Archiv der Pharmazie最新文献

{"title":"Click Chemistry-Aided Synthesis of Triazole-Tethered Benzothiazoles as Novel Multifunctional Agents Against Alzheimer's Disease","authors":"Mostafa M. Elbadawi,&nbsp;Abdullah A. Elgazar,&nbsp;Ahmed A. Hefny,&nbsp;Maha-Hamadien Abdulla,&nbsp;Thamer bin Traiki,&nbsp;Eslam Roshdy,&nbsp;Mohammad M. Al-Sanea,&nbsp;Manabu Abe,&nbsp;Wagdy M. Eldehna,&nbsp;Praveen P. N. Rao,&nbsp;Abdelrahman Hamdi","doi":"10.1002/ardp.70046","DOIUrl":"https://doi.org/10.1002/ardp.70046","url":null,"abstract":"<div>\u0000 \u0000 <p>In the current medical era, Alzheimer's disease (AD) stands as a challenging multifaceted neurodegenerative disorder characterized by diverse pathological features that necessitate the development of multi-target directed ligands (MTDLs) as a promising therapeutic approach. This study reports the design and synthesis of triazole-tethered benzothiazole derivatives (<b>10a–r</b> and <b>11a–e</b>) as MTDLs for AD. These molecules have been evaluated for their potential to inhibit cholinesterases, amyloid-β (Aβ) aggregation, and their reactive oxygen species (ROS) scavenging ability. Benzothiazoles <b>10f</b>, <b>10l</b>, and <b>11c</b> exhibited good inhibition of human acetylcholinesterase (<i>h</i>AChE) with IC₅₀ values of 100, 110, and 140 nM, respectively, and were better than tacrine (IC₅₀ = 160 nM). Furthermore, they inhibited Aβ42 aggregation with percent inhibition of 49.4%, 45.1%, and 39.3%, respectively. It should be emphasized that the most potent <i>h</i>AChE and Aβ42 dual inhibitors, <b>10f</b> and <b>10l</b>, displayed efficient antioxidant activities (57.2% and 47.5%, respectively) and were better than resveratrol (40.8%). Noteworthy, the developed molecules were not cytotoxic to mouse hippocampal neuronal cells (HT22) at 25 µM, with cell viability ranging from 79.2% to 113.3%, highlighting their potential to be considered as novel scaffolds for CNS drug development. A molecular docking study proposed that <b>10f</b> and <b>10l</b> interacted with both the catalytic and peripheral active sites of <i>h</i>AChE similar to donepezil and displayed favorable binding. Also, the docking study suggested the binding mode of <b>10f</b> to Aβ40 and Aβ42. These results show that benzothiazoles <b>10f</b> and <b>10l</b> are promising candidates for the development of novel MTDLs for the effective management of AD.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598723","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":"Synthesis, Anti-Alzheimer Evaluation and In Silico Study of 4-Methoxyphenyl)Sulfonyl Indole Hybrid Thiosemicarbazones","authors":"Uzma Ghaffar,&nbsp;Zahra Batool,&nbsp;Mussarat Tasleem,&nbsp;Nastaran Sadeghian,&nbsp;Parham Taslimi,&nbsp;Suraj N. Mali,&nbsp;Kholood A. Dahlous,&nbsp;Rahul D. Jawarkar,&nbsp;Shailesh S. Gurav,&nbsp;Xianliang Zhao,&nbsp;Iqra Munir,&nbsp;Zahid Shafiq","doi":"10.1002/ardp.70034","DOIUrl":"https://doi.org/10.1002/ardp.70034","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a multifaceted neurological disorder linked to behavioral, psychological, and language abnormalities as well as memory loss. A series of 1-[(4-methoxyphenyl)sulfonyl]−1<i>H</i>-indole-3-carbaldehyde-based thiosemicarbazones <b>5(a–v)</b> had been synthesized and screened for their potential against AD. The compounds were tested for their inhibitory effects against cholinesterases (AChE and BChE) and monoamine oxidase A (MAO-A). Compounds <b>5l</b>, <b>5v</b>, and <b>5r</b> showed remarkable activity on AChE, BChE, and MAO-A enzymes, having IC₅₀ values ranging between 1.57 and 4.56 nM (<i>K</i>_i = 1.43 ± 0.44 to 3.43 ± 0.21 nM), between 25.68 and 35.06 nM (<i>K</i>_i = 22.53 ± 7.70 to 34.82 ± 2.32 nM), and between 22.98 and 27.23 nM, respectively. Compound <b>5l</b> with trifluoromethyl substitution at the 3 and 5 positions was the most effective derivative of AChE and BChE, having <i>K</i>_i values of 1.43 ± 0.44 nM and 22.53 ± 7.70 nM, respectively. Compound <b>5v</b> with chloro substitution at the 2 and 6 positions of the phenyl ring was the most potent inhibitor of MAO-A, with IC₅₀ values of 22.98 nM. Structure–activity analysis exhibited that the electron-withdrawing substituents and di-substitution on the phenyl ring play a significant role in the inhibition potential of synthesized compounds. The most effective inhibitors’ binding interactions with the active sites of AChE, BChE, and MAO-A were described via molecular docking studies. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598724","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":"Rational Design, Green Synthesis, and Biological Evaluation of Novel Imidazole Derivatives as Potent EGFR Inhibitors via One-Pot Four-Component Reaction","authors":"Alaa Muqbil Alsirhani,&nbsp;Ibtisam Aali,&nbsp;Modather F. Hussein,&nbsp;Nadia A. A. Elkanzi,&nbsp;Ali M. Ali,&nbsp;Moustafa O. Aboelez","doi":"10.1002/ardp.70044","DOIUrl":"https://doi.org/10.1002/ardp.70044","url":null,"abstract":"<div>\u0000 \u0000 <p>This study reports a green, efficient, and high-yielding synthesis of novel imidazole derivatives <b>5a</b>–<b>i</b> via a one-pot, four-component reaction under microwave irradiation. The optimized protocol demonstrates satisfactory yields (86%–92%), short reaction times (9–14 min), easy workup, and avoidance of toxic solvents, in accordance with sustainable chemistry principles. The antiproliferative efficacy of derivatives <b>5a</b>–<b>i</b> was evaluated against H1975, A549, and A431 cells, using the MTT assay. The results indicated that derivatives <b>5b</b> and <b>5g</b> exhibited the greatest antiproliferative activity, with IC₅₀ values of 5.22 and 6.34 µM. The values obtained were markedly inferior to those of recognized EGFR inhibitors, such as osimertinib, gefitinib, and erlotinib. Compound <b>5b</b> was exhibited as the most potent inhibitor of both EGFR^WT and EGFR^T790M kinases, with IC₅₀ values of 30.1 and 12.8 nM, respectively. The findings exceeded those of osimertinib and gefitinib, which demonstrated IC₅₀ values of 54.3, 19.1, 9.1, and 356.8 nM, respectively, which may explain its notable antiproliferative effect against the H1975 cell line. Molecular docking and dynamics simulations confirmed the stable binding of derivatives <b>5b</b> and <b>5g</b> within the EGFR active sites, aligning with experimental findings. Furthermore, in silico ADME properties for the promising EGFR inhibitors <b>5b</b> and <b>5g</b>, conducted using the egg-boiled technique, demonstrated favorable lipophilicity, G.I.T. absorption, and BBB permeability. As a result, imidazoles <b>5a–i</b>, particularly <b>5b</b> and <b>5g</b>, exhibited promising antiproliferative properties, targeting EGFR^WT and EGFR^T790M kinase inhibitors.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598772","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":"Filtering of Active Components of Fuzi Lizhong Decoction on Gastric Ulcer by UHPLC/Q-Exactive MS Uniting Network Pharmacology","authors":"Haijun Wang,&nbsp;Yang Yu,&nbsp;Kaichen Yu,&nbsp;Qingzhu Yang,&nbsp;Ming Zhao,&nbsp;Yang Xin","doi":"10.1002/ardp.70036","DOIUrl":"https://doi.org/10.1002/ardp.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>To filter the active components of Fuzi Lizhong decoction (FLD) treating gastric ulcer (GU), compound information of herbs making up FLD was collected. Components in FLD extract were identified using ultrahigh performance liquid chromatography coupled with quadrupole-exactive orbitrap mass spectrometry (UHPLC/Q-Exactive MS). After that, network pharmacology and molecular docking were applied for predicting active components. Next, GES-1 cell survival rate experiments were conducted to verify the active components. At last, real-time fluorescent quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was applied to confirm active components. Results showed that a total of 58 components in FLD were qualified and 55 of them functioned on 310 GU-relevant targets, involved in 154 signaling pathways. Through molecular docking of the top 30 components with the top 30 targets and referring to the reference, 9 components and their targets were predicted to be active components. Among them, atractylenolide II, tyrosine, and