RSC medicinal chemistry最新文献

{"title":"Structure-based design of potent pyrazolo[1,5-<i>a</i>]pyrimidine CDK4/6 inhibitors: biological evaluation and computational validation.","authors":"Faizah A Binjubair, Mahmoud S Elkotamy, Amr A Mattar, Bjad K Almutairy, Sara T Al-Rashood, Mohamed M Eldesouki, Jalloul Bouajila, Hatem A Abdel-Aziz, Mariam M Fakhry","doi":"10.1039/d5md01147g","DOIUrl":"https://doi.org/10.1039/d5md01147g","url":null,"abstract":"<p><p>Dysregulation of cyclin-dependent kinases (CDKs) drives uncontrolled cell cycle progression in several malignancies, making CDK4 and CDK6 appealing therapeutic targets. This paper details the rational design, synthesis, and thorough assessment of fifteen new pyrazolo[1,5-<i>a</i>]pyrimidine derivatives (19a-o) as cyclin-dependent kinase inhibitors. Structure-activity relationship research identified compound 19i as the primary candidate, exhibiting enhanced antiproliferative efficacy against HCT-116 colorectal cancer cells with an IC₅₀ of 1.02 μM, slightly higher than that of doxorubicin (IC₅₀, 1.08 μM). Mechanistic investigations demonstrated that 19i generates significant G0/G1 phase cell cycle arrest and substantial apoptotic cell death, with total apoptosis reaching 47.76% of the treated cells. ELISA analysis verified the activation of p53-dependent intrinsic apoptosis, evidenced by a 6.90-fold increase in p53, a 3.03-fold increase in Bax, a 0.39-fold decrease in Bcl-2, and a 9.56-fold increase in caspase-3 activity. Biochemical kinase tests revealed significant suppression of CDK4 (IC₅₀ 0.087 μM) and CDK6 (IC₅₀ 0.114 μM). Molecular docking revealed essential binding interactions, including hydrogen bonds with Lys35 and Val101, aromatic π-π stacking, and a new halogen bond with Glu94. Molecular dynamics simulations validated prolonged protein conformational stability and efficient target engagement. These findings collectively designate the pyrazolo[1,5-<i>a</i>]pyrimidine scaffold as a viable framework for CDK-targeted anticancer therapies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779735","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":"Recent advances in the development of acridine-based hybrids with antiproliferative activity.","authors":"Mahdi Gallala, Najeh Tka, Sonia Aroui","doi":"10.1039/d6md00023a","DOIUrl":"https://doi.org/10.1039/d6md00023a","url":null,"abstract":"<p><p>Cancer remains a leading cause of mortality worldwide, with the limitations of conventional single-target therapies, such as severe side effects and drug resistance, driving the need for innovative treatment strategies. Molecular hybridization has emerged as a powerful rational drug design approach to develop multi-target agents capable of simultaneously modulating various oncogenic pathways. Among the diverse scaffolds explored, the acridine core, a tricyclic, planar heteroaromatic structure, stands out due to its inherent DNA-intercalating ability and potent antiproliferative activity through mechanisms like topoisomerase inhibition. This review provides a comprehensive overview of recent advances (2019-2025) in the design, synthesis, evaluation, and perspectives of acridine-based hybrids as antiproliferative agents. It systematically surveys a vast array of hybrids, classifying them by their dominant secondary pharmacophores to offer a structured and practical overview of the field. Particular attention is given to structure-activity relationships (SARs), illustrating how strategic modifications can affect cytotoxicity, selectivity, and underlying mechanistic pathways. The biological evaluation of these hybrids encompasses a range of <i>in vitro</i> assays, including cytotoxicity against diverse human cancer cell lines, enzyme inhibition studies, antiangiogenic assays, and preliminary <i>in vivo</i> experiments, reflecting their multifaceted pharmacological profiles. Computational approaches, such as molecular docking, molecular dynamics, and quantitative SAR (QSAR), have further contributed mechanistic insights and informed rational optimization of pharmacokinetic and pharmacodynamic properties. The review concludes by addressing current challenges and future directions, emphasizing the transformative potential of integrating artificial intelligence (AI) with computer-aided drug