IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-05 DOI: 10.1002/cmdc.70560

Chahrazed Benzaid, Abdeslem Bouzina, Rachida Mansouri, Manel Lina Djendi, Yousra Ouafa Bouone, Abir Ramoul, Lina Raghad Klaiaia

{"title":"Molecular Dynamics and Density Functional Theory Analysis of Novel Acridine Derivatives Targeting Bacterial Topoisomerase IV","authors":"Chahrazed Benzaid, Abdeslem Bouzina, Rachida Mansouri, Manel Lina Djendi, Yousra Ouafa Bouone, Abir Ramoul, Lina Raghad Klaiaia","doi":"10.1002/cmdc.70560","DOIUrl":"10.1002/cmdc.70560","url":null,"abstract":"A series of nine 9-substituted acridine derivatives was prepared by a catalyst-free microwave-assisted method and evaluated for antibacterial, antibiofilm, antioxidant, antihemolytic, and urease-inhibitory activities. Compounds A2 and A3 displayed the strongest antibacterial effects against both Gram-positive and Gram-negative bacteria, including selected clinical and references isolates (MIC = 31.25–500 µg mL−1). Compound A7 exhibited the highest antibiofilm activity and the most potent urease inhibition against jack bean and Helicobacter pylori ureases (IC50 = 97.3 ± 1.89 and 156.2 ± 2.41 µg mL−1, respectively). A5 showed the best DPPH radical-scavenging capacity, while A1, A5, A7, and A9 produced marked antihemolytic effects. Molecular docking against Escherichia coli topoisomerase IV and xanthine oxidase, followed by a 300 ns molecular dynamics simulation of the A7–topoisomerase IV complex, provided structural hypotheses consistent with the experimental data. DFT calculations further indicated favorable electronic properties for selected derivatives. Overall, A7 emerges as a promising acridine scaffold for further structural optimization and experimental target validation.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149331835","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}

引用次数: 0

Stimuli-Responsive Hydrogels for Cancer Therapy: Design Strategies, Mechanisms, and Challenges in Clinical Translation 刺激反应水凝胶用于癌症治疗：设计策略、机制和临床转化中的挑战。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-05 DOI: 10.1002/cmdc.70552

Negar Paknia, Hadis Soltanimehr, Hadieh Rahbar Kafshboran, Soheila Ghasemi

{"title":"Stimuli-Responsive Hydrogels for Cancer Therapy: Design Strategies, Mechanisms, and Challenges in Clinical Translation","authors":"Negar Paknia, Hadis Soltanimehr, Hadieh Rahbar Kafshboran, Soheila Ghasemi","doi":"10.1002/cmdc.70552","DOIUrl":"10.1002/cmdc.70552","url":null,"abstract":"Stimuli-responsive hydrogels (SRHs) are versatile soft biomaterials capable of dynamically responding to environmental cues, enabling controlled and site-specific drug release for cancer therapy. Advances in polymer chemistry and nanotechnology have facilitated the development of SRHs that respond to tumor-associated stimuli, including pH, redox potential, temperature, enzymatic activity, light, and glucose gradients. Among these systems, pH- and redox-responsive hydrogels exploit the acidic and oxidative tumor microenvironment, while thermo- and photo-responsive platforms enable spatiotemporal regulation of therapeutic payloads. Recent studies have demonstrated highly efficient, stimulus-triggered drug release and enhanced therapeutic outcomes in vitro and in vivo. This review systematically examines the design strategies, molecular mechanisms, and structure–function relationships governing SRHs in oncology. Emerging hydrogel architectures—such as injectable systems, hybrid nanocomposites, and multifunctional platforms integrating targeting or imaging capabilities—are critically discussed. Importantly, the review addresses key challenges in clinical translation, including biocompatibility, scalability, regulatory considerations, and reproducibility. Finally, future perspectives are outlined, highlighting the potential of artificial intelligence-assisted material design, computational modeling, and wearable or implantable bioelectronic interfaces for real-time monitoring and adaptive cancer therapy. By integrating mechanistic insights with translational and regulatory viewpoints, this review aims to guide the rational development of next-generation smart hydrogel therapeutics for clinical oncology.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149339964","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}