atractylenolide III were verified to inhibit GES-1 cell apoptosis, confirmed to reverse the gene expression of GU-relevant targets involving <i>PPARG</i>, <i>EGFR</i>, <i>MAPK1</i>, and <i>ESR1</i> in GES-1 cells. So, atractylenolide II, tyrosine, and atractylenolide III were considered as active components of FLD treating GU. In conclusion, active components of FLD treating GU were filtered by applying UHPLC/Q-Exactive MS, uniting network pharmacology with the assistance of molecular docking and RT-qPCR. FLD might exert anti-GU effect through atractylenolide II, tyrosine, and atractylenolide III functioning as the relevant targets.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582149","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":"Structural Optimizations on the Scaffold of 7H-Pyrrolo[2,3-d]Pyrimidine to Develop Potent iNOS Inhibitors With Improved Antiarthritis Activity In Vivo","authors":"Wenchu Wang,&nbsp;Tingsheng Qin,&nbsp;Xianjing Feng,&nbsp;Mengyang Xu,&nbsp;Zhen Ling,&nbsp;Xin Xie,&nbsp;Min Zhang,&nbsp;Yanqin Huang,&nbsp;Jiayuan Luo,&nbsp;Sisi Cao,&nbsp;Xiaoyang Yue,&nbsp;Jie Zhang,&nbsp;Fengyuan Deng,&nbsp;Linhong He","doi":"10.1002/ardp.70038","DOIUrl":"https://doi.org/10.1002/ardp.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Inducible nitric oxide synthase (iNOS) is an attractive target to develop drugs for the treatment of rheumatoid arthritis (RA), whose overexpression leads to the release of abundant NO. In this study, a series of compounds were designed and synthesized bearing the scaffold of 7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidine to improve CLogP values and in vivo anti-inflammatory activity via molecular hybridization, whose derivatives in a previous study demonstrated good inhibition toward NO production but high CLogP values and weak potency in vivo. Among them, <b>N3b</b> effectively suppressed NO production in a concentration-dependent manner (IC₅₀ = 4.66 ± 0.19 μM) in LPS-induced RAW264.7 cells. Mechanically, <b>N3b</b> mildly inhibited the protein expression of iNOS (IC₅₀ = 13.60 ± 0.39 μM), without remarkable influence on the mRNA levels of iNOS or other classical pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α at the high concentration of 30 µM. With favorable drug-likeness, <b>N3b</b> significantly alleviated paw edema at the dose of 30 mg/kg in the acute inflammation model and mitigated paw swelling and joint damage at a dosage of 10 mg/kg in the chronic arthritis model. Furthermore, <b>N3b</b> did not cause any obvious weight loss and pathological changes of important organs in treated mice, indicating that <b>N3b</b> is a potent candidate iNOS inhibitor for the treatment of RA.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582037","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":"Exploring the SAR of 1,2,3-Triazoles as Tumor-Associated Carbonic Anhydrases IX and XII Inhibitors for Anticancer Applications","authors":"Naveen Chauhan,&nbsp;Neelam Yadav,&nbsp;Prince Kumar,&nbsp;Suresh Kumar,&nbsp;Ranjana Aggarwal","doi":"10.1002/ardp.70041","DOIUrl":"https://doi.org/10.1002/ardp.70041","url":null,"abstract":"<div>\u0000 \u0000 <p>The search for novel anticancer agents has brought carbonic anhydrase (CA) isoforms IX and XII into focus due to their critical role in tumor growth and survival, particularly under hypoxic conditions. These tumor-associated enzymes regulate pH and ion transport in cancer cells, making them attractive therapeutic targets. Among the compounds explored as CA inhibitors, 1,2,3-triazoles stand out for their versatile CA inhibition potential and favorable pharmacokinetic properties. 1,2,3-triazole scaffold, easily synthesized via click reactions, offers a promising framework for developing selective inhibitors against CA IX and XII. Recent research highlights the anticancer potential of 1,2,3-triazole derivatives, which selectively inhibit these isoforms, impairing tumor microenvironment regulation and thus enhancing cancer treatment efficacy. The present review explores the structure–activity relationships (SAR) of 1,2,3-triazole scaffolds as tumor-associated CA IX and XII inhibitors. We provide insights into their design and therapeutic potential by examining key structural modifications that enhance potency and selectivity. This comprehensive analysis aims to guide the future development of 1,2,3-triazole-based CA inhibitors for use as antitumor agents.