Chemical Biology & Drug Design最新文献_第10页

Discovery of New 4-Aminoquinoline–Thiazolidinone Hybrid Analogs as Antiproliferative Agents Inhibiting TLR4–LPS-Mediated Migration in Triple-Negative Breast Cancer Cells 新型4-氨基喹啉-噻唑烷酮杂化类似物抑制tlr4 - lps介导的三阴性乳腺癌细胞迁移的抗增殖作用

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-24 DOI: 10.1111/cbdd.70089

S. K. Batin Rahaman, Satyajit Halder, Kuldeep K. Roy, Pallab K. Halder, Utsab Debnath, Kuladip Jana

{"title":"Discovery of New 4-Aminoquinoline–Thiazolidinone Hybrid Analogs as Antiproliferative Agents Inhibiting TLR4–LPS-Mediated Migration in Triple-Negative Breast Cancer Cells","authors":"S. K. Batin Rahaman, Satyajit Halder, Kuldeep K. Roy, Pallab K. Halder, Utsab Debnath, Kuladip Jana","doi":"10.1111/cbdd.70089","DOIUrl":"https://doi.org/10.1111/cbdd.70089","url":null,"abstract":"<div>\u0000 \u0000 <p>The Toll-like receptor 4 (TLR4) signaling pathway plays a leading role in triggering proinflammatory responses by targeting lipopolysaccharide (LPS) molecules from different bacteria. Meanwhile, it is also expressed at higher levels in breast cancer cells than in normal breast tissue. After LPS binding, it initiates downstream signaling pathways that promote inflammation and cell apoptosis. Thus, targeting TLR4–LPS presents a promising dual therapeutic strategy for breast cancer treatment by not only inhibiting tumor growth but also reducing inflammation within the tumor microenvironment. To achieve this, the discovery of a new antiinflammatory agent is needed to reduce LPS-mediated cancer cell proliferation and migration. In this study, a series of 4-aminoquinoline–thiazolidinone hybrid analogs (4a-m) have been synthesized to explore their antiinflammatory as well as anticancer activity to find a new lead. Among them, 4e revealed the most promising antiinflammatory (IC50 = 2.38 ± 0.77 μM) as well as anticancer activity (IC50 = 3.26 ± 1.06 μM) in RAW 267.7 cell line and triple-negative breast cancer (TNBC) cell line, respectively. Further structure–activity relationship study followed by MD simulation analysis was carried out to identify probable binding residues of TLR4 which may play a significant role in developing antiinflammatory activity for promoting cell apoptosis in cancer cells.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690158","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

Potential Role of Hesperidin in Improving Experimental Pulmonary Arterial Hypertension in Rats via Modulation of the NF-κB Pathway 橙皮苷通过调节NF-κB通路改善大鼠实验性肺动脉高压的潜在作用

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-20 DOI: 10.1111/cbdd.70068

Jun He, Jun-hua Liao

{"title":"Potential Role of Hesperidin in Improving Experimental Pulmonary Arterial Hypertension in Rats via Modulation of the NF-κB Pathway","authors":"Jun He, Jun-hua Liao","doi":"10.1111/cbdd.70068","DOIUrl":"10.1111/cbdd.70068","url":null,"abstract":"<div>\u0000 \u0000 <p>This study was designed to evaluate the therapeutic effects of hesperidin, an anti-inflammatory compound, on pulmonary arterial hypertension (PAH). A PAH rat model was established using monocrotaline (MCT, 60 mg/kg). Next, the experimental animals were assigned into the following four groups (<i>n</i> = 6 per group): Control group, MCT group, MCT + H20 group (20 mg/kg hesperidin), and MCT + H40 group (40 mg/kg hesperidin). According to the experimental outcomes, the PAH rat model was built successfully. In PAH animals, hesperidin significantly reduced right ventricular systolic pressure, Fulton index, and mean pulmonary arterial pressure. Concurrently, it improved pulmonary artery velocity-time integral and acceleration time, as well as alleviated pulmonary artery and right ventricular remodeling. On a molecular level, hesperidin inhibited the expression of vascular endothelial-cadherin, alpha-smooth muscle actin, matrix metalloproteinase-9, and transforming growth factor beta. Also, hesperidin downregulated pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, IL-18, chemokine C-C motif ligand 2, and C-X-C motif chemokine ligand 1 levels, and reduced the number of CD68+ cells in tissue samples. Further analysis revealed that hesperidin could inhibit the activation of p-IκB-α and p-p65 in samples induced by MCT. Collectively, these findings suggest that hesperidin may inhibit inflammation through the NF-κB pathway, thereby improving experimental PAH in rats induced by MCT.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665745","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

