Archiv der Pharmazie最新文献

{"title":"Electro-Mechanical Uncoupling of KV7.1 Voltage Sensor and Pore by 1,4-Benzodiazepines Is Modulated by Decoration of Position 1","authors":"Florian Roßner,&nbsp;Thomas Jepps,&nbsp;Bo Hjorth Bentzen,&nbsp;Nathalie Strutz-Seebohm,&nbsp;Bernhard Wünsch,&nbsp;Guiscard Seebohm","doi":"10.1002/ardp.70305","DOIUrl":"10.1002/ardp.70305","url":null,"abstract":"<p>The voltage-gated potassium channel K_V7.1 (KCNQ1) is essential for cardiac repolarization. Loss-of-function mutations prolong the action potential and cause long QT syndrome 1, predisposing to malignant arrhythmias. Pharmacological activators of K_V7.1 are therefore of therapeutic interest. Among them, the 1,4-benzodiazepine derivative (R)-L3 is a potent activator that not only increases current amplitude but also slows activation and deactivation kinetics and abolishes inactivation by uncoupling the voltage sensor from the pore. To explore the structure–activity relationships (SAR) of (R)-L3, we synthesized and functionally characterized a series of novel 1,4-benzodiazepine derivatives and examined their effects on K_V7.1 gating. Human K_V7.1 channels were heterologously expressed in <i>Xenopus laevis</i> oocytes. Two-electrode voltage clamp recordings were performed to assess current amplitude and kinetic parameters of activation, deactivation, and inactivation. 1,4-Benzodiazepines modified at 1-position reproduced the canonical effects of (R)-L3, including increased current amplitude and suppression of inactivation to varying degrees. Some derivatives displayed completely altered profiles: Modulation of activation, altered (de-)activation kinetics or exerting attenuated effects on inactivation could be uncoupled. These differences suggest that modifications of the 1,4-benzodiazepine scaffold at 1-position shift the interaction between pore binding and voltage sensor–pore uncoupling to isolate kinetic effects. Our data demonstrates that (R)-L3 analogues can differentially modulate K_V7.1 gating. By identifying structural determinants of efficacy, this study provides a framework for rational design of next-generation K_V7.1 activators. Such compounds may serve as pharmacological tools for dissecting electromechanical coupling in K_V7.1 and hold promise as candidates for antiarrhythmic therapy in long QT syndrome.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Indole and Azaindole Hybrid Agents for Leukemia Therapy: Recent Research Advances and Therapeutic Potential","authors":"Yanjing Cheng,&nbsp;Lianlian Chen,&nbsp;Danchen Zhao,&nbsp;Jun Yu,&nbsp;Yafei Zhuang","doi":"10.1002/ardp.70307","DOIUrl":"10.1002/ardp.70307","url":null,"abstract":"<div>\u0000 \u0000 <p>Leukemia represents a heterogeneous and refractory hematological malignancy, with current clinical therapies, including conventional chemotherapy, targeted therapy, and hematopoietic stem cell transplantation, still limited by drug resistance, off-target toxicity, and poor efficacy against high-risk subtypes. Indole/azaindole is a privileged heterocyclic scaffold in medicinal chemistry with versatile structural modification potential and inherent antileukemic bioactivity. Rational hybridization of indole/azaindole with diverse pharmacophores has become a core strategy for developing novel antileukemic agents, thereby enabling synergistic efficacy, reversal of drug resistance, and reduced toxicity. This review systematically summarizes the research progress of indole-based hybrids and closely related indole bioisosteres (azaindole hybrids) with antileukemic activity from 2021 to the present. Distinct from previous descriptive reviews, we stratified all candidate compounds by evidence hierarchy: in vitro antiproliferative activity, molecular mechanistic validation, and in vivo preclinical efficacy. This work focuses on structure-activity relationships (SARs), multi-target mechanisms, and preclinical pharmacological characteristics of indole- and azaindole-based antileukemic hybrids, aiming to provide targeted guidance for the rational design and clinical translation of novel indole- and azaindole-based antileukemic drugs.