design (CADD) and advanced delivery systems. By compiling these developments, this work aims to serve as a useful reference to assist researchers in the design of new, more effective acridine-based anticancer agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842232","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":"Decoding the association of polycystic ovary syndrome with metabolic-associated fatty liver: insights into CK18 and LC3II/ATG7/P62 autophagy axis and adjunct therapeutics of metformin and levothyroxine.","authors":"Sameeah Mejbel Hamad Algenabi, Anwar Nather Seiwan, Maha Hussein Hashem Sabra, Doaa I Mohamed, Lobna Fouad Abd ElAziz Bassyouni, Dalia Alaa El-Din Aly El-Waseef, Samar F Ezzat, Omnyah A El-Kharashi, Hanaa F Abd El-Kareem, Hyfa A Alzahrani, Fawzyah Obeedallah Albaldi, Ahmed Shokry Elharoun, Mansour Altayyar, Amal Fahmy Dawood, Hebatallah H Abo Nahas, Ahmed Abdel-Salam M Elmelegy","doi":"10.1039/d5md00819k","DOIUrl":"https://doi.org/10.1039/d5md00819k","url":null,"abstract":"<p><strong>Background: </strong>polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder often associated with insulin resistance and metabolic-associated fatty liver disease (MAFLD), both linked to impaired autophagy. This study evaluates the effects of metformin and levothyroxine on autophagy regulation in a PCOS-induced MAFLD rat model.</p><p><strong>Materials and methods: </strong>PCOS was induced in female Wistar rats by testosterone enanthate (7.5 mg, E16-19). Post-weaning, rats were assigned to control, model, metformin (300 mg kg^-1 per day), levothyroxine (50 μg kg^-1 per day), or combination groups. Body/liver weight, serum markers (ALT, AST, TSH, lipid profile, testosterone, LH, estradiol), insulin sensitivity, autophagy-related proteins (LC3II, ATG7, p62, CK18), and histology were assessed. Network pharmacology, protein-protein interaction, KEGG enrichment, and molecular docking were performed.</p><p><strong>Results: </strong>combination therapy reduced body weight (10.29%) and liver weight (37.08%) and lowered ALT (26.17%), AST (42.69%), TSH (77.9%), cholesterol (41.32%), triglycerides (32.37%), and LDL (43.42%). Testosterone and LH declined (37.25%, 14.43%), while estradiol rose (37.4%). HOMA-IR decreased by 51.85%. Autophagy markers (CK18, LC3II, P62, ATG7) were suppressed, with improved hepatic and ovarian histology. Network analysis identified NOS2, KRT18, MAP1LC3B, ATG7, and SQSTM1 as key targets, with KEGG pathways implicated in autophagy, mitophagy, ferroptosis, and apelin signaling. Docking analysis showed stronger binding of levothyroxine to LC3II and ATG7, suggesting a direct modulatory role.</p><p><strong>Conclusion: </strong>metformin and levothyroxine synergistically improve PCOS-related MAFLD by restoring autophagy and metabolic-endocrine balance. System-level and docking analyses support autophagy regulation as a key therapeutic mechanism, highlighting the potential role of levothyroxine in modulating autophagy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13071933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147692070","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":"Beyond acrylamide: a structure-guided investigation of covalent warheads in the development of CDK7 inhibitors.","authors":"Yu Cao, Yiqing Huang, Yunlong Pan, Jialuo Mao, Lixin Gao, Jiankang Zhang, Huajian Zhu, Shourong Liu, Rangxiao Zhuang, Yang Liu, Yubo Zhou, Jiaan Shao","doi":"10.1039/d6md00088f","DOIUrl":"https://doi.org/10.1039/d6md00088f","url":null,"abstract":"<p><p>To achieve covalent CDK7 inhibitors with superior antiproliferative activity and enhanced selectivity, we designed and synthesized a series of covalent CDK7 inhibitors bearing diverse warheads based on the THZ1 scaffold. Experimental validation confirmed that 2-chloroacrylamide-based covalent inhibitors possess potent CDK7 kinase inhibitory activity. HRMS results revealed that the interaction between these compounds and the cysteine residue of CDK7 extends beyond a simple Michael addition, potentially involving nucleophilic substitution at the covalent warhead. Among them, compound B19 exhibited potent CDK7 kinase inhibition with an IC₅₀ value of 0.370 ± 0.0200 nM, as well as strong anti-proliferative activity against MV-4-11 (IC₅₀ = 0.820 ± 0.0500 nM), Molm-13 (IC₅₀ = 1.14 ± 0.0900 nM) and MDA-MB-231 (IC₅₀ = 20.2 ± 1.34 nM) cells. Furthermore, B19 strongly suppressed CDK7-mediated downstream signaling and induced apoptosis and G0/G1 phase arrest in MV-4-11 cells, supporting its potent antitumor effects. Wash-out assays indicated that compound B19 possesses a prolonged activity profile compared with THZ1. Additionally, B19 displayed favorable selectivity across a panel of other kinases. Collectively, these results identify B19 as a promising lead compound for targeting CDK7.