Chemical Biology & Drug Design最新文献

{"title":"Erianin Protects Human Umbilical Vein Endothelial Cells From Oxidized Low-Density Lipoprotein-Induced Apoptosis and Oxidative Stress Through Activation of Nuclear Factor E2-Related Factor 2 Signaling","authors":"Zhaowei Wang,&nbsp;Linru Wang,&nbsp;Yuanyuan Wang,&nbsp;Juanzi Zhang","doi":"10.1111/cbdd.70104","DOIUrl":"https://doi.org/10.1111/cbdd.70104","url":null,"abstract":"<div>\u0000 \u0000 <p>Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell damage plays an important role in the pathogenesis of atherosclerosis (AS). This study aimed to investigate the ability of Erianin to protect human umbilical vein endothelial cells (HUVECs) against ox-LDL-induced oxidative stress and its underlying mechanisms. HUVECs were treated with Erianin (0, 5, 10, and 20 μM) for 2 h and then stimulated with ox-LDL (100 μg/mL) for 24 h. Flow cytometry and MTT assay determined cell apoptosis and viability, respectively. The protein levels of caspase-9, caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1), nuclear factor E2-related factor 2 (Nrf2), histone H3, NAD(P)H: quinone oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1), cytochrome c, and cytochrome c oxidase subunit IV (COX IV) were evaluated by Western blot. Matrix metalloproteinase (MMP) membrane potential was measured. The impact of Erianin on ox-LDL-induced injury in HUVECs was confirmed by using small interfering RNA si-Nrf-2. Erianin pretreatment notably rescued the impaired ox-LDL-treated HUVEC viability and apoptosis and inhibited ox-LDL-induced mitochondrial dysfunction in HUVECs. Furthermore, Erianin reduced ox-LDL-induced oxidative stress by enhancing Nrf2 signaling activation, and Nrf2 knockdown by siRNAs diminished the anti-oxidative role of Erianin in HUVECs. These suggest that Erianin suppresses ox-LDL-induced apoptosis and oxidative stress by regulating Nrf2 signaling in HUVECs.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244488","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":"Discovery of Small Molecule PD-L1 Inhibitors via Optimization of Solvent-Interaction Region for Cancer Immunotherapy","authors":"Binbin Cheng,&nbsp;Ting Liu,&nbsp;Hao Cao,&nbsp;Jin Liu,&nbsp;Yichang Ren,&nbsp;Junli Huang,&nbsp;Dulin Kong,&nbsp;Ting Chen,&nbsp;Yong Liu,&nbsp;Jianjun Chen","doi":"10.1111/cbdd.70141","DOIUrl":"https://doi.org/10.1111/cbdd.70141","url":null,"abstract":"<div>\u0000 \u0000 <p>Despite extensive research, the topic of anti-PD-L1 small-molecule inhibitors remains elusive. Herein, we report the design, synthesis, and bioevaluation of a series of small molecule PD-L1 inhibitors via optimization of the solvent-interaction region. Among them, compound <b>GJ19</b> showed the most potent anti-PD-L1 effects with an IC₅₀ of 32.06 nM in the HTRF (homogenous time-resolved fluorescence) assay, better than <b>BMS-202</b> (IC₅₀ = 62.1 nM). In addition, the SPR (surface plasmon resonance) assay revealed that <b>GJ19</b> can effectively bind to human/murine PD-L1 protein with <i>K</i>_D values of 171 and 290 nM, respectively. Furthermore, <b>GJ19</b> concentration-dependently promoted HepG2 cell mortality in a co-culture model of HepG2/hPD-L1 and Jurkat T/hPD-1 cells. In the in vivo efficacy studies, <b>GJ19</b> (intraperitoneal injection, 15 mg/kg) effectively suppressed tumor growth with a TGI of 56.8% in a B16-F10 melanoma mouse model by activating antitumor immunity. In conclusion, <b>GJ19</b> represents a potential small molecule inhibitor of PD-L1, deserving further investigation for tumor immunotherapy.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244489","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":"Ferulic Acid Inhibits Partial Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells and Mitigates Renal Interstitial Fibrosis by Regulating the HIF-1α/Twist Signaling Pathway","authors":"Lin Xu,&nbsp;Dongsheng Yao,&nbsp;Tianying Lan,&nbsp;Yurou Chen,&nbsp;Dongping Chen,&nbsp;Minghai Shao,&nbsp;Yijing Zhou,&nbsp;Chaoyang Ye,&nbsp;Di Huang","doi":"10.1111/cbdd.70133","DOIUrl":"https://doi.org/10.1111/cbdd.70133","url":null,"abstract":"<div>\u0000 \u0000 <p>Ferulic acid (FA), a natural phenolic compound, shows potential therapeutic effects on renal interstitial fibrosis, although its antifibrotic mechanism remains unclear. This study investigated the molecular mechanisms of FA by focusing on epithelial-mesenchymal transition (EMT) and related signaling pathways. By using a hypoxia-induced HK2 cell model, the optimal FA concentration was determined by CCK-8 assay, and the cells were assigned to low-, medium-, and high-FA groups. Renal fibrosis-associated protein and mRNA levels were evaluated by western blotting (WB) and reverse transcription-quantitative polymerase chain reaction. In a 5/6 nephrectomy-induced chronic renal failure rat model, renal oxygen consumption, serum creatinine, and blood urea nitrogen levels were measured, while ultrastructural and morphological changes in renal tissues were examined by transmission electron microscopy (TEM), hematoxylin–eosin (HE) staining, and Masson's trichrome staining. Renal fibrosis-related indicators were further assessed by Western Blot (WB) and immunofluorescence assay. The results showed that FA treatment significantly reduced fibronectin, HIF-1α, and α-SMA expression; inhibited partial EMT in vivo and in vitro; improved renal function; and attenuated fibrosis in kidney tissues. Combining siTwist or oe-HIF-1α transfection with FA treatment revealed that FA targeted the HIF-1α/Twist signaling pathway, impeding EMT and delaying renal fibrosis. In conclusion, FA inhibited partial EMT of tubular epithelial cells and suppressed the HIF-1α/Twist pathway, thereby mitigating renal interstitial fibrosis and providing a foundation for FA-based treatment of chronic kidney disease.