Medicinal Chemistry Research最新文献

{"title":"QSAR modeling and in vitro studies of the selective action of triphenylphosphonium salts as anticancer agents against the rhabdomyosarcoma cell line","authors":"Diana Hodyna,&nbsp;Vasyl Kovalishyn,&nbsp;Olena Trokhimenko,&nbsp;Serhii Soloviov,&nbsp;Oksana Bahrieieva,&nbsp;Maryna Kachaeva,&nbsp;Larysa Metelytsia","doi":"10.1007/s00044-026-03593-8","DOIUrl":"10.1007/s00044-026-03593-8","url":null,"abstract":"<div><p>The development of innovative anticancer agents is essential for addressing cancer-related complications and reducing mortality rates associated with the disease. This study employed a machine learning approach to assess the anticancer efficacy of various triphenylphosphonium salt derivatives against the rhabdomyosarcoma cell line (RD). The research used resources from the publicly accessible Online Chemical Database and Modelling Environment (OCHEM). The dataset for QSAR modeling included 751 compounds exhibiting cytotoxic activity against RD cells. The predictive performance of the QSAR models was comprehensively validated using both cross-validation techniques and external test sets. Five compounds identified by the QSAR models as having high anticancer activity were then evaluated in vitro on RD cell lines. Based on cytotoxicity indices of the various types of non-oncogenic cell lines used in the presented in vitro study - L20B (modified mouse fibroblasts), BHK-21 (baby hamster kidney), and CEF (chicken embryonic fibroblasts) - to determine the potential selective action of the studied phosphonium salts as anticancer agents, the obtained results indicate that salt <b>2</b> can be considered the most promising object with a highly selective mechanism of anticancer action. The remaining salts, which demonstrated lower, more specific cytostatic activity and, accordingly, a less pronounced selective cytotoxicity index, can serve as useful and promising scaffolds for further research into the analysis and development of new effective anticancer agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1487 - 1496"},"PeriodicalIF":3.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro enzymatic assays invalidate dihydromyricetin as a potential inhibitor against enterovirus A71 3C protease: beware of fluorescence quenching artifacts","authors":"Jiankai Ye,&nbsp;Mingrui Zhang,&nbsp;Jiahao Zhou,&nbsp;Chunlei Xu,&nbsp;Yunyu Chen","doi":"10.1007/s00044-026-03592-9","DOIUrl":"10.1007/s00044-026-03592-9","url":null,"abstract":"<div><p>Enterovirus A71 (EV-A71) is an important pathogen that causes hand, foot, and mouth disease (HFMD) outbreaks worldwide. Although vaccines against EV-A71 have been approved in China, there are currently no efficacious antivirals for HFMD treatment. The 3C protease (3Cpro) of EV-A71, an essential enzyme involved in viral replication, represents an attractive target for antiviral development. Despite being proposed as a promising 3Cpro inhibitor through structure-based virtual screening, 3Cpro inhibition by dihydromyricetin (DHM) remains to be rigorously investigated. In this study, our quantitative enzymatic assays, including a fluorescence resonance energy transfer (FRET)-based approach and a dimeric RFP cleavage assay (DRCA), invalidated DHM as a potential 3Cpro inhibitor in vitro. Our study revealed that fluorescence quenching, a common screening artifact, should be carefully considered when natural products are identified as 3Cpro inhibitors. Candidate hit compounds from primary screening require rigorous pharmacological assessments before being reported as new findings.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1479 - 1486"},"PeriodicalIF":3.