引用次数: 0

From Generative Molecular Design to Agentic Artificial Intelligence in Drug Discovery 从生成分子设计到药物发现中的人工智能。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-05 DOI: 10.1002/cmdc.70564

Andrea Mastropietro, Jürgen Bajorath

引用次数: 0

What Method and Library Size Is Best for Fragment Screening? 片段筛选的最佳方法和文库大小是什么？

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-03 DOI: 10.1002/cmdc.70503

Stephen W. Fesik

引用次数: 0

Tandem Cyclization–Ring Opening of Chromenylamidines: A Direct Route to Pyrido[2,3‍-‍d]pyrimidin-4(1H)-Ones With Anticancer Activity 串联环化-开环：通往吡啶的直接途径[2,3‍-‍d]具有抗癌活性的嘧啶-4(1H)- 1。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-03 DOI: 10.1002/cmdc.70540

Fábio P. Lima, Mónica Cerqueira, Ana Silva, Beatriz Sousa, Mariana G. Coelho, Julieta Afonso, Fátima Baltazar, Marta Costa, Fernanda Proença

引用次数: 0

Amino Acid Functionalization Influences the Binding of Thiophene-Vinylene-Benzothiazolium-Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer’s Disease Pathology 氨基酸功能化影响阿尔茨海默病病理组织切片中噻吩-乙烯基-苯并噻唑基荧光配体与蛋白质沉积物的结合

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-11-03 DOI: 10.1002/cmdc.70558

Linnea Björk, Ruben Vidal, Bernardino Ghetti, Mikael Lindgren, Therése Klingstedt, K. Peter R. Nilsson

{"title":"Amino Acid Functionalization Influences the Binding of Thiophene-Vinylene-Benzothiazolium-Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer’s Disease Pathology","authors":"Linnea Björk, Ruben Vidal, Bernardino Ghetti, Mikael Lindgren, Therése Klingstedt, K. Peter R. Nilsson","doi":"10.1002/cmdc.70558","DOIUrl":"10.1002/cmdc.70558","url":null,"abstract":"Detecting and distinguishing between structurally diverse protein aggregates involved in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), remain key challenges in the development of molecular imaging tools. Recently, bi-thiophene-vinyl-benzothiazoliums (bTVBTs), a class of thiophene-based optical ligands, were synthesized and shown to enable selective labeling of tau pathology in AD brain tissue. Building on this framework, we report here the design and evaluation of a novel series of bTVBT ligands functionalized with L-amino acids (glycine, alanine, valine, tyrosine, or glutamate) to explore their influence on ligand–filament interactions. When applied to sporadic AD brain tissue sections, the ligands displayed preferential binding to tau deposits when using 100 nM ligand, whereas all ligands bound to both amyloid-β (Aβ) and tau aggregates at higher concentrations. The glycine-functionalized bTVBT scaffold demonstrated the strongest fluorescence upon binding and was labeling all types of tau inclusions present in sAD brain tissue, whereas the glutamate-functionalized ligand was the least potent. Thus, the chemical nature of the amino acid influenced the binding mode of the ligand to protein deposits. The observed trend in the ligands’ binding mode to the protein aggregates could also be correlated with distinct solvatochromic effects, indicating that certain amino acid side chains interfere with favorable interligand π–π stacking, thereby reducing binding specificity. Collectively, these results pinpoint that minor chemical alterations of the bTVBT scaffold influence the binding mode of the ligands to protein deposits, and we foresee that our findings will aid in designing ligands targeting proteinaceous aggregated species in AD and related neurodegenerative diseases.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13731923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316448","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}

引用次数: 0

Drug Discovery for Snakebite Envenoming: Wanderings Amid Historical Antidotes and Emerging Therapeutic Opportunities 蛇咬伤的药物发现：在历史解毒剂和新出现的治疗机会中徘徊

