Chemical Biology & Drug Design最新文献

{"title":"Current Perspectives on STING Agonists for Anticancer Drug Development","authors":"Dilay Kahvecioglu Cicek","doi":"10.1111/cbdd.70370","DOIUrl":"10.1111/cbdd.70370","url":null,"abstract":"<p>The cyclic GMP-AMP (cGAS) synthase and stimulator of interferon genes signaling pathway plays a central role in bridging innate and adaptive immunity, particularly within the context of cancer. Activation begins when cytosolic double-stranded DNA is detected, leading to the production of cyclic GMP-AMP (cGAMP) and subsequent activation of STING. This initiates a cascade that induces the expression of type I interferons (IFN) and proinflammatory cytokines, enhancing antitumor immune responses through the stimulation of dendritic cells, cytotoxic T lymphocytes, and natural killer cells. Despite strong therapeutic potential, many currently available cyclic dinucleotide (CDN) and synthetic noncyclic dinucleotide (non-CDN) STING agonists face critical limitations. Common issues include poor pharmacokinetics, low cellular permeability, enzymatic degradation, and inadequate systemic bioavailability. In some cases, excessive immune activation has been observed, resulting in toxicity, chronic inflammation, or immunosuppressive tumor microenvironments. Furthermore, species-specific activity restricts the translational relevance of several compounds. These limitations highlight the need for the development of novel STING agonists with improved potency, selectivity, safety, and pharmacological profiles. This review presents a detailed analysis of molecular design approaches and structure–activity relationship (SAR) data for STING agonists, emphasizing their relevance in cancer therapy. A total of 60 synthetic compounds with diverse chemical scaffolds are examined to identify structural features linked to enhanced STING activation. These findings may support the discovery of novel STING-targeted molecules that could improve therapeutic outcomes in cancer treatment.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13402778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148595099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidation of DNA Primase as a Drug Target in Leishmania donovani: Structure-Guided Inhibitor Identification and Biochemical Validation","authors":"Deep Bhowmik,&nbsp;Anupama Sharma,&nbsp;Ravi Prakash Arya,&nbsp;Diwakar Kumar","doi":"10.1111/cbdd.70362","DOIUrl":"10.1111/cbdd.70362","url":null,"abstract":"<p>Replication is started by DNA primase, which synthesizes an oligoribonucleotide primer that DNA polymerases extend. Effective chemotherapy is still needed to manage and treat leishmaniasis, which continues to pose a threat to public health around the world. Repurposing drugs offers alternative uses for drugs with established pharmacological effects, saving money and increasing the pool of human resources available to create novel anti-leishmanials. Here, we used a non-radioactive primase-pyrophosphatase assay to biochemically characterize the <i>Leishmania donovani</i> nuclear DNA primase (<i>LdPri</i>) subunits, followed by in silico evaluation of inhibitors targeting <i>LdPri</i>. The best-evaluated inhibitors showed <i>LdPri</i> inhibition in vitro under conditions similar to those of the primase-pyrophosphatase experiment. The MTT assay also confirmed the inhibitors' anti-leishmanial properties. Parasite growth and morphological analysis were performed by culturing cells in the presence of inhibitors. Biochemical characterization revealed that <i>LdPriS</i> activity was unstable, but was highly stabilized upon association with <i>LdPriL</i> in <i>LdPri</i>. <i>LdPri</i> was found to be thermostable and possesses 3′-terminal nucleotidyltransferase activity. Additionally, in silico and in vitro studies evaluated Pritelivir (BAY 57-1293) as the most efficient <i>LdPri</i> complex inhibitor, followed by Epigallocatechin Gallate (EGCG). Moreover, kinetic studies showed that Pritelivir and EGCG exhibit competitive and uncompetitive inhibition, respectively, for both NTP and DNA substrates. Pritelivir effectively disrupted the <i>L. donovani</i> cell cycle, and the replication mechanism in treated promastigotes showed irregular shapes and short flagella.