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148704212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of reported small molecule P2Y6 receptor antagonists","authors":"Chianna Dane,&nbsp;André D.J. McKenzie,&nbsp;Andrew P. Montgomery,&nbsp;Jonathan Du,&nbsp;Eryn L. Werry,&nbsp;Michael Kassiou","doi":"10.1007/s00044-026-03591-w","DOIUrl":"10.1007/s00044-026-03591-w","url":null,"abstract":"<div><p>Interest in the P2Y6 receptor (P2Y6R) has increased substantially over the past decade, driven by evidence that pharmacological inhibition is beneficial in neurodegenerative disease models, inflammatory pathologies, and cancer. However, therapeutic targeting of the P2Y6R has remained a challenge due to a lack of available drug-like molecules. In 2023 and 2024, benzimidazole and quinoline chemotypes respectively, were reported as potent P2Y6R antagonists with pharmacological relevance in an inflammatory bowel disease model. In the present study positive and negative controls from each chemotype were selected, and their functional activity at hP2Y6R was assessed prior to chemical diversification. Contrary to the published literature, none of the antagonists exhibited functional activity in our Ca²⁺ mobilisation assay reported herein. These findings emphasise the ongoing challenges in reliably assessing pharmacological activity at the hP2Y6R and highlight a key barrier to progression of the field.</p><div><figure><div><div><picture><img></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 10","pages":"2055 - 2072"},"PeriodicalIF":3.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03591-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149176426","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":"Alisols A-C and their acetate derivatives: a review of natural occurrence, pharmacology, semisynthesis, pharmacokinetics, and metabolism","authors":"Duong Quang Huan,&nbsp;Huynh Thi Ngoc Ni,&nbsp;Huy Dinh Vu,&nbsp;Tran Thi Thanh Thuy,&nbsp;Nguyen Hoang Ngan,&nbsp;Vu Kim Thoa,&nbsp;Nguyen Thi Hue,&nbsp;Ninh The Son","doi":"10.1007/s00044-026-03590-x","DOIUrl":"10.1007/s00044-026-03590-x","url":null,"abstract":"<div><p>Alisols, a distinctive group of protostane-type triterpenoids predominantly found in the rhizomes of <i>Alisma orientale</i> (Sam.) Juzep., have attracted due to their broad pharmacological potential. This review first provides an integrated overview of alisol A (<b>1</b>), alisol A 23-acetate (<b>2</b>), alisol A 24-acetate (<b>3</b>), alisol B (<b>4</b>), alisol B 23-acetate (<b>5</b>), alisol C (<b>6</b>), and alisol C 23-acetate (<b>7</b>), focusing on their natural occurence, pharmacological activities, semisynthesis, pharmacokinetic and metabolic profiles. References were collected from PubMed, Web of Science, Scopus, Google Scholar, and SciFinder using keywords alisols, protostane triterpenoids, <i>Alisma orientale</i>, semisynthesis, pharmacology, mechanisms, and pharmacokinetics. Original research articles from the 1970s reporting chemical characterization and pharmacology were included, while studies lacking relevance were excluded. Alisols <b>1–7</b> exhibited wide-ranging pharmacological activities, including anticancer, antidiabetes, antiallergic, antibacterial, anti-viral, anti-hyperlipidemic, anti-obesity, and vasorelaxant activities. They also protect the neurons, liver, kidneys, gastrointestinal tract, bones, and skin. These activities are associated with apoptosis, autophagy, and cytokine and oxidative inhibitions, and the modulation of various signaling pathways, such as the AMPK, PI3K, Akt, mTOR, and FXR. Semisynthesis, particularly esterification, dehydration, and epoxidation, enhanced pharmacological values and revealed structure-activity relationships. Pharmacokinetic data indicated rapid biotransformation, pH-dependent interconversion, and gut microbiota-associated metabolism.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 8","pages":"1389 - 1413"},"PeriodicalIF":3.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148704194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyridine-containing antitumor agents: structure-oriented medicinal chemistry, structure–activity relationships, and ADMET liabilities","authors":"Wei Zhao,&nbsp;Beibei Bie,&nbsp;Juning Wang,&nbsp;Xueying Liu,&nbsp;Huanle Fang,&nbsp;Rui Niu","doi":"10.1007/s00044-026-03588-5","DOIUrl":"10.1007/s00044-026-03588-5","url":null,"abstract":"<div><p>Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure–activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody–drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1316 - 1329"},"PeriodicalIF":3.