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastroprotective Activity of Myrtenol Derivatives Obtained by Biocatalytic Esterification and Photooxidation","authors":"Ana Flávia Seraine Custódio Viana,&nbsp;Mateusz Kutyła,&nbsp;Hélio de Barros Fernandes,&nbsp;Boris Timah Acha,&nbsp;Gabriel Henrique Oliveira,&nbsp;Rita de Cássia Meneses Oliveira,&nbsp;Marek Stankevič,&nbsp;Mariusz Trytek","doi":"10.1002/ardp.70304","DOIUrl":"10.1002/ardp.70304","url":null,"abstract":"<div>\u0000 \u0000 <p>Many naturally occurring substances exhibit anti-ulcer properties. One promising area of research is the identification of terpenoid compounds with enhanced therapeutic and gastroprotective properties. The present study aimed to synthesize new terpenoid derivatives of myrtenol via biotransformation using freeze-dried <i>Cladosporium cladosporioides</i> mycelium or via porphyrin-based biomimetic transformation, and to evaluate their gastroprotective activity in an ethanol-induced gastric lesion model. Five myrtenyl esters (acetate, butyrate, caprylate, pelargonate, and laurate) and two oxidative derivatives (myrtenal and myrtenal oxide) were obtained with a high degree of purity (&gt; 94%, GC). The anti-ulcer preventive effects of the compounds were evaluated in mice at doses ranging from 6.25 to 25 mg per kg of body weight. The mice were treated orally prior to the induction of ethanol-induced gastric lesions. All compounds exerted a gastroprotective effect, reducing the lesion area (mm²) compared to the negative control group. Notably, the gastroprotective effects of myrtenyl caprylate, myrtenyl pelargonate, and myrtenyl laurate were equivalent to those promoted by the clinical medicine pantoprazole.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial Activity, Mechanism, and Future Prospects of Baicalin as an Antimicrobial Agent and Adjuvant","authors":"Guorui Chen,&nbsp;Mingyan Li,&nbsp;Yunliu Zeng,&nbsp;Xueyang Guo,&nbsp;Chenghan Li,&nbsp;Wubin Xu,&nbsp;Fengbin Wu,&nbsp;Linlan Yang,&nbsp;Fuzhou Yang,&nbsp;Dongming Zheng","doi":"10.1002/ardp.70297","DOIUrl":"10.1002/ardp.70297","url":null,"abstract":"<div>\u0000 \u0000 <p>Baicalin is a bioactive flavonoid compound extracted from plants of the <i>Scutellaria</i> genus, such as <i>Scutellaria baicalensis</i>, and exhibits a wide range of pharmacological effects. Studies have shown that it has antibacterial activity against a variety of clinically common pathogens. Meanwhile, it can inhibit the development of antimicrobial resistance, thereby enhancing the antibacterial activity of traditional antibiotics. This highlights the potential of baicalin as an antimicrobial agent and antibiotic adjuvant. This review systematically summarizes the antibacterial activity, antibiofilm effects, beneficial properties, and underlying mechanisms of baicalin, both when used alone and in combination with antibiotics, in <i>in vitro</i> and <i>in vivo</i> models. At the same time, the pharmacokinetic properties and cytotoxicity studies of baicalin were also reviewed. Given its relatively low bioavailability in vivo, the development of baicalin-based nanoformulations and other dosage forms has been highlighted as a promising strategy to enhance its bioavailability and expand its potential applications. Finally, this article discusses the limitations and shortcomings of current research and outlines future research directions. We emphasize the need to evaluate the medication strategies, clinical efficacy, and safety of baicalin in the treatment of microbial infections through higher-quality research. This review aims to provide new insights and references for the further development and clinical application of baicalin.