RSC medicinal chemistry最新文献

{"title":"Simultaneous exploitation of phaeanthine - a bisbenzylisoquinoline alkaloid for dual anti-metastatic and anti-angiogenic potential by disruption of Akt/NF-κB/MMP regulatory pathways.","authors":"Alisha Valsan, Vishnu Priya Murali, Murugan Thulasi Meenu, Anuja Gracy Joseph, Kokkuvayil Vasu Radhakrishnan, Daisy R Sherin, Kaustabh Kumar Maiti","doi":"10.1039/d6md00545d","DOIUrl":"10.1039/d6md00545d","url":null,"abstract":"<p><p>Metastasis and angiogenesis are critical drivers of cancer progression, contributing to tumor aggressiveness and therapeutic resistance. Phaeanthine (PHA), a bisbenzylisoquinoline alkaloid isolated from <i>Cyclea peltata</i>, has previously demonstrated anticancer activity by inhibiting Akt signaling. The present study investigated the anti-metastatic and anti-angiogenic potential of PHA in triple-negative breast cancer (TNBC) and analysed the molecular changes associated with its activity using experimental and computational approaches. Anti-metastatic activity was evaluated in MDA-MB-231 cells using wound-healing, adhesion, and transwell invasion assays, followed by Western blot analysis of key regulatory proteins. Anti-angiogenic effects were assessed in EA.hy926 endothelial cells using tube formation assays and VEGFR2 immunofluorescence analysis. Molecular docking and molecular dynamics (MD) simulations were performed to investigate potential molecular interactions. PHA significantly inhibited the migration, adhesion, and invasion of MDA-MB-231 cells at sub-micromolar concentrations and induced apoptosis. It suppressed the expression of metastasis-associated proteins, including MMP-2, MMP-9, integrins, Akt, NF-κB, and HIF-1α, while reversing epithelial-mesenchymal transition, as evidenced by reduced N-cadherin and vimentin expression. In EA.hy926 cells, PHA markedly inhibited tube formation at 2 μM and downregulated VEGFR2 expression. <i>In silico</i> studies revealed favourable binding affinities (<-6.0 kcal mol^-1) toward multiple metastatic and angiogenic targets. Subsequently, MD simulations provided computational support for potential interactions of PHA with MMP-2 and MMP-9, consistent with their pronounced downregulation observed experimentally. Collectively, these findings indicate the dual anti-metastatic and anti-angiogenic effects of PHA through coordinated modulation of Akt/NF-κB/HIF-1α/MMP-associated proteins, extracellular-matrix remodeling and angiogenesis. This study provides the first evidence of the activity of PHA against TNBC and its anti-angiogenic potential, supporting further investigation of PHA as a potential lead phytochemical against TNBC-associated metastatic and angiogenic processes.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13609873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Arylidene-3-aryl-imidazol-4-ones as dual VEGFR-2/c-Met inhibitors: design, synthesis, and anticancer evaluation.","authors":"Hend E Elshafey, Mostafa M Elbadawi, Marwa Balaha, Abeer H A Abdelhafiz, Tarfah Al-Warhi, Mahmoud A El Hassab, Viviana di Giacomo, Abdelrahman Hamdi, Ahmed I Khodair","doi":"10.1039/d6md00415f","DOIUrl":"https://doi.org/10.1039/d6md00415f","url":null,"abstract":"<p><p>Cancer remains a major global health challenge characterized by uncontrolled proliferation, angiogenesis, and metastasis. Dysregulation of receptor tyrosine kinases, particularly VEGFR-2 and c-Met, plays a central role in tumor growth and vascularization, rendering their dual inhibition an attractive therapeutic strategy. Herein, a novel series of 5-arylidene-3-aryl-imidazol-4-ones 8a-i, thioacetyl aryl hydrazides 12a-d, and 4-chlorophenylthiazole thioacetamide analogs 16a-b were designed, synthesized, and evaluated for anticancer activity. <i>In vitro</i> cytotoxicity against HepG2 and HCT-116 cell lines was evaluated and the thioacetyl aryl hydrazide derivatives 