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00044-026-03588-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434767","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":"Medicinal Chemistry Research Welcomes the Inaugural Cohort of the Early Career Editorial Board (ECEB) Members","authors":"Longqin Hu","doi":"10.1007/s00044-026-03589-4","DOIUrl":"10.1007/s00044-026-03589-4","url":null,"abstract":"","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1235 - 1236"},"PeriodicalIF":3.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, biological evaluation, and computational studies of N-benzoylethylenediamine derivatives as cholinesterase inhibitors","authors":"Xue-Wei Zhou,&nbsp;Chao-Yue Zhang,&nbsp;Qian Liu,&nbsp;Yi-Xuan Wang,&nbsp;Shi-Hao Qin,&nbsp;Zheng-Yue Ma","doi":"10.1007/s00044-026-03587-6","DOIUrl":"10.1007/s00044-026-03587-6","url":null,"abstract":"<div><p>In this study, a series of <i>N</i>-benzoylethylenediamine derivatives (<b>16a-16u</b>) was rationally designed and successfully synthesized using a strategy that combines cholinesterase (ChE) inhibition with antioxidant activity. The inhibitory activities of all compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), along with their antioxidant capacity, were systematically evaluated in vitro. Most compounds exhibited moderate to potent inhibition against both enzymes. Notably, compound <b>16 L</b> showed the best dual inhibitory activity, with IC₅₀ values of 1.71 µM for AChE and 2.38 µM for BuChE, both superior to those of the reference drug, galantamine. (AChE: IC₅₀ = 5.17 µM, BuChE: IC₅₀ = 11.06 µM). Furthermore, the DPPH radical scavenging assay indicated that compound <b>16a</b> exhibited the strongest antioxidant activity (IC₅₀ = 27.69 µM), which was slightly stronger than that of the positive control ascorbic acid (IC₅₀ = 32.59 µM). Enzyme kinetic studies revealed that compound <b>16 L</b> acts as a mixed-type inhibitor of AChE. Molecular docking results further demonstrated that <b>16 L</b> interacts with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, consistent with the kinetic data; however, for BuChE, <b>16 L</b> interacts only with the CAS. Molecular dynamics (MD) simulations confirmed the stability of the <b>16 L</b>-AChE/BuChE complexes. Collectively, these findings validate compound <b>16 L</b>’s research value as a dual inhibitor of AChE and BuChE.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1367 - 1384"},"PeriodicalIF":3.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of pyrrolo[2,3-d]pyrimidine derivatives with inhibitory effect on liver cancer stem cell","authors":"Xuecong Zhang,&nbsp;Xuechun Chen,&nbsp;Liwei Wang,&nbsp;Yiyuan Chang,&nbsp;Jiaxin Li,&nbsp;Jijian Yang,&nbsp;Dongxuan Ni,&nbsp;Ruihan Zhang,&nbsp;Rong Liu,&nbsp;Weilie Xiao","doi":"10.1007/s00044-026-03586-7","DOIUrl":"10.1007/s00044-026-03586-7","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The malignancy of HCC is closely linked to liver cancer stem cells (CSCs), making the application of anti-CSC drugs a promising therapeutic approach. In this study, we report the discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as potent inhibitors of liver CSC. Structural optimization and anti-CSC screening led to the identification of improved compounds <b>6i</b>, <b>6j</b>, and <b>7e</b>, which significantly inhibited Huh7 sphere formation while exhibiting low toxicity to standard 2D-cultured tumor cells. Notably, compound <b>6i</b> sensitizes both parental and Lenvatinib-resistant HCC cells to Lenvatinib treatment, showing a synergistic interaction. Collectively, these findings establish the pyrrolo[2,3-d]pyrimidine as a promising scaffold for targeting liver CSC and provide a potential combination strategy to overcome Lenvatinib resistance in advanced HCC.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1352 - 1366"},"PeriodicalIF":3.