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purine and Pyrrolopyrimidine-Based Small Molecules as Multitarget Therapeutics","authors":"Federica Borghi,&nbsp;Antonio Laus,&nbsp;Claudia Sorbi,&nbsp;Giulio Rastelli","doi":"10.1002/ardp.70296","DOIUrl":"10.1002/ardp.70296","url":null,"abstract":"<p>Purines and pyrrolo[2,3-<i>d</i>]pyrimidines are privileged heterocyclic scaffolds widely represented in small molecules targeting a broad range of therapeutically relevant targets, including kinases, folate-metabolizing enzymes, histone deacetylases (HDACs), bromodomain containing proteins, membrane transporters, phosphodiesterases (PDEs), ion channels, and toll-like receptors (TLRs). While these scaffolds have been extensively investigated in medicinal chemistry, their role in multitarget drug design has received comparatively less attention. This review provides a comprehensive overview of purine- and pyrrolopyrimidine-based compounds reported over the last two decades from a multitarget medicinal chemistry perspective, with particular emphasis on the design principles and SAR underlying simultaneous modulation of multiple biological targets. By systematically comparing compounds across different target classes, we highlight the key structural features responsible for multitarget activity and discuss how specific scaffold modifications influence potency, selectivity, and polypharmacological profiles. Representative examples are presented to illustrate the successful application of these scaffolds in the development of dual- and multitarget inhibitors with promising anticancer, anti-inflammatory, and drug resistance-overcoming activities. Particular attention is devoted to compounds capable of overcoming drug resistance through the simultaneous modulation of complementary biological pathways. Overall, this review provides an integrated medicinal chemistry framework for understanding multitarget purine- and pyrrolopyrimidine-based ligands and identifies emerging opportunities and challenges for the development of next-generation polypharmacological agents.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant TMPRSS6-Protease Regulation of Disease Mutant HCN4–KCNE1 Channel Complex Depends on the KCNE1-G38S Polymorphism","authors":"David Linhoff,&nbsp;Minay Mertens,&nbsp;Ricarda Zimmermann,&nbsp;Stefan Peischard,&nbsp;Christoph Brenker,&nbsp;Thomas Budde,&nbsp;Sven Meuth,&nbsp;Christos Gatsogiannis,&nbsp;Annika Lüttjohann,&nbsp;Liudmila Sosulina,&nbsp;Jürgen Hescheler,&nbsp;Nathalie Strutz-Seebohm,&nbsp;Guiscard Seebohm","doi":"10.1002/ardp.70303","DOIUrl":"10.1002/ardp.70303","url":null,"abstract":"<p>The sinoatrial node pacemaker channel HCN4 plays a central role in cardiac automaticity, and disease-associated variants can predispose to atrial arrhythmias. Here, we investigated the functional interplay between the HCN4 variant P883R and the potassium channel β-subunit KCNE1, focusing on the common atrial fibrillation–associated KCNE1 variant G38S and its regulation by the iron-induced serine protease TMPRSS6. Electrophysiological analyses revealed that HCN4-P883R decreases net HCN4 currents <i>I</i>_f, consistent with impaired automaticity. Co-expression of KCNE1, either wild-type or polymorphic KCNE1-G38S, restored functional properties of the mutant channel, indicating that KCNE1 is a key modulator of HCN4 activity. Importantly, TMPRSS6-mediated proteolytic processing of KCNE1 reduced HCN4 currents, whereas HCN4 expressed alone was insensitive to TMPRSS6, identifying KCNE1 as the direct regulatory target. Notably, KCNE1-G38S altered the HCN4–KCNE1 complex to TMPRSS6-dependent downregulation, resulting in a reduced suppression of HCN4-P883R–mediated currents compared with wild-type KCNE1. Mechanistically, differential TMPRSS6 cleavage depended on the membrane positioning of the KCNE1-³²RRSPRSS³⁸ motif. These findings reveal a protease-dependent buffering mechanism that counteracts HCN4 loss-of-function and establish TMPRSS6 as a molecular switch controlling pacemaker activity in a KCNE1 genotype–dependent manner. This dynamic regulatory framework may contribute to the phenotypic variability of sinoatrial node dysfunction and atrial fibrillation.