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148595065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Antiviral Design: Integrating Natural Products, Computation and Targeted Delivery","authors":"Adedayo Ayodeji Lanrewaju,&nbsp;Abimbola Motunrayo Folami,&nbsp;Saheed Sabiu,&nbsp;Feroz Mahomed Swalaha","doi":"10.1111/cbdd.70365","DOIUrl":"10.1111/cbdd.70365","url":null,"abstract":"<p>The COVID-19 pandemic highlighted the role of rapid viral mutation and global connectivity in accelerating viral emergence and spread, emphasising the necessity for expedited and adaptable antiviral drug discovery and development. Despite ongoing efforts to develop effective, low-toxicity therapeutics, the number of antivirals that have achieved clinical approval remains limited. The shortfall is especially significant in developing countries, where access to new antivirals is limited by high prices, few options, import dependence, unstable supply chains and weak purchasing systems. The challenge is further heightened by the emergence of increasingly drug-resistant variants while vaccines often provide inadequate protection against newly mutated or novel viruses. Consequently, the identification of novel antiviral agents that are both effective and cost-efficient via innovative strategies for antiviral drug discovery is essential to manage and control viral infections. Therefore, this review examines the different challenges associated with conventional antiviral drugs alongside recent strategies in antiviral drug discovery and development, such as the exploitation of plant secondary metabolites with antiviral properties, advanced microscopy technologies, computer-aided drug design, artificial intelligence and machine learning, gene-editing technologies, drug combination therapy and nanotechnology-enhanced drug delivery systems. Additionally, this study proposes a simple decision-focused pathway integrating natural products, computation and targeted delivery to guide candidate prioritisation, optimisation and translation from discovery to implementation. While these emerging strategies offer considerable promise, challenges related to validation, toxicity, scalability and equitable access remain important considerations for successful clinical translation. Future research should therefore integrate complementary technologies to accelerate the development of effective antiviral agents against current and emerging viral threats.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Insights Into DYRK1A From Molecular Function to Therapeutic Advancement","authors":"Sampriti Paul,&nbsp;Sonal Dubey,&nbsp;Prashant Tiwari","doi":"10.1111/cbdd.70366","DOIUrl":"10.1111/cbdd.70366","url":null,"abstract":"<p>Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), located within the Down syndrome critical region and implicated in Alzheimer's disease (AD), Parkinson's disease (PD), and context-dependent cancer biology, represents a high-value yet challenging therapeutic target. This review compiles comprehensive structure–activity relationship (SAR) insights essential for medicinal chemists designing selective DYRK1A inhibitors. We detail the molecular architecture of the ATP-binding pocket of DYRK1A, key regulatory residues (Lys188, Phe238, Glu239, Leu241), and structure–function relationships governing inhibitor classes: ATP-competitive agents, ATP-non-competitive inhibitors, and Proteolysis-Targeting Chimeras (PROTAC) degraders with emphasis on functional group modifications and scaffold optimization strategies. Readers will gain actionable insights on binding mode predictions, potency-selectivity trade-offs, and prioritization of lead compounds for preclinical validation. The framework addresses pharmacokinetic property optimization and selectivity profiling across kinase families, enabling researchers to accelerate rational inhibitor design and facilitate translation of DYRK1A therapeutics into clinical trials for neurodegenerative and developmental disorders.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148581671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Potent Antimalarial Agents Targeting Plasmodium falciparum DNA Gyrase B by Integrating Computational and Experimental Approaches","authors":"Biswajit Naik,&nbsp;Welka Sahu,&nbsp;Guneswar Sethi,&nbsp;Cherish Prashar,&nbsp;Gajendra Mohan Baldodiya,&nbsp;Jyoti Poswal,&nbsp;Chandi C. Mandal,&nbsp;Jeong Ho Hwang,&nbsp;Kailash C. Panday,&nbsp;K. Sony Reddy,&nbsp;Dhaneswar Prusty","doi":"10.1111/cbdd.70364","DOIUrl":"10.1111/cbdd.70364","url":null,"abstract":"<p>The global spread of drug-resistant <i>Plasmodium falciparum</i>, particularly artemisinin-resistant