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical constituents in the rhizome of Curcuma longa and the pharmacological importance of curcumin hybrids","authors":"A. Jerin Rex,&nbsp;P. Parthiban","doi":"10.1007/s00044-026-03581-y","DOIUrl":"10.1007/s00044-026-03581-y","url":null,"abstract":"<div><p><i>Curcuma longa</i> (turmeric) is a well-known medicinal plant that is rich in bioactive phytochemicals, among which curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the principal constituents responsible for diverse pharmacological activities, ranging from antibacterial to anticancer. Despite its multifaceted therapeutic potential and clinical safety, the unfavorable pharmaceutical properties are limiting its clinical efficacy and hence are not able to attain the drug standard. Interestingly, this review provides a comprehensive overview of the complete phytochemical constituents of <i>C. longa</i>, and on the other hand, recent advancements (2020-2025) in the design and development of curcumin-based hybrid molecules aimed at overcoming the aforementioned limitations. Literature was systematically analyzed, focusing on structural modifications of curcuminoids, including functional group transformations, heterocycle incorporation, and monocarbonyl scaffold simplification to exploit these strategies’ significance on pharmacokinetic properties, metabolic stability, and anticancer activity. In particular, monocarbonyl curcumin-piperidone hybrids exhibit improved cytotoxicity, redox modulation, and multitarget mechanisms compared with curcumin and its other hybrids. Overall, curcumin hybridization represents a promising approach that bridges traditional herbal knowledge with modern drug discovery, offering valuable candidates for the development of effective anticancer therapeutics.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1237 - 1315"},"PeriodicalIF":3.5,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and growth inhibitory activity of sinomenine derivatives against cervical cancer SiHa cells through targeting the AKT-CyclinD1-p21/p27 pathway","authors":"Haozhe Yang,&nbsp;Xiaorui Li,&nbsp;Zhaoning Cai,&nbsp;Yueqing Li,&nbsp;Zhigang Gao,&nbsp;Shisheng Wang,&nbsp;Xiuhan Guo","doi":"10.1007/s00044-026-03584-9","DOIUrl":"10.1007/s00044-026-03584-9","url":null,"abstract":"<div><p>Cervical cancer remains a leading cause of female malignancy worldwide, with current therapies limited by systemic toxicity and inadequate efficacy. Sinomenine, a natural isoquinoline alkaloid derived from <i>Sinomenium acutum</i>, exhibits moderate anticancer potential but requires structural modification to enhance its activity. Herein, we synthesized 15 sinomenine derivatives via Ritter reaction-mediated amidation of the C-1 hydroxymethyl group and esterification of the C-4 phenolic hydroxyl group. The in vitro anticancer activities of these derivatives were evaluated against three cervical cancer cell lines (HeLa, SiHa, and C33A) using MTT assay. Among them, compound <b>S14</b> displayed the most potent cytotoxicity, with IC₅₀ values of 3.32 ± 0.31 µM, 1.96 ± 0.08 µM, and 6.20 ± 0.55 µM against HeLa, SiHa, and C33A cells, respectively. Colony formation, wound healing, and Transwell experiments demonstrated that <b>S14</b> inhibited the proliferation, migration, and invasion of SiHa cells in a concentration-dependent manner. Flow cytometry assays revealed that <b>S14</b> induced G₂/M phase cell cycle arrest and late apoptosis in SiHa cells. Mechanistically, Western blot assays indicated that <b>S14</b> downregulated the expression of AKT, phosphorylated AKT (p-AKT), and CyclinD1, while upregulating the cyclin-dependent kinase inhibitors p21 and p27, suggesting the involvement of the AKT-CyclinD1-p21/p27 signaling pathway. Moreover, AKT silencing via siRNA transfection significantly attenuated <b>S14</b>-induced cell cycle arrest and apoptosis. Collectively, these findings highlight that <b>S14</b>, a structurally optimized sinomenine derivative, exerts anticancer effects by targeting the AKT-CyclinD1-p21/p27 pathway, and thus holds promise as a potential therapeutic candidate for cervical cancer treatment.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"35 7","pages":"1341 - 1351"},"PeriodicalIF":3.5,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}