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medicinal Insights Into FLT3 Inhibitors as Anticancer Agents: Current Status and Future Direction","authors":"Ankush Kumar,&nbsp;Pallvi Kumari,&nbsp;Keshav Raj Paudel,&nbsp;Rajwinder Kaur,&nbsp;Rohit Bhatia","doi":"10.1002/ardp.70302","DOIUrl":"10.1002/ardp.70302","url":null,"abstract":"<p>FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) important for hematopoietic stem cell proliferation, differentiation, and survival. Ligand-induced dimerization activates the downstream pathways such as RAS/MAPK, PI3K/AKT, and STAT5. Mutations such as internal tandem duplications (ITD) and tyrosine kinase domain (TKD) cause constitutive activation, poor prognosis, and driving leukemogenesis in acute myeloid leukemia (AML). Over the past 5 years, FLT3-targeted therapy has advanced significantly. Second-generation FLT3 inhibitors such as gilteritinib and quizartinib displayed improved selectivity and durable efficacy. Quizartinib was approved in 2023 for FLT3-ITD–positive AML alongside intensive chemotherapy. Clinical trials have explored some compounds such as crenolanib, momelotinib, and various novel molecules in combination regimens, which are enhancing remission rates. This review comprehensively compiles diverse chemical scaffolds investigated as FLT3 inhibitors such as pyrimidine, benzimidazole, imidazole, indole, isoxazole, quinazoline, and so on. Structure–activity relationship (SAR) analyses and molecular docking studies are briefly discussed along with highlighting potency against FLT3-ITD and resistant FLT3-TKD mutants. Despite therapeutic gains, resistance through secondary mutations or compensatory pathway activation remains a challenge. Future directions should focus on structure-guided design, rational combination therapies, and expanding applications to other FLT3-altered malignancies. This review integrates updated FLT3 biology, clinical outcomes, medicinal chemistry, and computational insights to support personalized FLT3-targeted treatment strategies.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148402987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Optimization Strategy for α,β-Unsaturated Ketone TrxR Inhibitors: From Enhanced Pharmacokinetics to Improved Tumor Selectivity","authors":"Xinyan Wang,&nbsp;Yanqing Du,&nbsp;Wei Ning,&nbsp;Baojun Shen,&nbsp;Guodong Liang,&nbsp;Yan Zhao,&nbsp;Lu Ga","doi":"10.1002/ardp.70298","DOIUrl":"10.1002/ardp.70298","url":null,"abstract":"<div>\u0000 \u0000 <p>Thioredoxin reductase (TrxR), a master regulator of intracellular redox homeostasis, is a validated antitumor target. <i>α,β</i>-Unsaturated ketones are potent irreversible TrxR inhibitors with robust in vitro anticancer activity, yet their clinical translation is hindered by critical druggability deficits: poor pharmacokinetics (low solubility, metabolic instability, and low bioavailability) and insufficient tumor selectivity (off-target toxicity and weak tumor tropism). This review systematically summarizes structural optimization strategies to address these limitations. To improve pharmacokinetics, core tactics include introducing polar heterocycles/hydrophilic groups, modifying skeletons, replacing labile moieties, and hybridizing pharmacophores with subcellular targeting motifs. To enhance tumor selectivity, electronic effect modulation, lipophilicity tuning, scaffold rigidification, tumor-targeting moiety conjugation, and electrophilic center regulation reduce off-target effects. Additionally, tumor-specific redox properties are harnessed to boost intratumoral enrichment. The review further highlights current limitations (e.g., overreliance on natural product modifications, lack of universal SAR frameworks, and inadequate ADME regulation) and prospects future directions: structure-based rational design, tumor microenvironment-responsive prodrugs, multi-target synergism, reversible-irreversible switchable inhibitors, and nanodelivery integration. Collectively, these optimizations lay a theoretical foundation for developing safe, effective TrxR inhibitors to advance precision cancer therapy.