strains, underscores the urgent need for novel antimalarial agents with distinct mechanisms of action and improved therapeutic potential. In this study, we employed an integrated in silico and in vitro strategy to identify compounds with inhibitory activity against <i>P. falciparum</i> apicoplast Gyrase B (PfGyrB). High-throughput virtual screening identified hit compounds with favorable predicted interactions against the target protein, which were subsequently evaluated using biochemical ATPase inhibition and parasite growth inhibition assays. UNC8153 and Fexofenadine hydrochloride demonstrated time-dependent antiplasmodial activity, with lower IC₅₀ values at 96 h than at 48 h under prolonged exposure conditions. UNC8153 exhibited greater antiplasmodial activity (~25-fold) than the reference compound novobiocin during the second intraerythrocytic cycle. Morphological analysis indicated impaired parasite development during the second intraerythrocytic cycle under prolonged exposure conditions. Importantly, UNC8153 retained inhibitory activity against the artemisinin-resistant C580Y strain and exhibited minimal cytotoxicity toward HEK-293 cells under the tested experimental conditions. Structural similarity analysis indicated that the identified compounds are chemically distinct from currently used antimalarial drugs, supporting their structural novelty. Collectively, these findings identify UNC8153 as a structurally distinct new antiplasmodial scaffold warranting further mechanistic, pharmacological, and in vivo evaluation.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Integrative Methylation-Metabolism Gene Signature Defines Prognosis and Immunosuppressive Microenvironment in Prostate Cancer","authors":"Chao Zhang,&nbsp;Likun Liu,&nbsp;Kai Wu","doi":"10.1111/cbdd.70360","DOIUrl":"10.1111/cbdd.70360","url":null,"abstract":"<p>The synergistic crosstalk between epigenetic dysregulation and metabolic reprogramming underlies to prostate cancer (PCa) development and treatment resistance, yet an integrated prognostic signature reflecting this nexus remains poorly defined. We developed and validated a gene signature associated with methylation and amino acid metabolism for patient stratification and exploring its connection to tumor microenvironment (TME) remodeling. RNA sequencing data and independent datasets were integrated with predefined gene sets for DNA methylation (<i>n</i> = 79) and amino acid metabolism (<i>n</i> = 471). A analytical workflow was employed: identification of hub genes and least absolute shrinkage and selection operator (LASSO)—Cox modeling; construction of a prognostic nomogram; comprehensive TME profiling; and validation through single-cell RNA sequencing (scRNA-seq) cellular dynamics analysis and immunohistochemistry (IHC) on a prostate cancer tissue microarray. A novel six-gene prognostic model (ASPM, WDR86, CCK, HOXA2, EGF, ZFHX4) was developed. This model efficiently discriminates patients into groups based on risk level though divergent overall survival (<i>p</i> &lt; 0.001) and exhibited high predictive accuracy in external validation sets (3-year area under the curve (AUC) = 0.87). A nomogram incorporating the signature, pathologic T stage, and Gleason score surpassed individual clinical factors (5-year AUC = 0.73). Functional annotation indicated that high-risk tumors were characterized by downregulated androgen response and activated E2F/G2M checkpoint pathways. The signature was correlated with an immunosuppressive TME, which was supported by a negative correlation between ZFHX4 and monocyte infiltration (<i>r</i> = −0.37, <i>p</i> &lt; 0.001) and a positive correlation between ASPM and activated CD4⁺T cells (<i>r</i> = 0.44, <i>p</i> &lt; 0.001). Single-cell trajectory analysis exhibited that epithelial cells, fibroblasts, and natural killer T (NKT) cells was key cellular expressors of the signature. We utilized immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) to confirm the differential expression. We developed and validated an integrative methylation-amino acid metabolism gene signature that effectively predicts prognosis and reflects an immunosuppressive TME in PCa. This study provides a translational framework for precision oncology, bridging epigenetic-metabolic crosstalk to disease aggressiveness, and offers potential biomarkers for informing risk-stratified therapy and immunotherapy approaches.