12a and 12c were identified as the most potent compounds, exhibiting IC₅₀ values of 5.34 and 3.92 μM against HepG2 and 3.26 and 1.38 μM against HCT-116, respectively. Enzyme inhibition assays confirmed their potent dual kinase inhibition: 12a exhibited IC₅₀ values of 16.40 and 15.91 nM towards VEGFR-2 and c-Met, respectively, whereas 12c displayed respective IC₅₀ values of 16.61 and 22.95 nM. Noteworthily, 12c did not exhibit a significant inhibition against EGFR, CDK2, CDK4, and Aurora A suggesting its VEGFR-2 and c-Met selectivity. Furthermore, in HCT-116 cells, 12c induced a marked increase in G₂/M population up to 64.97%, with respect to 10.97% for the control and significantly enhanced apoptosis, elevating the total apoptotic fraction from 8.75% of the control to 22.27%. Moreover, 12c increased Bax, caspase-9, and Beclin-1 expression, while reducing Bcl-2 levels. Molecular docking studies revealed favorable binding affinities and stable binding conformations of 12c within VEGFR-2 and c-Met active sites. Collectively, these results highlight 12a and 12c as promising dual VEGFR-2/c-Met inhibitors with potent anticancer activity, meriting further optimization.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformationally restrained <i>de novo</i> peptides to modulate Skp1-Skp2 interaction of the SCF E3 ligase.","authors":"Simran Tolani, Nitesh Mani Tripathi, Himanshu Antil, Sourav Ghosh, Debarghya Mitra, Anirban Banerjee, Sushil Kumar, Anupam Bandyopadhyay, Ashutosh Kumar","doi":"10.1039/d6md00660d","DOIUrl":"10.1039/d6md00660d","url":null,"abstract":"<p><p>Skp2, the substrate-recognition component of the SCF ubiquitin ligase complex, has been widely implicated in oncogenesis across diverse malignancies, positioning it as a compelling therapeutic target. The protein-protein interaction interface of Skp1-Skp2 offers an effective intervention point, as disruption of this interaction can impair the ability of Skp2 to identify and bind to its downstream substrates. However, inhibiting this interface with small-molecule inhibitors poses considerable challenge. Here, we introduce <i>de novo</i> peptide sequences through <i>in silico</i> screening of a peptide pool to target the Skp1-Skp2 core interface. The screening identified four linear precursors, which were further conformationally restricted to increase affinity and conformational stability by deploying cysteine-mediated late-stage crosslinking. Biophysical and cellular analyses of these crosslinked peptides revealed candidate peptides, P2SS and P4SS, which bind effectively to the desired interface and reduce Skp2 protein expression. Skp2 reduction further attenuates p27 ubiquitination, leading to the accumulation of p27 and subsequent G0/G1 cell-cycle arrest, ultimately resulting in cell death. Collectively, our findings establish the potential of first-in-class peptides in targeting the Skp1-Skp2 interface for the treatment of cancers driven by Skp2.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tryptoline urea derivatives for sensitizing resistant breast cancer cells to doxorubicin.","authors":"Filipa Barbosa, Karankumar Balamurugan, N Rajendra Prasad, Maria-José U Ferreira","doi":"10.1039/d6md00580b","DOIUrl":"10.1039/d6md00580b","url":null,"abstract":"<p><p>Drug resistance is a major challenge in cancer therapy. One promising approach to address this problem is the development of compounds that, when used together with anticancer drugs, can synergistically improve their therapeutic effectiveness. Aiming at sensitizing resistant human breast adenocarcinoma cells (MCF-7/DXR), a set of new urea derivatives (2-9) was prepared by reaction of the natural β-carboline indole alkaloid tryptoline (1) with different aromatic and aliphatic isocyanates. The P-glycoprotein (P-gp) inhibitory potential of compounds 1-9 was assessed by a functional assay. The most significant results