Archiv der Pharmazie最新文献

{"title":"Combating Drug-Resistant Protozoal Infections: A Review of Emerging Therapeutics","authors":"Anju A. Tom,&nbsp;Sreya A. Sunilkumar,&nbsp;Ahammed A. Thottasseri,&nbsp;Tharanikkarasu Kannan","doi":"10.1002/ardp.70029","DOIUrl":"https://doi.org/10.1002/ardp.70029","url":null,"abstract":"<div>\u0000 \u0000 <p>Protozoal infections remain a significant global health burden despite significant progress in understanding these infections in recent years due to the continuing emergence of multidrug resistance among protozoal parasites. This review focuses on recent innovations in protozoal disease treatment aimed at combating this growing challenge of drug resistance. The escalating prevalence of multidrug resistance among protozoal parasites, especially those responsible for widespread diseases such as malaria, leishmaniasis, and trypanosomiasis, is rapidly emerging as a grave threat to human health worldwide. This resistance undermines the efficacy of existing treatments, making it imperative to develop and explore novel therapeutic approaches. Diverse strategies, including the concept of hybrid drugs, the development of advanced analogs of existing drugs, and drug repurposing, have been employed to counter drug resistance by outmaneuvering the evolution of resistant parasites and restoring the effectiveness of treatments. In this review, we delve into the significant findings reported between 2020 and 2024, with the aim of providing an overview of the state of protozoal disease treatment, highlighting the progress made, exploring promising avenues for tackling these devastating diseases, and offering insights into future directions for overcoming the persistent challenge of drug resistance. Given that the emergence of drug resistance calls for a multifaceted approach to address protozoal infections, long-term success depends on interdisciplinary research collaborations, equitable access to treatment, and appropriate drug resistance surveillance, in addition to the advancement of research and the development of therapeutic strategies described in this review.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666253","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":"Emerging Coumestans in Cancer Therapy With Mechanistic Insights and Clinical Potential","authors":"MD Tameem Tabbasum,&nbsp;Subashini R","doi":"10.1002/ardp.70058","DOIUrl":"https://doi.org/10.1002/ardp.70058","url":null,"abstract":"<div>\u0000 \u0000 <p>Coumestans are natural phytoestrogens with strong therapeutic potential for inhibiting hormone-induced cancers, such as breast, ovarian, and prostate malignancies. They regulate many signaling pathways, including the PI3K/AKT, MAPK, NF-κB, and JAK/STAT pathways. Challenges regarding the clinical application of coumestans include their poor bioavailability and distribution, rapid metabolic rate, low water solubility, and formulation. This review aims to provide a comprehensive overview of the anticancer mechanisms of a few important coumestan derivatives, namely coumestrol, wedelolactone, isofraxidin, and psoralidin. Methods for increasing the coumestan efficacy via synthetic biology, bioinformatics, and artificial intelligence are described in this review. To bridge the gap between bench to bedside, future directions should focus on emphasizing clinical validation and developing targeted delivery systems to understand the therapeutic potential of coumestans.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666375","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–Activity Relationships of Inactive-Conformation Binding EGFR Inhibitors: Linking the ATP and Allosteric Pockets","authors":"Surbhi P. Chitnis,&nbsp;Florian Wittlinger,&nbsp;Mareike Möllers,&nbsp;Tyler J. Hartman,&nbsp;Marcel Günther,&nbsp;Michael J. Eck,&nbsp;Stefan A. Laufer,&nbsp;David E. Heppner","doi":"10.1002/ardp.70027","DOIUrl":"https://doi.org/10.1002/ardp.70027","url":null,"abstract":"<p>The epidermal growth factor receptor (EGFR) tyrosine kinase is an important therapeutic target in non-small cell lung cancer (NSCLC). However, the continual emergence of resistance mutations in the treatment of EGFR mutation-positive NSCLC with currently approved tyrosine kinase inhibitors warrants the development of next-generation inhibitors. Since research for ATP-competitive EGFR tyrosine kinase inhibitors (TKIs) that extend into the back pocket has been neglected in the recent past, we survey the extent to which such binding functional groups can be incorporated into an ATP-site imidazole scaffold. We find that <i>meta</i>-substituted amide linkers derivatized with fluorine in 2,6-positions and/or a hydroxy group in 3-position of the back pocket phenyl exhibit the highest potency. Structural insights into how the back pocket groups are bound through points of connection provide new directions for the discovery and optimization of inactive conformation targeting agents in EGFR and other kinases.