors":"Cristina Quiroga ,&nbsp;Marcelo Incerti ,&nbsp;Diego Benítez ,&nbsp;Martin Luzardo ,&nbsp;Eduardo Manta ,&nbsp;Alejandro Leyva ,&nbsp;Margot Paulino ,&nbsp;Marcelo A. Comini ,&nbsp;Andrea Medeiros","doi":"10.1016/j.ejmech.2025.117675","DOIUrl":"10.1016/j.ejmech.2025.117675","url":null,"abstract":"<div><div>Several species of trypanosomatids cause fatal and disabling diseases in humans and livestock animals. The current chemotherapy is limited and new drug candidates with improved efficacy and safety are needed. The benziso-thiazolone (e.g. Ebsulfur, EbS) and -selenazolone (e.g. Ebselen, EbSe) have been extensively investigated for their promising action towards transmissible and non-transmissible diseases.</div><div>Here, we synthetized 23 benzisothiazolones and tested their anti-trypanosomatid activity against the clinically relevant stages of three major trypanosomatid species (<em>Trypanosoma brucei brucei</em>, <em>Trypanosoma cruzi</em> and <em>Leishmania infantum</em>). Several compounds presented nM or low μM activity and, at least a two-digit selectivity against <em>Trypanosoma</em> sp. but most proved inactive towards <em>L. infantum</em>. Structure-activity relationship analysis reveals that the chemotype of the top hits consisted of phenyl and benzyl rings occupying the <em>N</em>² position of the benzisothiazolone scaffold and harboring polar substituents in the <em>para</em> position. Most compounds from these two clusters induced a rapid redox unbalance in the intracellular pool of low molecular weight thiols. None of the hits, but EbSe and EbS, affected Trypanothione synthetase activity (the enzyme producing the major low molecular weight thiol of trypanosomatids). However, at large enzyme:compound ratios, some inhibited irreversibly (and covalently) Trypanothione reductase (the enzyme maintaining trypanothione in a reduced state). Some hits exerted a minor effect on the rate of glucose consumption. Preliminary assessment of therapeutic efficacy in a murine infection model of acute African trypanosomiasis, the top candidate could not reduce parasite burden (monitored by <em>in vivo</em> imaging) but extended animal survival.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117675"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862702","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 novel 4-(thieno[3,2-d]pyrimidin-4-yl)morpholine derivatives as potent antitumor agents","authors":"Ju Liu ,&nbsp;Junfeng Gao ,&nbsp;Rui Jing ,&nbsp;Siyu Lin ,&nbsp;Yunpeng Zhou ,&nbsp;Zhicheng Zhang ,&nbsp;Enhui Han ,&nbsp;Fanqi Jin ,&nbsp;Yunlei Hou ,&nbsp;Chunyan Li ,&nbsp;Ye Chen ,&nbsp;Jiwei Shen ,&nbsp;Shi Ding","doi":"10.1016/j.ejmech.2025.117671","DOIUrl":"10.1016/j.ejmech.2025.117671","url":null,"abstract":"<div><div>A series of 4-(thieno[3,2-<em>d</em>]pyrimidin-4-yl)morpholine derivatives were designed, synthesized and evaluated for their <em>in vitro</em> inhibitory activities against PI3Kα and antiproliferative activities against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cancer cell lines. Inhibitory activities against PI3Kα evaluation indicated that some compounds showed excellent PI3Kα activity <em>in vitro</em>, and IC₅₀ values of eight compounds (<strong>17c</strong>, <strong>17e</strong>, <strong>17f</strong>, <strong>17h</strong>, <strong>17l</strong>, <strong>17m</strong>, <strong>17o</strong>, <strong>17p</strong>) were less than 100 nM. The most promising compound <strong>17f</strong> (PI3Kα: IC₅₀ = 0.039 μM) showed remarkable antiproliferative against PC-3, 22RV1, MDA-MB-231 and MDA-MB-453 cell lines with IC₅₀ values of 3.48 μM, 1.06 μM, 2.21 μM and 0.93 μM, respectively. Furthermore, <strong>17f</strong> effectively reduced p-PI3K protein expression and inhibited the activation of downstream signaling AKT and mTOR proteins in MDA-MB-453 cells. In addition, <strong>17f</strong> induced cell apoptosis by down-regulating the expression levels of anti-apoptotic proteins Bcl-XL and Bcl-2 and up-regulating the expression of anti-apoptotic protein BAX, and in MDA-MB-453 cells. All these results indicated the potential of compound <strong>17f</strong> to develop as potent anticancer agent.