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-31 DOI: 10.1002/cmdc.70478

Elisa Bianconi, Emidio Camaioni, Paulina Oszajca, Antonio Macchiarulo

{"title":"Drug Discovery for Snakebite Envenoming: Wanderings Amid Historical Antidotes and Emerging Therapeutic Opportunities","authors":"Elisa Bianconi, Emidio Camaioni, Paulina Oszajca, Antonio Macchiarulo","doi":"10.1002/cmdc.70478","DOIUrl":"https://doi.org/10.1002/cmdc.70478","url":null,"abstract":"Snakebite envenoming is acknowledged as neglected tropical disease affecting populations of regions with limited access to healthcare systems. However, it had posed a major threat to human health since classical antiquity, when plant- and animal-based remedies were extensively used as antidotes to counteract bites by venomous snakes. Although the provision of safe and effective treatments by 2030 is among the strategic objectives of the World Health Organization, clinically approved therapies currently available remain animal-derived polyclonal antibodies, which suffer from significant limitations, including high production costs, limited cross-species efficacy, and risk of adverse immune reactions. In this review, we survey some historical antidotes used to treat snakebite envenoming in classical antiquity and early modern Europe such as theriac, mithridatum, Orvietan and Mattioli's scorpion oil. We then discuss natural compounds that, while found also as active ingredients in medical plants used for the preparation of the historical antidotes, over the last decades have inspired research efforts aimed at characterizing their evidence-based antivenom activity with the aim of offering potential alternatives to biologic-based therapies. Finally, we outline emerging therapeutic opportunities that, arising from drug repurposing efforts, may pave the way for the development of novel, broadly effective therapies against multiple venomous snake species.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.70478","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149312787","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}

引用次数: 0

Morpholine-Based Chalcones as Potent and Selective MAO-B Inhibitors With Preliminary CNS Drug-Like Properties 基于吗啡的查尔酮是一种有效的选择性MAO-B抑制剂，具有初步的中枢神经系统药物样特性。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-30 DOI: 10.1002/cmdc.70515

Asmar Taghiyeva, Jaeyeop Lim, Abanish Biswas, Subodh Mondal, Ritika Uppal Mukherjee, Vinay N. Basavanakatti, Nilüfer Bayrak, Venkatesan Jayaprakash, Man-Jeong Paik, Hoon Kim, Amaç Fatih TuYuN

{"title":"Morpholine-Based Chalcones as Potent and Selective MAO-B Inhibitors With Preliminary CNS Drug-Like Properties","authors":"Asmar Taghiyeva, Jaeyeop Lim, Abanish Biswas, Subodh Mondal, Ritika Uppal Mukherjee, Vinay N. Basavanakatti, Nilüfer Bayrak, Venkatesan Jayaprakash, Man-Jeong Paik, Hoon Kim, Amaç Fatih TuYuN","doi":"10.1002/cmdc.70515","DOIUrl":"10.1002/cmdc.70515","url":null,"abstract":"A series of morpholine-based chalcone derivatives containing alkoxy substituents was designed and synthesized using a rapid and environmentally friendly microwave-assisted protocol. The synthesized compounds were fully characterised by NMR, FTIR, and HRMS analyses and evaluated in vitro against primarily monoamine oxidases, as well as acetylcholinesterase, butyrylcholinesterase, and β-site amyloid precursor protein cleaving enzyme 1, which are closely associated with neurodegenerative disorders. Although most compounds showed weak inhibition of AChE, BChE, and BACE1, they exhibited potent and selective MAO-B inhibitory activity. Among them, MBC21 emerged as the most potent MAO-B inhibitor (IC50 = 0.069 ± 0.0075 μM; SI 243.33), acting as a competitive and reversible inhibitor. In addition, MBC1, MBC2, and MBC24 displayed notable BChE inhibitory activity, while MBC24 demonstrated multi-target activity against MAO-B, AChE, and BChE. Molecular docking and molecular dynamics simulations revealed that the selectivity of MBC21 towards hMAO-B is associated with stable hydrophobic interactions and π–π stacking with TYR326. Furthermore, in silico ADME prediction, microsomal stability, and PAMPA-BBB studies demonstrated favorable drug-like properties, improved metabolic stability, and moderate brain permeability for MBC21. Taken together, these findings identify MBCs, particularly MBC21, as promising lead candidates for the development of selective MAO-B inhibitors for neurodegenerative disease therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293459","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}