Artesunate Suppresses the Migration and Invasion of Thyroid Cancer Cells via Upregulating PTEN to Block M2 Polarization of Tumor-Associated Macrophages 青蒿琥酯通过上调PTEN抑制肿瘤相关巨噬细胞M2极化抑制甲状腺癌细胞的迁移和侵袭

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-18 DOI: 10.1111/cbdd.70076

Zhiwei Xu, Xiuping Li, Daoping Zhuang

{"title":"Artesunate Suppresses the Migration and Invasion of Thyroid Cancer Cells via Upregulating PTEN to Block M2 Polarization of Tumor-Associated Macrophages","authors":"Zhiwei Xu, Xiuping Li, Daoping Zhuang","doi":"10.1111/cbdd.70076","DOIUrl":"https://doi.org/10.1111/cbdd.70076","url":null,"abstract":"<div>\u0000 \u0000 <p>Immunotherapy holds promise for thyroid cancer (TC) treatment. In the context of our previous findings that artesunate (ART) could inhibit the migration and invasion of TC cells through phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), this study was engineered to investigate whether ART regulates the tumor microenvironment in TC. THP-1 cells were differentiated into M0 macrophages by the induction of 100 ng/mL of phorbol 12-myristate 13-acetate and transfected as needed. M0 macrophages were treated with different concentrations of ART (10 and 20 μM) for 24 h. The co-culture of macrophages and TC cells was conducted. Flow cytometry and enzyme-linked immunosorbent assay were used to identify M2 macrophages. The viability, migration, and invasion of TC cells were detected by cell counting kit-8, wound healing, and transwell assays. The mRNA or protein expressions of examined genes were measured by quantitative real-time polymerase chain reaction or Western blot. In co-cultured macrophages, protein expressions of CD206, CD163, and Arginase-1, as well as the secretion of IL-10 and CCL18, were promoted, but phosphatase and tensin homolog (PTEN) mRNA expression was inhibited, which were reversed by different concentrations of ART. In the co-culture system, 20 μM of ART downregulated mRNA expressions of CD206, CD163, and Arginase-1 in macrophages and diminished viability, migration, invasion, as well as ratios of p-PI3K/PI3K and p-Akt/Akt in TC cells, which were offset by PTEN deletion in macrophages. Collectively, ART suppresses the migration and invasion of TC cells via inhibiting the PI3K/Akt pathway by PTEN upregulation-blocked M2 polarization of tumor-associated macrophages.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645739","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

Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential MEP 通路中 IspC 酶的非羟氨酸盐抑制剂：结构洞察力与药物开发潜力