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13131966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820176","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":"Phenoxyacetic acid scaffold as a platform for dual anticonvulsant and anti-inflammatory drug design.","authors":"Mohamed K Elgohary, Mahmoud Abdelrahman Alkabbani, Aya Mohamed Ahmed Ibrahim, Ahmed Elsonbaty, Mayada H Mohamed, Abdulrahman A Almehizia, Ahmed M Naglah, Mohamed Fares, Hatem A Abdel-Aziz","doi":"10.1039/d6md00097e","DOIUrl":"https://doi.org/10.1039/d6md00097e","url":null,"abstract":"<p><p>Neuroinflammation is increasingly recognized as a critical contributor to epileptogenesis and antiepileptic drug resistance, emphasizing the need for multi-target therapeutic strategies. In the present study, a series of phenoxyacetic acid-based hydrazone derivatives were rationally designed and synthesized as dual anti-inflammatory and antiepileptic agents through positional modification of the phenoxyacetic acid scaffold followed by hydrazone formation with diverse hydrazides. The synthesized compounds were spectroscopically characterized and evaluated using an integrated <i>in silico</i>, <i>in vitro</i>, and <i>in vivo</i> workflow. ADME and ProTox-3.0 predictions suggested favorable drug-likeness and low acute oral toxicity, while molecular docking indicated that the lead compound 7b established stable interactions with voltage-gated calcium channels and cyclooxygenase-2, exhibiting binding modes comparable to sodium valproate and celecoxib, respectively. Biologically, compound 7b emerged as the most active derivative, demonstrating potent anti-inflammatory activity in the carrageenan-induced paw edema model with 55.38% early inhibition and sustained suppression of 49.15% at 5 h, together with the lowest paw weight increase (21.28%), representing a 59.25% reduction <i>versus</i> the carrageenan group. This effect correlated with marked downregulation of tumor necrosis factor (TNF-α) and prostaglandin E₂ (PGE₂), supporting effective modulation of inflammatory signaling. Compound 7b also exhibited strong analgesic activity, increasing nociceptive latency by 37.76% at 30 min and reaching 52.08% at 120 min in the hot-plate assay. Remarkable anticonvulsant efficacy was observed in both the pentylenetetrazole (PTZ) induced seizure model and pilocarpine-induced seizure model, where 7b afforded 90% seizure protection with complete prevention of mortality, delayed seizure onset by 156.43%, reduced seizure severity by 70.53%, and achieved 100% survival, surpassing sodium valproate. Mechanistically, 7b markedly attenuated hippocampal neuroinflammation and excitotoxicity, reducing TNF-α, IL-6, and glutamate levels while suppressing glial activation markers glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1, confirming pronounced neuroprotective and anti-neuroinflammatory effects.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13066825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147676373","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":"Recent advances towards BACE1 drug discovery and therapeutics design.","authors":"Saim Imran, Meera Patel, Meissam Noroozifar, Kagan Kerman","doi":"10.1039/d5md01095k","DOIUrl":"10.1039/d5md01095k","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood-brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723582","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":"Bicyclic monoterpenoid-based orthopoxvirus inhibitors: design, synthesis, and biological assessment of a novel amide series.","authors":"Serafim A Tishchenko, Anastasiya S Sokolova, Valeriya V Samsonova, Julia G Pushkareva, Nikolay I Bormotov, Ivan A Moskalev, Daria E Solomina, Artem D Rogachev, Alina V