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148537807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Biofilm Inhibition Potential of Imidazo-Pyridine Linked Tetrazoles Against Candida albicans: Synthesis, Biological Evaluation With Computational Studies","authors":"Madalambika,&nbsp;A. C. Kumar,&nbsp;P. M. BharathKumar,&nbsp;K. B. Vilas Gowda,&nbsp;Ramith Ramu,&nbsp;Nagaraja Naik","doi":"10.1111/cbdd.70359","DOIUrl":"https://doi.org/10.1111/cbdd.70359","url":null,"abstract":"<div>\u0000 \u0000 <p>Infectious diseases remain one of the major global health challenges due to their rapid transmission and evolving pathogenic mechanisms. Among them, <i>Candida albicans</i> has emerged as a significant opportunistic antifungal pathogen, which is responsible for biofilm-associated infections. In the present study, a library of new tetrazole bearing imidazo-pyridine molecules <b>(4a–4j)</b> was synthesised and characterised through spectroscopic techniques (¹H, ¹³C and MS) for structural confirmation. Their in vitro antifungal potential was evaluated against <i>C. albicans,</i> where compound <b>4d</b> emerged as the most promising lead among all by exhibiting a MIC of 7 μg/mL and MFC of 45 μg/mL, conquering the reference fluconazole (FLC) which showed 8 μg/mL and 64 μg/mL of MIC and MFC, respectively. Compound <b>4d</b> also demonstrated 75% and 86% inhibition of fungal filamentation and of biofilm formation, respectively. qRT-PCR analysis confirmed the significant downregulation of important virulence genes, and SEM imaging further validated biofilm prevention. Toxicity assessment through hemolytic and cytotoxic assays on HEK293 cell line indicated low toxicity across tested concentrations. Additionally, computational evaluation including molecular docking and ADMET parameters supported the predicted binding affinities and pharmacokinetic properties of the synthesised compounds.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contextual Representation Learning With ResNet Refinement and Deep Classification for Enhanced Drug Target Interaction Prediction","authors":"Essmily Simon,&nbsp;Sanjay Bankapur","doi":"10.1111/cbdd.70358","DOIUrl":"https://doi.org/10.1111/cbdd.70358","url":null,"abstract":"<div>\u0000 \u0000 <p>Accurate prediction of drug target interactions (DTIs) plays a pivotal role in drug discovery and repositioning. However, it remains challenging due to the structural complexity of proteins and small-molecule compounds, along with the limited generalisation capability of existing computational approaches. Drug target interaction prediction is important in computer-aided drug design and drug repurposing, especially for complex diseases where multiple targets are involved. This study aims to develop a robust deep learning framework that enhances DTI prediction accuracy by effectively capturing contextual and biochemical features from both protein and drug representations. Four standard DTI datasets and a combined drug repurposing dataset are used to learn interaction patterns across multiple targets. We propose a novel deep learning framework that leverages pre-trained BERT-based language models to extract contextual embeddings from protein and drug sequences. These modality-specific representations are refined using a proposed dedicated ResNet-based subnetwork to preserve intrinsic biochemical characteristics. The refined embeddings are subsequently integrated and passed through a proposed deep feedforward neural network for final DTI prediction. The proposed model was evaluated on four benchmark datasets, namely DrugBank, <i>Caenorhabditis elegans</i>, BindingDB and GPCR. Experimental results demonstrate consistent performance improvements over baseline methods, including an F1-score gain of ~6.6% on the GPCR dataset and a 3.7% increase in classification accuracy on BindingDB. Stable F1-score improvements were also observed on DrugBank (0.4%) and <i>Caenorhabditis elegans</i> (0.8%). Statistical validation using paired ω-tests at a 5% significance level confirms the improvements are significant. Evaluation on an independent drug repurposing dataset achieved a 6.7% performance gain over existing approaches. The results demonstrate that the proposed framework effectively captures contextual and structural information, leading to improved prediction accuracy and generalisation, highlighting its robustness and practical applicability for drug discovery and drug repurposing.