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-18 DOI: 10.1111/cbdd.70086

Yaqing Zhou, Jili Wang, Yong Sun, Yarui Cheng, Wenhai Wu

{"title":"Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential","authors":"Yaqing Zhou, Jili Wang, Yong Sun, Yarui Cheng, Wenhai Wu","doi":"10.1111/cbdd.70086","DOIUrl":"https://doi.org/10.1111/cbdd.70086","url":null,"abstract":"<div>\u0000 \u0000 <p>1-Deoxy-D-xylulose-5-phosphate reductoisomerase (IspC) is a key enzyme in the MEP pathway, essential for many bacteria, human pathogens, and plants, thus being an attractive drug target. Fosmidomycin, a potent IspC inhibitor with hydroxamate metal-binding pharmacophores (MBPs), has entered clinical trials for malaria but is hampered by pharmacokinetic and toxicity issues of the hydroxamate fragment. This has led to increased interest in non-hydroxamate inhibitors. This review focuses on the crystal structure and active-site binding mode of IspC, and the structural types, inhibitory activities, and structure–activity relationships of non-hydroxamate IspC inhibitors. Early attempts to design such inhibitors involved direct removal or replacement of the hydroxamate MBPs, with varying results. Lipophilic inhibitors, bisubstrate inhibitors, and those developed for herbicidal applications have shown promise. However, challenges remain due to the sensitivity of the enzyme active site to ligand interactions. Future research could draw from other metalloenzyme studies to develop novel and efficient non-hydroxamate IspC inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639072","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

Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities 靶向cdc2样激酶4的小分子抑制剂：进展、挑战和机遇

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-17 DOI: 10.1111/cbdd.70087

Yu Jiang, Zihua Tang, Minggao Jiang, Jing Wang, Yanhai Wang

{"title":"Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities","authors":"Yu Jiang, Zihua Tang, Minggao Jiang, Jing Wang, Yanhai Wang","doi":"10.1111/cbdd.70087","DOIUrl":"https://doi.org/10.1111/cbdd.70087","url":null,"abstract":"<div>\u0000 \u0000 <p>Cdc2-like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small-molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure–activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4-targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632608","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

Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies 新型噻唑-吡唑类似物的合成：分子模拟、抗增殖/抗病毒活性和ADME研究

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70090

Hind A. Siddiq, Mohammed A. Imam, Shaker T. Alsharif, Roba M. S. Attar, Renad Almughathawi, Nadiyah M. Alshammari, Nuha M. Halawani, Nashwa M. El-Metwaly

{"title":"Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies","authors":"Hind A. Siddiq, Mohammed A. Imam, Shaker T. Alsharif, Roba M. S. Attar, Renad Almughathawi, Nadiyah M. Alshammari, Nuha M. Halawani, Nashwa M. El-Metwaly","doi":"10.1111/cbdd.70090","DOIUrl":"https://doi.org/10.1111/cbdd.70090","url":null,"abstract":"<div>\u0000 \u0000 <p>Twelve thiazole-pyrazole analogues <b>4</b>, <b>6</b>, and <b>8</b> were synthesized by introducing various pyrazole systems into the core, 2-((4-acetylphenyl)amino)-4-methylthiazole (<b>2</b>), through many synthetic approaches. The density functional theory (DFT) study of the synthesized analogues revealed coincided configurations of their highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), except for the nitro derivatives, in which the intramolecular charge-transfer (CT) may be denoted as π → π* and <i>n</i> → π*. In addition, the in vitro antiproliferative efficacy towards some cancer cell lines was examined (Panc-1, HT-29, MCF-7) and the non-cancerous (WI-38), using Dasatinib (Reference). The analogues <b>4c</b> and <b>4d</b> demonstrated the most potent anticancer effect, particularly against Panc-1 and MCF-7 cells. Moreover, the antiviral activity against H5N1, using a plaque reduction assay, showed that analogue <b>6a</b> exhibited the most potent antiviral activity (100% inhibition and TC<sub>50</sub> = 61 μg/μL), comparable to the reference drug amantadine (TC<sub>50</sub> = 72 μg/μL, 100% inhibition). Furthermore, the molecular docking disclosed that the analogues exhibited a range of interactions, such as H-bonding and π-π stacking, with binding affinities between −4.8558 and − 8.3673 kcal/mol. Additionally, the SwissADME predictions indicated that the synthesized analogues possess promising drug-like characteristics, but analogues <b>4a–d</b> and <b>8c</b> demonstrated inadequate solubility and bioavailability, which restricts their use as viable oral medications.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629885","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

The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results 纳米盘脂质的性质影响基于片段的药物发现结果