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635173","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":"Eriodictyol and Diosmetin Protective Potential in Skin Infection: Antimicrobial Action, Gene and Molecular Targets, and Keratinocyte Protection Against Bacteria-Induced Damage","authors":"Tamara Carević Milićević,&nbsp;Katarina Novović,&nbsp;Dejan Stojković,&nbsp;Marina Kostić,&nbsp;Eftichia Kritsi,&nbsp;Panagiotis Zoumpoulakis,&nbsp;Marija Ivanov","doi":"10.1002/ardp.70047","DOIUrl":"https://doi.org/10.1002/ardp.70047","url":null,"abstract":"<div>\u0000 \u0000 <p>Eriodictyol and diosmetin are bioactive flavonoids. This study explored their antimicrobial activities and antibiofilm potential along with the effect on pyocyanin and protease production and virulence-linked gene expression, followed by <i>in silico</i> molecular target predictions. Moreover, keratinocytes were used for the evaluation of cytotoxicity and protective antioxidant and anti-inflammatory effects in the infected cells. Both compounds have shown significant antibacterial capacity towards skin pathogens (minimal inhibitory concentrations 0.025–0.2 mg/mL). Their ability to prevent biofilm formation of <i>Pseudomonas aeruginosa</i> was drastic, as well as the impact on other virulence factors, proteases, and pyocyanin production. RT-qPCR determined downregulation of almost all genes examined (<i>lasI</i>, <i>lasR</i>, <i>lasB</i>, <i>rhlI</i>, <i>rhlR</i>, <i>rhlC</i>, <i>pqsH</i>, <i>pqsR</i>, <i>pvdS</i>, <i>pvdF</i>, <i>phzM</i>, and <i>algK</i>), while molecular docking predicted strong binding affinities to the LasI, LasR, PqsR, and QscR quorum-sensing proteins. Moreover, both compounds were not toxic to HaCaT and were able to reduce damage induced by <i>P. aeruginosa</i> in this cell line. Precisely, eriodictyol reduced levels of secreted IL-6 (from 335.32 to 261.76 pg), while both compounds reduced the formation of superoxide. Both eriodictyol and diosmetin displayed remarkable antimicrobial potential while employing a wide array of antimicrobial mechanisms, making them attractive candidates for further assessment and eventual incorporation into novel therapeutic strategies.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635174","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":"PDE4B Inhibition: Exploring the Landscape of Chemistry Behind Specific PDE4B Inhibitors, Drug Design, and Discovery","authors":"Veena Ks,&nbsp;Ashish Sunil Akkewar,&nbsp;Meshram Nikhil Murtikumar,&nbsp;Kalyan K. Sethi","doi":"10.1002/ardp.70030","DOIUrl":"https://doi.org/10.1002/ardp.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Phosphodiesterase 4 (i.e., PDE4A, PDE4B, PDE4C, and PDE4D) is an enzyme group that regulates intracellular cyclic adenosine monophosphate (cAMP) levels, which are involved in multiple physiological activities. PDE4B and PDE4D have closely identical amino acid sequences (~80%) and are highly expressed due to increases in cAMP levels and other factors like hormones, neurotransmitters, <i>etc</i>. Thus, selective PDE4B suppression and discovery of its inhibitors are quite challenging. The PDE4B isoform, highly expressed in inflammatory disorders, cancers, cognitive and metabolic disorders, represents a potential target for therapy and drug discovery. PDE4B inhibition is what produces the positive therapeutic results, whereas nonselective PDE4D inhibition leads to unfavorable side effects. In the realm of modern research, selective PDE4B inhibition is important and ought to be achieved to improve the safety and effectiveness of its inhibitors. This article highlights the advances in the development of selective PDE4BIs during the past decade. The chemical architecture for selective