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582294","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":"Structure Characterization and Antibacterial, Antifungal, and Antiquorum-Sensing Activity of New Metabolites From the Lipophilic Fractions of Platycodon grandiflorum Root","authors":"Hyukbean Kwon,&nbsp;Jimin Moon,&nbsp;Jeong-Hyeon Kim,&nbsp;Prima F. Hillman,&nbsp;Silviani Velina,&nbsp;Joo-Won Nam,&nbsp;Sang-Jip Nam,&nbsp;Inho Choi,&nbsp;Kyung Sik Song,&nbsp;Geum Jin Kim,&nbsp;Hyukjae Choi","doi":"10.1002/ardp.70043","DOIUrl":"https://doi.org/10.1002/ardp.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>The root of <i>Platycodon grandiflorum</i> has long been used as a vegetable and traditional medicine. Although the antibacterial activity of the plant's lipophilic (hexanes and dichloromethane) fractions has been reported, the specific antibacterial compounds have not been identified. In this study, chemical analysis of the lipophilic fractions of <i>P. grandiflorum</i> extracts led to the discovery of five new polyacetylenes (<b>1</b>–<b>5</b>) and nine known compounds (<b>6</b>–<b>14</b>). Their structures were elucidated and confirmed based on 1D and 2D NMR data together with mass spectra. In particular, the relative and absolute configurations of <b>1</b> were elucidated by coupling constants, NOESY and <i>J</i>-based configurational analysis in combination with Mosher's method. Compounds <b>1</b> and <b>2</b> demonstrated strong antifungal activity against <i>Candida albicans</i>. Additionally, compound <b>1</b> significantly inhibited quorum sensing in <i>Chromobacterium violaceum</i>, a commonly used biosensor strain. Compounds <b>2</b> and <b>14</b> also exhibited mild inhibitory activity. Compounds <b>8</b> and <b>12</b>–<b>14</b> exhibited potent antibacterial activity against <i>Escherichia coli</i>, <i>Kocuria rhizophila</i>, and <i>Staphylococcus aureus</i>, as well as antifungal activity against <i>Candida albicans</i>. These compounds may be responsible of the antimicrobial activity of <i>P. grandiflorum</i>.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582148","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":"Novel Purine-Based Natural Products as Inhibitors of Cholinesterases and Monoamine Oxidases Presenting Potential Multitarget Therapeutics Tackling Alzheimer's Disease","authors":"Amira E. Shaaban,&nbsp;Ahmed R. Ali,&nbsp;Seif N. Ayyad,&nbsp;Farid A. Badria","doi":"10.1002/ardp.70035","DOIUrl":"https://doi.org/10.1002/ardp.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) is a complex neurological disorder that arises from multiple factors. The innovative multitarget-directed ligand (MTDL) approach, which incorporates multiple pharmacophores into one molecule, enhances the development of effective therapeutics for AD. Eighteen novel natural product-based purine MTDLs were synthesized. These hybrids were evaluated In Vitro for their inhibitory effects on AChE, BChE, MAO-A, and MAO-B. The findings revealed that most hybrids effectively and selectively inhibited AChE. Hybrid <b>9b</b> demonstrated the highest inhibitory potency against AChE, BChE, MAO-A, and MAO-B, exhibiting IC₅₀ values of 5.52, 11.64, 25.99, and 34.78 µM, respectively. In addition, hybrid <b>9b</b> exhibited interesting antioxidant activity, with an IC₅₀ of 6.69 µM. The mechanism of action and the binding modes of hybrid <b>9b</b> were analyzed through molecular docking studies. Molecular dynamics simulation revealed that hybrid <b>9b</b> is stable within the AChE active site. In Silico assessments of physicochemical properties for hybrid <b>9b</b> indicate that it is well absorbed following oral administration and can penetrate brain tissue. Finally, hybrid <b>9b</b> stability studies in simulated gastric and intestinal conditions suggested that it could be absorbed into the bloodstream without significant degradation. Consequently, these findings reinforce the potential therapeutic applications of hybrid <b>9b</b> as a multifunctional therapeutic candidate for addressing AD.