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70080

Tim G. J. Knetsch, Henri van Son, Masakazu Kobayashi, Marcellus Ubbink

{"title":"The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results","authors":"Tim G. J. Knetsch, Henri van Son, Masakazu Kobayashi, Marcellus Ubbink","doi":"10.1111/cbdd.70080","DOIUrl":"https://doi.org/10.1111/cbdd.70080","url":null,"abstract":"<p>Membrane proteins (MPs) are important yet challenging targets for drug discovery. MPs can be reconstituted in protein-lipid Nanodiscs (NDs), which resemble the native membrane environment. Drug-membrane interactions can affect the apparent binding stoichiometry and affinity, as well as the kinetics of ligands for a particular target, which is important for the extrapolation to pharmacokinetic studies. To investigate the role of the membrane, we have applied fragment-based drug discovery (FBDD) methods to cytochrome P450 3A4 (CYP3A4), reconstituted in NDs composed of different phosphocholine lipids: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC). Surface plasmon resonance screening of fragments and marketed drugs revealed extensive binding to the empty ND, correlating with analyte hydrophobicity, and the binding was critically dependent on ND lipid composition. POPC NDs showed much higher binding of fragments than DMPC and DPhPC NDs, resulting in a lower hit rate for CYP3A4 in POPC NDs, which demonstrated that the choice of the ND lipid is crucial to the outcome of a screen. The number of binders that were rejected based on atypical binding kinetics was lower for monomeric CYP3A4 in NDs than for non-native oligomeric CYP3A4 without the ND. Several fragments were exclusively identified as hits for CYP3A4 in the presence of the ND membrane. It is concluded that the nature of the ND is a critical factor for fragment screening of membrane proteins.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629884","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

Pyrrole-Tethered Bisbenzoxazole Derivatives: Apoptosis-Inducing Agents Targeting Breast Cancer Cells 吡咯系缚双苯并恶唑衍生物：靶向乳腺癌细胞的凋亡诱导剂

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-13 DOI: 10.1111/cbdd.70078

Burak Kuzu, Derya Yetkin, Ceylan Hepokur, Oztekin Algul

{"title":"Pyrrole-Tethered Bisbenzoxazole Derivatives: Apoptosis-Inducing Agents Targeting Breast Cancer Cells","authors":"Burak Kuzu, Derya Yetkin, Ceylan Hepokur, Oztekin Algul","doi":"10.1111/cbdd.70078","DOIUrl":"https://doi.org/10.1111/cbdd.70078","url":null,"abstract":"<p>This study presents the design, synthesis, and biological evaluation of a series of novel pyrrole-tethered bisbenzoxazole (PTB) derivatives as potential apoptosis-inducing agents targeting the MCF-7 human breast cancer cell line. The anticancer activity of these compounds was evaluated in vitro using the MTT assay, with tamoxifen serving as the reference therapeutic agent. Compounds <b>B8</b>, <b>B14</b>, and <b>B18</b> demonstrated remarkable cytotoxicity against MCF-7 cells, exhibiting approximately 8-fold lower IC<sub>50</sub> values compared to tamoxifen, while showing minimal effects on healthy fibroblasts. Further investigations revealed that these compounds effectively induced early-stage apoptosis and selectively arrested the cell cycle at the G1 phase in cancer cells. Gene expression analysis confirmed selective activation of the caspase-9-mediated apoptotic pathway in MCF-7 cells, providing insights into their underlying molecular mechanisms. These findings highlight the promising potential of PTB derivatives as potent anticancer agents, laying the groundwork for the development of targeted therapies for breast cancer that leverage apoptosis induction for improved therapeutic outcomes.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602695","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

Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy 通过药物再利用和联合治疗鉴定耐甲氧西林金黄色葡萄球菌的潜在PBP2a抑制剂

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70088

Fangfang Jiao, Pinkai Wang, Derong Zeng, Yiqiong Bao, Yan Zhang, Jun Tao, Jingjing Guo