Fatyanova, Sophia S Borisevich, Olga I Yarovaya, Olga A Serova, Alena S Ovchinnikova, Alexander A Sergeev, Larisa N Shishkina, Artemiy A Sergeev, Alexander P Agafonov, Nariman F Salakhutdinov","doi":"10.1039/d6md00217j","DOIUrl":"https://doi.org/10.1039/d6md00217j","url":null,"abstract":"<p><p>This study reports the design, synthesis, and comprehensive biological evaluation of a new class of orthopoxvirus inhibitors utilizing natural bicyclic monoterpenoid scaffolds as strategic replacements for synthetic polycyclic cores. A focused library of amides based on camphor, apo-/isocamphane, and nopol-derived amines was synthesized and screened for activity against vaccinia (VACV), cowpox (CPXV), ectromelia (ECTV) and variola (VARV) viruses. Structure-activity relationship (SAR) analysis identified the importance of a <i>para</i>-substituted electron-withdrawing group on the benzamide moiety, with the apocamphanyl amine series yielding the most potent candidate, compound 13d. Compound 13d exhibited potent <i>in vitro</i> antiviral activity with IC₅₀ values of 0.32 μM (VACV), 4.43 μM (CPXV), 3.28 μM (ECTV), and 1.6 μM (VARV) coupled with high selectivity indices (up to 1226). Further profiling revealed metabolic stability of 13d in mouse blood and favorable pharmacokinetics in mice following a single intragastric dose (100 mg kg^-1), characterized by rapid absorption and a long elimination half-life (<i>T</i> _1/2 ∼ 6.7 h), supportive of once-daily dosing. Computational studies involving pharmacophore analysis, molecular docking, and MD simulations elucidated the binding mode to the p37 phospholipase domain and rationalized the observed SAR, highlighting the critical role of hydrophobic interactions and stereochemistry. These findings validate the bicyclic monoterpenoid platform as a promising strategy for discovering potent, metabolically stable anti-orthopoxvirus agents and establish 13d as a compelling lead candidate for further preclinical development.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779902","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":"Quinoline/thiazole compounds as selective acetylcholinesterase inhibitors: synthesis and biological assessment.","authors":"Berkant Kurban, Derya Osmaniye, Serkan Levent, Yusuf Özkay, Zafer Asım Kaplancıklı","doi":"10.1039/d6md00165c","DOIUrl":"https://doi.org/10.1039/d6md00165c","url":null,"abstract":"<p><p>Acetylcholine (ACh), acetylcholinesterase enzyme (AChE), and AChE inhibition are of great importance in the treatment of neurodegenerative diseases. When it comes to AChE inhibition, FDA-approved AChE inhibitors such as donepezil are actively used in the treatment of neurodegenerative disorders. However, there is still a need for novel and unique inhibitors for the radical treatment of these diseases. The aim of this study was to design and evaluate new inhibitors for the treatment of neurodegenerative diseases. To meet this need, a series of new quinoline/thiazole derivative compounds were designed and synthesized, and their structures were elucidated using ¹H-NMR, ¹³C-NMR and HRMS. There are many studies showing that quinolines and thiazoles have high potential efficacy in AChE inhibition. The compounds were synthesized through a multi-step synthetic route, and their inhibitory activities were subsequently examined using. Compound 3i emerged as the most promising derivative, distinguished by its interactions with amino acids such as Trp86 and Trp286 in <i>in silico</i> studies, and its potent <i>in vitro</i> activity against AChE with an IC₅₀ value of 0.027 ± 0.002 μM. These findings suggest that these novel quinoline/thiazole derivatives could be potential candidates for the development of new therapies for neurodegenerative diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779737","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":"Redefining the role of the thiol-based agent <i>N</i>-acetylcysteine in human health and disease and elucidating potential advantages of its amide derivative.","authors":"Hui-Qi Qu, Charlly Kao, Hakon Hakonarson","doi":"10.1039/d5md01173f","DOIUrl":"https://doi.org/10.1039/d5md01173f","url":null,"abstract":"<p><p><i>N</i>-Acetylcysteine (NAC) is the established antidote for acetaminophen toxicity and an approved mucolytic agent. Beyond