引用次数: 0

Sequence Scanning Improves Accuracy for Antibody–Antigen and Molecular Glue Ternary Complex Cofolding 序列扫描提高了抗体-抗原和分子胶三元配合物共折叠的准确性。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-30 DOI: 10.1002/cmdc.70553

Stephanie M. Linker, Tobias Ploetz, Andreas Evers, Djordje Musil, Jesko Kaiser, Christina Schindler

引用次数: 0

7-(Chloroquinolin-4-yl) Sulfanyl Derivatives, Optimization of the Synthesis, In Silico ADMET Profiling Studies, and Evaluation of the Biological Activity Against Leishmania mexicana 7-（氯喹啉-4-酰基）磺胺基衍生物、合成优化、ADMET分析研究及抗墨西哥利什曼原虫生物活性评价。

IF 3.5 4区医学

ChemMedChem Pub Date : 2026-10-29 DOI: 10.1002/cmdc.70550

Angelo Gelvez, Liesangerli Labrador-Fagúndez, Bruno G. Stella, Sugeins Rivero, Yaniska Ramirez, Thalia Vidal, Nathalia Martinez-Sotillo, Alírica Suárez, Katiuska Chávez, Hegira Ramírez, Zuleyma Blanco, Joyce Gutiérrez, Jaime Charris, Gustavo Benaim

{"title":"7-(Chloroquinolin-4-yl) Sulfanyl Derivatives, Optimization of the Synthesis, In Silico ADMET Profiling Studies, and Evaluation of the Biological Activity Against Leishmania mexicana","authors":"Angelo Gelvez, Liesangerli Labrador-Fagúndez, Bruno G. Stella, Sugeins Rivero, Yaniska Ramirez, Thalia Vidal, Nathalia Martinez-Sotillo, Alírica Suárez, Katiuska Chávez, Hegira Ramírez, Zuleyma Blanco, Joyce Gutiérrez, Jaime Charris, Gustavo Benaim","doi":"10.1002/cmdc.70550","DOIUrl":"10.1002/cmdc.70550","url":null,"abstract":"Leishmaniasis is a parasitic human infection that constitutes a major global health challenge due to limited therapeutic options, toxicity, resistance, and high costs of the drugs approved as therapy. In this study, a group of 7-chloroquinoline derivatives (5–12) was synthesized via an optimized route and evaluated against the human parasite Leishmania mexicana. Compounds were fully characterized and showed favorable in silico ADME/Tox profiles, including high predicted gastrointestinal absorption (>93%), although limited solubility and potential hepatotoxicity were observed for several derivatives. Biological assays demonstrated significant antileishmanial activity. Interestingly, intracellular amastigote assays revealed nanomolar potency and very high selectivity index (SI), with compound 12 exhibiting IC50 = 2.5 nM (SI = 21.030) and compound 9 IC50 = 5.2 nM (SI = 7.384). Mechanistic studies demonstrated concentration-dependent mitochondrial membrane depolarization and acidocalcisome alkalinization. Since these two organelles are both involved in bioenergetics and in parasite intracellular Ca2+ homeostasis, the results support the notion that intracellular Ca2+ disruption is an essential target for different drug actions. Overall, these findings support a multitarget mechanism and position these quinoline derivatives as promising chemical scaffolds for the development of improved antileishmanial strategies.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 21","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293531","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}

引用次数: 0

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