inhibitors includes different functional groups capable of producing the essential interactions with the catalytic domain of PDE4B. The In Silico interaction analysis revealed the importance of PDE4BIs' interaction with the Q (PHE-446 and GLU-443), M (Zn²⁺ and Mg²⁺), and S pockets, along with the CR3 domain of the enzyme. Additionally, a few of the natural products and their derivatives are also being explored as PDE4BIs. Dual activities of the PDE4BIs, i.e., PDE4B inhibition along with TRPA1 and M₃ inhibition and β₂ activation, are the future perspective for the treatment of inflammatory diseases like psoriasis, chronic obstructive pulmonary disease (COPD), asthma, autoimmune disorders, etc.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615208","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":"Nature-Inspired Compounds Targeting Escherichia coli WrbA as Biofilm-Modulating Agents: Computational Design, Synthesis, and Biological Evaluation","authors":"Matteo Mori,&nbsp;Enrico Mario Alessandro Fassi,&nbsp;Federica Villa,&nbsp;Erica Ginevra Milano,&nbsp;Fabio Forlani,&nbsp;Francesca Cappitelli,&nbsp;Alessandro Ratti,&nbsp;Fiorella Meneghetti,&nbsp;Gabriella Roda,&nbsp;Giovanni Grazioso,&nbsp;Stefania Villa","doi":"10.1002/ardp.70049","DOIUrl":"https://doi.org/10.1002/ardp.70049","url":null,"abstract":"<p>Biofilms pose significant challenges in multiple settings due to their resistance to conventional treatments. In this study, we designed and synthesized a novel class of nature-inspired 5,7-dihydroxy-2,2-dimethylchroman-4-one derivatives as binders of WrbA, a potential target for biofilm modulation. Using a structure-based computational approach, a small library of analogs with varied amide moieties was developed and synthesized. The evaluation of their binding affinity to WrbA demonstrated good-to-excellent <i>K</i>_d values, as confirmed by microscale thermophoresis (MST). Antibiofilm assays against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i> revealed different modulating effects on biofilm formation, conceivably linked to ROS production. These findings emphasize the importance of ROS levels in biofilm, as well as the pivotal role of WrbA as a target in its regulation.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"358 7","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598543","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":"2-Propyl-3-Aminoquinazoline-4(3H)-one Derivatives as Potential Androgen Receptor Inhibitors: Synthesis and Cytotoxicity Against PC3 Cell Line via In Vitro and In Silico Studies","authors":"Halil Şenol,&nbsp;Furkan Çakır,&nbsp;Şeyma Ateşoğlu,&nbsp;Pelin Tokalı,&nbsp;Ayşe Merve Şenol,&nbsp;Fahri Akbaş,&nbsp;Feyzi Sinan Tokalı","doi":"10.1002/ardp.70048","DOIUrl":"https://doi.org/10.1002/ardp.70048","url":null,"abstract":"<div>\u0000 \u0000 <p>Twenty-one novel quinazolin-4(3<i>H</i>)-one derivatives were synthesized and evaluated for their cytotoxic effects against the PC3 prostate cancer cell line. Structural characterization was performed using FTIR, NMR, and HRMS spectroscopy. Cytotoxicity assays revealed that compound <b>1</b> exhibited the highest potency (IC₅₀ = 4.29 ± 0.32 µM) and selectivity (SI = 20.1) against PC3 cells, surpassing the reference drug sorafenib. Compounds <b>10</b> and <b>11</b> also demonstrated significant selectivity (SI = 12.7 and 12.4, respectively), making them promising candidates for further investigation. Molecular docking studies confirmed strong binding affinities to the androgen receptor (AR), with compound <b>1</b> displaying the most favorable interaction (IFD Glide Score = −15.137 kcal/mol, MM-GBSA = –72.11 kcal/mol). MD simulations further supported the stability of compound <b>1</b> within the receptor binding site, highlighting key hydrogen bonding and π–π stacking interactions. ADME predictions indicated favorable pharmacokinetic properties, with all active compounds complying with drug-likeness criteria and exhibiting high oral absorption. Overall, these findings suggest that quinazolinone derivatives, particularly compound <b>1</b>, hold significant potential as selective anticancer agents targeting prostate cancer.</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":"144589609","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":"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}