were obtained for <i>N</i>-[<i>N</i>2'-(4″-acetylphenyl)carbamoyl]tryptoline (9), in agreement with molecular docking studies that revealed significant binding affinity to P-gp. Western blot and immunocytochemistry analyses showed that compound 9 led to downregulation of <i>ABCB1</i> expression, associated with concurrent downregulation of AKT1 signaling. Co-administration of compound 9 with doxorubicin (DOX) significantly reduced fold resistance in MCF-7/DXR cells, almost restoring their sensitivity to levels similar to the parental cell line (from 16.34- to 0.98-fold resistance). Moreover, compound 9 acted synergistically with DOX, markedly increasing its cytotoxicity, associated with a strong increase in apoptosis, reaching approximately 85% apoptotic cells. Molecular analysis showed activation of the intrinsic apoptotic pathway, with increased levels of pro-apoptotic proteins (p53, Bax, caspase-3, and caspase-9) and reduced levels of the anti-apoptotic protein Bcl-2. By increasing ROS production and subsequently inducing oxidative DNA damage, compound 9 markedly amplified DOX-induced cytotoxicity, reinforcing its potential as an effective chemosensitizing agent and warranting further preclinical investigation for potential therapeutic applications.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maslinic acid derivative induces the death of transitional bladder cancer cells through apoptosis and autophagy <i>via</i> the PI3K-AKT signaling pathway.","authors":"Jing-Jing Liu, Li Sun, Dan-Ting Guo, Yu-Jie Liang, Li-Qiong Zhang, Jun-Ji Chen, Quan-de Wang, Ke-Guang Cheng","doi":"10.1039/d6md00435k","DOIUrl":"https://doi.org/10.1039/d6md00435k","url":null,"abstract":"<p><p>l-Phenylalanine and l-glutamine were conjugated with maslinic acid and 3-<i>epi</i> maslinic acid to generate 16 derivatives. Most of them exhibited higher cytotoxic activity than maslinic acid towards various tumour cell lines. Based on the results from the human apoptosis array and western blotting assays, derivative 7, a 2α,3β-dipropionylated maslinic acid-l-phenylalanine conjugate, could promote autophagy and intrinsic and extrinsic apoptosis in the T24 cell line in a dose-dependent manner. Furthermore, 7 could decrease the mitochondrial membrane potential and overload mitochondrial Ca²⁺ and ROS. These effects can lead to significant apoptosis induction and activate apoptotic signaling <i>via</i> caspase-8 and caspase-9. In addition, 7 could decline proliferation activity by inhibiting the expression of the PI3K, AKT and EGFR proteins. RNA-seq analysis suggested that 7 can induce the formation of autophagosomes by upregulating WIPI1, p62, LC3B-I/II, and Beclin-1. Meanwhile, western blotting analysis revealed that 7 could simultaneously upregulate the pro-apoptotic factors (Bax and Bak) and autophagy proteins (Beclin-1, LC3B II/I, PI3-kinase class III, mTOR and p62). This implies that 7 could synergistically promote apoptosis and autophagy to induce cell death.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BHT-derived thiazolidin-4-ones: synthesis, radical scavenging activity, and <i>in silico</i> evaluation.","authors":"Melinda Gomes Victor, Bruna Caetano Moreira, Cinara Teiroba de Ávila, Natália Pontes Bona, Mayara Sandrielly Soares de Aguiar, Francieli Moro Stefanello, Wilson Cunico","doi":"10.1039/d6md00428h","DOIUrl":"https://doi.org/10.1039/d6md00428h","url":null,"abstract":"<p><p>Butylated hydroxytoluene (BHT) is a recognized antioxidant, while thiazolidin-4-ones are versatile scaffolds for bioactive molecule design. Here, BHT-functionalized thiazolidin-4-ones were synthesized with systematic variation at the N-3 position. Multicomponent synthetic strategies afforded thiazolidin-4-ones (4), a pyrazolo-thiazepinone derivative (5m), and a 1,2,3-triazole hybrid (7k). Antioxidant activity was evaluated using DPPH˙ and ABTS˙⁺ radical-scavenging