{"title":"Identification of Potential PBP2a Inhibitors Against Methicillin-Resistant Staphylococcus aureus via Drug Repurposing and Combination Therapy","authors":"Fangfang Jiao, Pinkai Wang, Derong Zeng, Yiqiong Bao, Yan Zhang, Jun Tao, Jingjing Guo","doi":"10.1111/cbdd.70088","DOIUrl":"https://doi.org/10.1111/cbdd.70088","url":null,"abstract":"<div>\u0000 \u0000 <p>Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented a strategy that combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric site from an FDA-approved drug database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) and two representative PBP2a structures. The combination of Glide SP and one representative PBP2a conformation showed the highest efficacy in identifying active compounds. The optimized parameters were then utilized to screen FDA-approved drugs, and 15 compounds were shortlisted for potential combination therapy with cefazolin, an ineffective cephalosporin against MRSA. Through biological assays—checkerboard, time-kill assays, and live/dead bacterial staining—we discovered that four compounds exhibited robust bactericidal activity (FICI < 0.5) compared to both untreated control and monotherapy with cefazolin alone. Scanning electron microscopy (SEM) confirmed that while cefazolin alone did not cause visible damage to MRSA cells, the combination treatment markedly induced cell lysis. Additional MM-GBSA studies underscored the strong binding affinity of mitoxantrone to the allosteric site. These findings introduce a combination therapy approach that potentially restores MRSA's susceptibility to β-lactam antibiotics.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595439","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

Targeting Blood-Stage Malaria: Design, Synthesis, Characterization, In Vitro, and In Silico Evaluation of Pyrrolidinodiazenyl Chalcones 靶向血期疟疾：吡咯烷二二氮基查尔酮的设计、合成、表征、体外和硅评价

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-12 DOI: 10.1111/cbdd.70081

Ahammed Ameen Thottasseri, Vinoth Rajendran, Deepthi Ramesh, Anju Agnes Tom, Roshiny Roy Thomas, Sreetama Ray, Gopika Gopan, Maheswaran Mani, Tharanikkarasu Kannan

{"title":"Targeting Blood-Stage Malaria: Design, Synthesis, Characterization, In Vitro, and In Silico Evaluation of Pyrrolidinodiazenyl Chalcones","authors":"Ahammed Ameen Thottasseri, Vinoth Rajendran, Deepthi Ramesh, Anju Agnes Tom, Roshiny Roy Thomas, Sreetama Ray, Gopika Gopan, Maheswaran Mani, Tharanikkarasu Kannan","doi":"10.1111/cbdd.70081","DOIUrl":"https://doi.org/10.1111/cbdd.70081","url":null,"abstract":"<div>\u0000 \u0000 <p>Malaria is a pervasive and deadly threat to the global population, and the resources available to treat this disease are limited. There is widespread clinical resistance to the most commonly prescribed antimalarial drugs. To address this issue, we synthesized a range of 4′-pyrrolidinodiazenyl chalcones using a covalent bitherapy approach to study their potential antimalarial properties. We examined the structure–activity relationships of these compounds, which could explain their antimalarial activities. The in vitro blood stage antimalarial activity of the compounds was evaluated against the mixed-blood stage culture (ring, trophozoites and schizonts) of <i>Plasmodium falciparum</i> 3D7, and the 50% inhibitory concentrations (IC<sub>50</sub>s) ranged from 3.3 to 22.2 μg/mL after 48 h of exposure. Compounds <b>11</b>, <b>19</b>, and <b>22</b> displayed pronounced IC<sub>50</sub> values of 7.6 μg/mL, 6.4 μg/mL, and 3.3 μg/mL, respectively. The in vitro cytotoxicity of the active compounds was evaluated on human-derived Mo7e cells and murine-derived BA/F3 cells. Compounds <b>11</b> and <b>19</b> were found to be noncytotoxic (> 40 μg/mL), whereas compound <b>22</b> displayed cytotoxicity at higher concentrations. Moreover, these compounds exerted negligible hemolytic effects on human RBCs at their active concentrations. Molecular docking of these compounds revealed good hydrophobic and hydrogen bonding interactions with the binding sites of <i>Plasmodium falciparum</i>-dihydrofolate reductase, providing a rationale for their antimalarial activity, which is consistent with the in vitro results.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595440","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