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582147","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":"DCAF16-Based Covalent Molecular Glues for Targeted Protein Degradation of Histone Deacetylases","authors":"Tao Sun,&nbsp;Shiyang Zhai,&nbsp;Stephan Lepper,&nbsp;Beate König,&nbsp;Mateo Malenica,&nbsp;Irina Honin,&nbsp;Finn K. Hansen","doi":"10.1002/ardp.70045","DOIUrl":"https://doi.org/10.1002/ardp.70045","url":null,"abstract":"<p>Histone deacetylases (HDACs) are intriguing cancer targets due to their high expression in many tumors. Consequently, inhibition or degradation of HDACs can be beneficial for cancer therapy. Targeted protein degradation using molecular glues represents a promising therapeutic approach, enabling the specific degradation of numerous disease-causing proteins. However, the rational design of molecular glues in a target-based manner remains challenging. A recent study has described the identification of a DCAF16-based covalent linker-less chemical handle for molecular glues. This covalent warhead can be attached to protein of interest ligands to induce the targeted degradation of various protein classes. Inspired by this, we designed and synthesized a new class of DCAF16-based covalent molecular glues utilizing different zinc-binding groups for the targeted degradation of HDACs. This approach led to the discovery of an efficient molecular glue (<b>10a</b>) that reduced HDAC1 levels in multiple myeloma MM.1S cells in a potent and preferential manner.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582146","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":"Combining Cyclic Triimidazo Triazine Core With Ethynyl-N-Methyl-Pyridinium Groups for Targeting G-Quadruplex Structures","authors":"Chiara Platella,&nbsp;Stefano Di Ciolo,&nbsp;Andrea Criscuolo,&nbsp;Daniele Malpicci,&nbsp;Rosa Gaglione,&nbsp;Angela Arciello,&nbsp;Domenica Musumeci,&nbsp;Elena Lucenti,&nbsp;Elena Cariati,&nbsp;Daniela Montesarchio,&nbsp;Clelia Giannini","doi":"10.1002/ardp.70037","DOIUrl":"https://doi.org/10.1002/ardp.70037","url":null,"abstract":"<p>The synthesis and characterization of a mini-library of cyclic triimidazo triazine (<b>TT</b>) derivatives functionalized with one, two, or three ethynyl-<i>N</i>-methyl-pyridinium moieties are reported here. These compounds were designed with the aim of targeting cancer-related DNA G-quadruplex structures. The newly synthesized compounds were tested for their ability to bind G-quadruplexes from both telomeric and oncogene promoter sequences using an affinity chromatography-based assay, spectroscopic and electrophoretic techniques, as well as molecular docking analysis. The obtained results demonstrated the effective capacity of the investigated compounds to specifically recognize the selected G-quadruplex models, with their <b>TT</b> cores targeting the outer G-quartets and their positively charged <i>N</i>-methyl-pyridinium groups interacting with the top edge of G-quadruplex grooves. Notably, the trisubstituted cyclic triimidazole compounds showed higher stabilizing properties than the related disubstituted derivatives, which in turn were stronger binders than their monosubstituted analogs. However, the mono- and disubstituted derivatives showed higher G-quadruplex versus duplex recognition selectivity compared with the trisubstituted ones. Altogether, the biophysical experiments, also in agreement with the biological assays, underlined the advantage of introducing an alkyne linker between the triimidazole core and the methylpyridinium group, proving to be beneficial to increase both the stabilizing effects on the G-quadruplexes and the anticancer activity compared with the analogs of the same family lacking the alkyne linker.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537052","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}