assays and rat brain homogenates assessing ROS, nitrite, TBARS, and thiol levels. Compound 4d showed the strongest chemical radical-scavenging activity, while 4a and 4b were particularly active in the ABTS˙⁺ assay. Compound 4h showed intermediate chemical activity but also demonstrated biological effects. In conclusion, N-3 substitution modulated both chemical and biological antioxidant responses, and chemical radical-scavenging potency did not fully predict activity in the biological oxidative-stress model. Docking results showed no clear correlation with the experimental findings.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triphosphate and diphosphate nucleoside prodrugs: broadening the therapeutic potential of nucleoside-based treatments.","authors":"Michaela Serpi, Camille Tisnerat, Daniel Krysa, Fabrizio Pertusati","doi":"10.1039/d6md00584e","DOIUrl":"10.1039/d6md00584e","url":null,"abstract":"<p><p>Multiple prodrug strategies have been developed to deliver nucleoside monophosphates (NMPs) and thereby overcome the initial kinase-mediated intracellular phosphorylation of nucleoside analogues (NAs), a major bottleneck in their activation. However, some NAs are limited by a second and/or third slow and inefficient phosphorylation step, which can lead to accumulation of mono- and diphosphate intermediates with associated toxicity. In addition, the metabolic pathways leading to the formation of the active nucleoside triphosphates remain poorly characterised for many reported analogues. Consequently, di- and triphosphate prodrug strategies for NAs have gained increasing attention in recent years. Here, we provide a comprehensive overview of the current approaches for development of these higher phosphorylated nucleotide analogues, including their activation pathways in different media, biological activity, synthetic methodologies, and their applicability across a broad range of NAs. Taken together, this review highlights both the potential of NDP and NTP prodrug strategies and the challenges associated with their development, providing a framework to guide future advances in their rational design and broader application.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of novel coumarin-derived as oral SERDs with favorable bioavailability.","authors":"Shiyun Chen, Mengyu Chen, Xiongxiang Huang, Hao Zhang, Zhizheng Wu, Zengye Wu, Fengqiu Guo, Shanhe Wan, Zhonghuang Li, Jie Zhao, Jiajie Zhang, Yuanxin Tian","doi":"10.1039/d6md00577b","DOIUrl":"10.1039/d6md00577b","url":null,"abstract":"<p><p>To address the pharmacokinetic limitations of current selective estrogen receptor degraders (SERDs) and explore structurally novel ERα-targeted degraders, a series of coumarin derivatives were designed, synthesized, and biologically evaluated. Structure-activity relationship studies indicated that the phenoxy linker, 7- and 3-position bisphenolic hydroxyl groups, and <i>R</i>-configured basic side chain were critical for activity. Among them, compound 23g bearing an (<i>R</i>)-3-methylpyrrolidine moiety showed the most potent antiproliferative activity against MCF-7 cells, with an IC₅₀ value of 0.015 μM. SPR analysis confirmed its high ERα affinity (<i>K</i> _d = 3.4 nM). 23g induced concentration-dependent ERα degradation <i>via</i> the ubiquitin-proteasome pathway and showed limited cytotoxicity toward ERα-negative and normal mammary epithelial cells. Pharmacokinetic profiling in Sprague-Dawley rats demonstrated favorable oral bioavailability (27.45%) and a prolonged elimination half-life (11.82 h), supporting 23g as a promising coumarin-based SERD candidate.