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Characterization, Molecular Docking Study and Biological Evaluation of Novel 1,3,4-Thiadiazole-Based Heterocycles as Potential Anticancer and Antioxidant Agents","authors":"Nashwa M. El-Metwaly,&nbsp;Abdulmajeed F. Alrefaei,&nbsp;Hossa F. Alshareef,&nbsp;Samar J. Almehmadi,&nbsp;Fatimah A. Alotaibi,&nbsp;Nadiyah M. Alshammari,&nbsp;Manal S. Ebaid,&nbsp;Hanadi A. Katouah","doi":"10.1111/cbdd.70361","DOIUrl":"10.1111/cbdd.70361","url":null,"abstract":"<p>The design, synthesis, and biological assessment of new heterocyclic compounds containing the 1,3,4-thiadiazole moiety, a well-known pharmacophore with substantial medicinal significance, are the main topics of this study. To create a variety of thiadiazole-based heterocyclic systems, such as pyrazoles, triazoles, pyrimidines, and thiophenes, a novel cyanoacetohydrazide derivative was created and used as a crucial intermediate. IR, ¹H-NMR, ¹³C-NMR, and mass spectrometry were the spectroscopic methods used to confirm the structures of produced compounds. The synthesized compounds' biological properties were assessed for their potential as antioxidants and anticancer agents. Several derivatives showed impressive activity in cytotoxicity tests against HePG-2 and MCF-7 cancer cell lines, with several compounds showing greater potency than the reference medication 5-fluorouracil. Compounds <b>17</b>, <b>18</b>, and <b>13</b> exhibited the strongest anticancer activity, highlighting the significance of structural and electronic properties in improving biological performance. Furthermore, an assessment of the synthesized compounds' antioxidant activity revealed that they have differing levels of free radical scavenging activity, with compounds <b>17</b> and <b>18</b> exhibiting the most notable benefits, albeit still less than ascorbic acid. Electron-donating and electron-withdrawing groups, molecular conjugation, and lipophilicity all play a part in regulating antioxidant and anticancer actions, according to structure–activity relationship (SAR) studies. Additionally, substantial interactions between specific drugs and the EGFR tyrosine kinase domain were suggested by molecular docking studies, indicating their possible mode of action. All things considered, our work shows that thiadiazole-based heterocycles are attractive candidates for the creation of novel antioxidants and anticancer medicines and offers insightful information for future drug design.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Guided Optimization of 1,2,4-Triazole-Thione-Based Mannich Derivatives as Dual-Target Modulators: AChE/MAO-B","authors":"Hasan Erdinç Sellitepe,&nbsp;Ahmet Buğra Aksel,&nbsp;Hilal Zıvalı,&nbsp;Ezgi Pehlivanlar Yavrucu,&nbsp;Begüm Nurpelin Sağlık Özkan,&nbsp;İnci Selin Doğan,&nbsp;Kutsal Özcan Kosif","doi":"10.1111/cbdd.70347","DOIUrl":"10.1111/cbdd.70347","url":null,"abstract":"<div>\u0000 \u0000 <p>Diseases such as Alzheimer's, Parkinson's, and depression result from neurotransmitter imbalances. In particular, for AD, it is critical to inhibit AChE to preserve the decline in acetylcholine levels and to block excessive MAO-B activity, which leads to nerve damage and cognitive impairment. As current scientific research has moved away from the “one drug for one target” approach toward a “multi-target” strategy, dual-acting inhibitors that simultaneously inhibit both AChE and MAO-B enzymes are considered the most promising new drug candidates for the treatment of Alzheimer's disease. In this study, we investigated the inhibition of AChE, BChE, MAO-A, and MAO-B in the pathophysiology of AD as a working group. Within the scope, 10 new compounds (<b>5a</b>–<b>j</b>) were synthesized, consisting of a phenolic ring, a secondary or tertiary amine tail, and a 1,2,4-triazole core. The cholinesterase and MAO inhibitory profiles of the compounds were investigated using both in vitro and <i>in silico</i> methods. Compound <b>5b</b> exhibited dual inhibitory activity against AChE and MAO-B enzymes, with IC₅₀ values of 0.136 ± 0.006 μM and 0.108 ± 0.005 μM, respectively. In accordance with <b>5b</b>, it interacted with crucial amino acids of the <i>h</i>AChE and <i>h</i>MAO-B enzymes in the docking studies. These results suggest that <b>5b</b> is a dual-target inhibitor of AChE and MAO-B and represents a promising therapeutic option for the treatment of Alzheimer's disease.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148440010","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}