these traditional uses, increasing evidence highlights its broader role as a modulator of thiol-redox biology. Rather than functioning as a nonspecific antioxidant, NAC modulates glutathione metabolism, redox-sensitive signaling, immune checkpoints, thiol-based post-translational modifications, ferroptosis susceptibility, and glutamatergic neurotransmission. This review synthesizes mechanistic, preclinical, and clinical evidence across pulmonary, hepatic, neuropsychiatric, metabolic, cardiovascular, and oncologic disorders, emphasizing how variability in baseline redox state, pharmacogenetics, and delivery contributes to heterogeneous outcomes. Strategies to improve pharmacokinetics and tissue targeting include structural derivatives such as <i>N</i>-acetylcysteine amide (NACA), and combination regimens such as NAC with probenecid or GlyNAC. Emerging applications span long COVID, neurodegeneration, psychiatric disorders, microbiome-redox interactions, environmental toxicology, and cancer immunotherapy. NAC and NACA exemplify the evolution of redox-targeted therapeutics. NAC is well established for safety and clinical utility, but its pharmacokinetic and tissue distribution properties constrain broader efficacy. NACA, a lipophilic amide derivative, enhances membrane permeability and cellular uptake, suggesting it may achieve higher tissue exposure at lower doses. Future progress will rely on biomarker-guided, precision approaches that optimize dosing, formulation, and delivery while exploring rational combinations across disease contexts defined by redox biology.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13055913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639661","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":"Novel zerumbone-amide-triazole hybrids as potential NF-κB pathway inhibitors: design, synthesis, cytotoxicity evaluation, computational studies, and mechanistic insights.","authors":"Pham The Chinh, Pham Thi Tham, Vu Thi Lien, Dao Thi Nhung, Le Thi Thuy Loan, Khieu Thi Tam, Vu Tuan Kien, Cao Thanh Hai, Phan Thanh Phuong, Truong Thi Thao, Vuong Truong Xuan, Le Thi Lien","doi":"10.1039/d6md00148c","DOIUrl":"https://doi.org/10.1039/d6md00148c","url":null,"abstract":"<p><p>A series of fifteen novel zerumbone-amide-triazole hybrids 12a-i and 15a-f were successfully designed and synthesized from azazerumbone II (2) <i>via</i> click reaction. The cytotoxicity of these derivatives was evaluated against four human cancer cell lines: gastric carcinoma (AGS), hepatocellular carcinoma (HepG2), lung carcinoma (A549), and acute leukemia (HL-60). Most derivatives displayed significantly improved cytotoxicity compared with the parent compound 9, and several hybrids showed low-micromolar potency. These results highlight the crucial role of the simultaneous incorporation of secondary amide and 1,2,3-triazole pharmacophores into the zerumbone scaffold in enhancing anticancer activity. In particular, compound 12g was the most active derivative, exhibiting IC₅₀ values of 3.25 μM (AGS), 2.21 μM (HepG2), 3.84 μM (A549) and 2.43 μM (HL-60), while 15e also demonstrated consistently strong activity across all cell lines. Molecular docking suggested that the hybrids preferentially associate with non-canonical surface regions within the Rel homology domain (RHD) of NF-κB p65, rather than occupying the DNA-binding groove, with key contacts involving residues such as Phe298, Phe301, Pro303, Lys337 and Lys318. To further assess interaction stability, 50 ns molecular dynamics simulations and MM-GBSA calculations were performed, supporting productive surface binding for the most active ligands and helping discriminate less active candidates. Mechanistically, Western blot analysis in HepG2 cells showed that compound 12g reduced NF-κB p65 and phospho-p65 (Ser536) levels, together with phospho-IκB-α (Ser32), predominantly at 2× IC₅₀, suggesting attenuation of NF-κB activation at higher effective concentrations. Overall, the combined experimental and computational results support zerumbone-amide-triazole hybrids as promising cytotoxic leads, with NF-κB p65 modulation likely contributing to their biological effects.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779650","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}