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and biological evaluation of a novel 1,2,3-triazole-tethered 5-aminosalicylate-metronidazole hybrid as a dual anti-<i>Helicobacter pylori</i> and anti-inflammatory agent.","authors":"Hajjaj H M Abdu-Allah, Sasikala Muthusamy, Alshaimaa A B Abdelmoez, Shang-Chuen Wu, Chun-Hung Lin","doi":"10.1039/d6md00472e","DOIUrl":"10.1039/d6md00472e","url":null,"abstract":"<p><p><i>Helicobacter pylori</i> (<i>H. pylori</i>) infection is the major cause of peptic ulcer disease and gastric cancer. The increasing prevalence of antibiotic resistance necessitates the development of new therapeutic strategies. Although metronidazole exhibits potent anti-<i>H. pylori</i> activity, its clinical utility is limited by the development of resistance. Previous studies suggest that salicylic acid derivatives, including aspirin, may act synergistically with metronidazole against <i>H. pylori</i>. Herein, we report the design and synthesis of a bifunctional hybrid integrating metronidazole and 5-aminosalicylic acid (5-ASA), a well-established anti-inflammatory agent for gastrointestinal disorders. The hybrid demonstrated potent anti-<i>H. pylori</i> activity against all tested strains (MIC < 4.98 μM), representing an approximately 6-fold improvement over metronidazole (MIC 29.23-35.07 μM). Mechanistic studies indicated that the hybrid retains DNA-damaging activity characteristic of metronidazole. In addition, the hybrid displayed enhanced anti-inflammatory properties with low cytotoxicity. It showed 17.5-fold greater potency against COX-2 (IC₅₀ 3.23 μM), 5-fold improved selectivity for COX-2, and a 6-fold greater potency against 5-LOX (IC₅₀ 5.85 μM) compared to 5-ASA. Furthermore, the hybrid inhibited NF-κB signaling downstream genes such as TNF-α and IL-8. These <i>in vitro</i> results demonstrate that the new hybrid possesses enhanced anti-<i>H. pylori</i> and anti-inflammatory activities with minimal cytotoxicity; however, further studies are required to determine its therapeutic potential.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of carbazole-acrylamide-pyridinium hybrids as dual acetylcholinesterase/butyrylcholinesterase inhibitors and evaluation of their cytotoxic profile on SH-SY5Y and HEK293 cell lines.","authors":"Amir Mohammad Taherkhani, Halil Şenol, Yousef Valizadeh, Seyedeh Niloufar Ghafouri, Navid Dastyafteh, Aydın Aktaş, Nastaran Sadeghian, Fatemeh Moradkhani, Bagher Larijani, Mahmood Biglar, Parham Taslimi, Maryam Mohammadi-Khanaposhtani, Mohammad Mahdavi","doi":"10.1039/d5md01075f","DOIUrl":"10.1039/d5md01075f","url":null,"abstract":"<p><p>A novel series of seventeen carbazole-acrylamide-pyridinium-<i>N</i>-phenylacetamide hybrids (12a-q) was designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for potential Alzheimer's disease therapy. Their inhibitory activity was evaluated against both enzymes using tacrine and galantamine as reference standards. Tacrine exhibited IC₅₀ values of 58.34 nM against AChE and 160.50 nM against BChE, while galantamine showed 124.72 nM and 216.23 nM, respectively. The synthesized derivatives demonstrated IC₅₀ values ranging from 6.41 to 74.93 nM against AChE and from 38.05 to 191.96 nM against BChE. All compounds were more potent than galantamine, and most outperformed tacrine as well. Compound 12i was the most potent AChE inhibitor (IC₅₀ = 6.41 nM), showing 9.1-fold and 19.5-fold higher potency than tacrine and galantamine, respectively. Compound 12g was the strongest BChE inhibitor (IC₅₀ = 38.05 nM), with 4.2-fold and 5.7-fold higher activity than tacrine and galantamine. Kinetic analysis revealed that all of the most potent compounds act as competitive inhibitors. Cytotoxicity evaluation revealed that compounds 12i and 12g exhibited lower toxicity toward HEK293 cells than sorafenib, with favorable selectivity toward SH-SY5Y cells. These results establish the carbazole-acrylamide-pyridinium scaffold as a promising lead for developing safer cholinesterase inhibitors for Alzheimer's disease.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"5017-5033"},"PeriodicalIF":4.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}