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117671"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858199","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":"Exploring indole-dihydropyrimidinone derivatives: Design, synthesis, biological assessment, SAR analysis, and evaluation of mode of action in experimental visceral leishmaniasis","authors":"Garvita Mishra ,&nbsp;Arvind Kumar Jaiswal ,&nbsp;Ajay Kishor Kushawaha ,&nbsp;Abhishek Kumar ,&nbsp;Hemlata Bhatt ,&nbsp;Alisha Ansari ,&nbsp;Amol Chhatrapati Bisen ,&nbsp;Rupa Hansda ,&nbsp;Sristi Agrawal ,&nbsp;Payel Acharjee ,&nbsp;Rajdeep Guha ,&nbsp;Rabi Sankar Bhatta ,&nbsp;Bidyut Purkait ,&nbsp;Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117667","DOIUrl":"10.1016/j.ejmech.2025.117667","url":null,"abstract":"<div><div>The emergence of drug resistance and the non-availability of vaccines encouraged us to identify novel chemical scaffolds as new anti-leishmanial agents. In doing so, a series of thirty-four indole-dihydropyrimidinone hybrid compounds were synthesized using the Biginelli multicomponent reaction. These synthesized compounds were tested against <em>L. donovani in vitro</em> and <em>in vivo</em> in experimental golden hamster model of visceral leishmaniasis. Compounds <strong>4f</strong> and <strong>4m</strong> were found to have promising anti-leishmanial properties against intracellular amastigotes (IC₅₀ <strong>4.54</strong> &amp; <strong>5.05</strong> μM, respectively) with minimal cytotoxicity against J774.1 macrophage. <strong>4f</strong> and <strong>4m</strong> were tested <em>in vivo</em>, and only 4f effectively cleared the parasite burden (&gt;65 %) in infected golden hamsters. Mode of action studies discloses that <strong>4f</strong> induces oxidative stress-mediated mitochondrial dysfunction and impairment of ATP production and triggers apoptosis. SAR and PK studies revealed that compound <strong>4f</strong> (indole-dihydropyrimidinone hybrid) may be used as a lead for developing future chemotherapeutic options for VL.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117667"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862704","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":"Novel tacrine-based multi-target directed Ligands: Enhancing cholinesterase inhibition, NMDA receptor antagonism, and CNS bioavailability for Alzheimer's disease treatment","authors":"Barbora Svobodova ,&nbsp;Zuzana Moravcova ,&nbsp;Anna Misiachna ,&nbsp;Gabriela Novakova ,&nbsp;Ales Marek ,&nbsp;Vladimir Finger ,&nbsp;Jitka Odvarkova ,&nbsp;Jaroslav Pejchal ,&nbsp;Jana Zdarova Karasova ,&nbsp;Jakub Netolicky ,&nbsp;Marek Ladislav ,&nbsp;Martina Hrabinova ,&nbsp;Ales Sorf ,&nbsp;Lubica Muckova ,&nbsp;Lenka Fikejzlova ,&nbsp;Marketa Benkova ,&nbsp;Martin Novak ,&nbsp;Lukas Prchal ,&nbsp;Jan Capek ,&nbsp;Jiri Handl ,&nbsp;Jan Korabecny","doi":"10.1016/j.ejmech.2025.117678","DOIUrl":"10.1016/j.ejmech.2025.117678","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder for which current treatments provide only symptomatic relief, primarily through cholinesterase (ChE) inhibition and <em>N</em>-methyl-<span>d</span>-aspartate receptor (NMDAR) antagonism. To improve therapeutic efficacy and safety, we designed and synthesized 16 novel tacrine derivatives modified at position 7 with various (hetero)aryl groups or deuterium substitution. Initially, <em>in silico</em> screening predicted favorable CNS permeability and oral bioavailability. Subsequent <em>in vitro</em> evaluations demonstrated significant inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with derivatives <strong>5i</strong> and <strong>5m</strong> displaying particularly promising profiles. Metabolic stability assessed using human liver microsomes revealed enhanced stability for compound <strong>5e</strong>, whereas <strong>5i</strong> and <strong>5m</strong> underwent rapid metabolism. Notably, compound <strong>7</strong> showed improved metabolic stability attributed to deuterium incorporation. The newly synthesized compounds were further tested for antagonistic activity on the GluN1/GluN2B subtype of NMDAR, with compound <strong>5m</strong> exhibiting the most potent and voltage-independent inhibition. The ability of these compounds to permeate the blood-brain barrier (BBB) was confirmed through <em>in vitro</em> PAMPA assays. In preliminary hepatotoxicity screening (HepG2 cells), most derivatives exhibited higher cytotoxicity than tacrine, emphasizing the ongoing challenge in hepatotoxicity management. Based on its overall favorable profile, compound <strong>5m</strong> advanced to <em>in vivo</em> pharmacokinetic studies in mice, demonstrating efficient CNS penetration, with brain concentrations exceeding plasma levels (brain-to-plasma ratio 2.36), indicating active transport across the BBB. These findings highlight compound <strong>5m</strong> as a promising tacrine-based multi-target-directed ligand, supporting further preclinical development as a potential therapeutic candidate for AD.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"292 ","pages":"Article 117678"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862703","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}