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148402998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Progress and Therapeutic Potential of Indole Hybrids Against Colorectal Cancer","authors":"Danchen Zhao,&nbsp;Kesong Zhu,&nbsp;Jie Mou,&nbsp;Donghong Wang,&nbsp;Xinling Pu,&nbsp;Yu Li,&nbsp;Yafei Zhuang","doi":"10.1002/ardp.70301","DOIUrl":"10.1002/ardp.70301","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) represents one of the most prevalent and lethal malignancies worldwide, with rapidly increasing global incidence and mortality. Current clinical therapies for CRC are severely compromised by tumor metastasis, intrinsic and acquired drug resistance, and unsatisfactory prognosis for advanced patients, highlighting an urgent demand for novel and effective therapeutic candidates. As privileged multifunctional scaffolds, indole hybrids integrate diverse pharmacophores to achieve simultaneous modulation of multiple CRC-associated oncogenic signaling pathways and mutant proteins, enabling them to overcome the limitations of traditional single-target drugs, reduce systemic toxicity, and optimize pharmacokinetic performance. This review comprehensively summarizes the research progress of novel indole hybrids for anti-CRC therapy reported since 2021, excluding indole–pyrimidine and indole–pyridine hybrids covered in previous studies. Notably, among all summarized subclasses, indole–chalcone/chromene, indole–hydroxamic acid/benzamide, and indole–azole hybrids, show the most prominent and promising therapeutic outcomes. These three dominant hybrid categories display potent antiproliferative activity against both drug-sensitive and drug-resistant CRC cell lines, exert robust in vivo tumor growth inhibition in xenograft models, and possess favorable safety profiles with low cytotoxicity to normal cells. We systematically elaborate their key structure–activity relationships, core anti-CRC molecular mechanisms, including cell cycle arrest, apoptosis induction, and targeted pathway regulation, as well as superior preclinical pharmacological characteristics. Furthermore, the current challenges and future research directions for indole hybrid-based anti-CRC drug development are discussed.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"1,2,3-Triazole-Linked Chalcones as Privileged Scaffolds in Anticancer Agents","authors":"Sumeyya Koldas,&nbsp;Guler Yagiz Erdemir,&nbsp;Ahsen Kilic,&nbsp;Neslisah Barlak,&nbsp;Omer Faruk Karatas,&nbsp;Aliye Altundas","doi":"10.1002/ardp.70291","DOIUrl":"10.1002/ardp.70291","url":null,"abstract":"<p>A new series of extended-functionality triazole-substituted chalcone derivatives was synthesized, and their <i>in vitro</i> anti-proliferative and cytotoxic profiles were evaluated using cancer and non-cancer cell models. First, all compounds were screened in the FaDu head and neck squamous cell carcinoma cell line to identify the most active candidates with comparatively lower IC₅₀ values. Compounds <b>6c</b>, <b>6e</b>, and <b>6f</b> reduced FaDu cell viability to 42.62 ± 12.21%, 34.49 ± 4.99%, and 31.13 ± 4.76% of control, respectively. These three compounds also decreased viability of CaCo-2 human colon cancer cells and A549 human lung adenocarcinoma cells, showing micromolar-range activity (IC₅₀ &lt; 50 µM) across cancer cell lines of different origins. To obtain a preliminary indication of selectivity, we additionally tested a non-cancer, immortalized prostate epithelial cell line (PNT1a). In this model, <b>6c</b>/<b>6e</b>/<b>6f</b> displayed relatively lower cytotoxicity than in cancer cells, suggesting a preliminary selectivity window within the tested assay framework. Among them, <b>6f</b> the most active compound in our series—significantly reduced colony formation, comparable to paclitaxel. In apoptosis-related assessments, <b>6f</b> increased apoptosis-associated readouts in cancer cells relative to control, although further confirmation is needed with additional orthogonal assays. Overall, our results identify <b>6c</b>, <b>6e</b>, and especially <b>6f</b> as moderately active lead compounds for further optimization of triazole-chalcone hybrids and support continued structure–activity-guided development to improve potency and selectivity.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 6","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}