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244396","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":"Identification of a Selective Cell-Active Inhibitor of Protein Arginine Methyltransferase 5 (PRMT5) for the Treatment of Prostate Cancer by Structure-Based Virtual Screening","authors":"TongXiang Diao,&nbsp;Chen Feng,&nbsp;Shuai Liu,&nbsp;Jia-Li Song,&nbsp;Kong-kai Zhu,&nbsp;Cheng-Shi Jiang,&nbsp;Qiang Fu","doi":"10.1111/cbdd.70136","DOIUrl":"https://doi.org/10.1111/cbdd.70136","url":null,"abstract":"<p>Protein arginine methyltransferase 5 (PRMT5) is an epigenetic-related enzyme that has been shown to be a promising target for the treatment of human cancers. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the androgen receptor (AR), but this method has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. We hope to design and synthesize a new compound that can inhibit prostate cancer at different stages. A series of candidate PRMT5 inhibitor molecules were designed on the basis of virtual molecular docking screening, and the binding mode was predicted via molecular docking simulation. Prostate cancer cell proliferation was detected by CCK-8, EdU, and flow assays, which verified the changes in the cancer cell cycle. Migration and invasion assays verified the effects of the compounds on the metastatic function of prostate cancer cells. Finally, Western blotting was used to detect the mechanism of action of the compounds in the treatment of prostate cancer. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the AR, but it has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. <b>SJL2-1</b> may be a promising compound for novel therapies for early androgen-sensitive prostate cancer and advanced castration-resistant prostate cancer (CRPC).</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213776","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":"A Naturally Derived Glycosylated Oleanolic Acid Derivative Suppresses NF-κB Translocation and Induces Intrinsic Apoptosis in Lung Adenocarcinoma Cells","authors":"Sankar Pajaniradje,&nbsp;Srividya Subramanian,&nbsp;Kumaravel Mohankumar,&nbsp;Larance Ronsard,&nbsp;Parthiban Anaikutti,&nbsp;Rukkumani Rajagopalan","doi":"10.1111/cbdd.70137","DOIUrl":"https://doi.org/10.1111/cbdd.70137","url":null,"abstract":"<div>\u0000 \u0000 <p>This study investigates the molecular mechanism of action of F4B1, a novel oleanolic acid derivative in human lung adenocarcinoma cells. F4B1 is a naturally occurring oleanolic acid derivative that was isolated and purified from the leaves of <i>Sesbania grandiflora</i>. Structural analyses were carried out using 1D and 2D NMR, FT-IR, and mass spectrometric analyses. MTT assay was employed to evaluate antiproliferative effects in A549 (a model for lung cancer), MCF-7 (a model for breast cancer), HEP-2 (a model for head and neck cancer) and in MRC-5 (human lung fibroblast cells). Fluorescence staining, scanning electron microscopy, and flow cytometry were employed to study apoptosis and cell cycle. Western blotting, RT-PCR, and immunofluorescence techniques were followed to study the mechanisms of cell death. Schrodinger software was employed for docking studies. While preliminary screening was conducted in multiple cell lines, A549 cells were chosen for further mechanistic exploration based on their higher sensitivity to F4B1 treatment. F4B1 blocks the proliferation and causes intrinsic mode of cell death in lung adenocarcinoma cells. In particular, the above anticancer effect was mediated through a mechanism that is associated with the inactivation of NF-kappa B signaling and suppression of cyclin D1 expression leading to cell cycle arrest at the G1/S phase. Our study confirms that F4B1 induces apoptosis, as confirmed through Annexin V staining results. It is intrinsic apoptosis, as evidenced by upregulation of pro-apoptotic markers (BAX), downregulation of anti-apoptotic markers (BCL-2), cytochrome C release, activation of caspase-9, and caspase-3. These results establish the involvement of the mitochondrial-mediated apoptotic pathway. The pathway also involved the suppression of the proto-oncogene c-Myc both at the transcriptional and translational levels. Docking studies show that F4B1 has a high affinity binding towards CXCR4 and SRC kinase. Our findings specifically contribute to understanding the mechanism of F4B1, the isolated molecule from <i>S. grandiflora,</i> as an anticancer drug candidate and will hopefully pave the way toward further studies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213764","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":"Identification and Evaluation of Besifloxacin as Repurposed Antifungal Drug in Combination With Fluconazole Against Candida albicans","authors":"Shuvechha Chakraborty,&nbsp;Ameya Pawaskar,&nbsp;Siddhanath Metkari,&nbsp;Taruna Madan,&nbsp;Susan Idicula-Thomas","doi":"10.1111/cbdd.70138","DOIUrl":"https://doi.org/10.1111/cbdd.70138","url":null,"abstract":"<div>\u0000 \u0000 <p>Emergence of life-threatening fungal infections like systemic candidiasis concurrently with bacterial infections and limitations of current antifungal therapies warrant the discovery of novel inhibitors. We identified besifloxacin (BS), an FDA-approved antibacterial, as a potent antifungal inhibitor. A combination of besifloxacin with fluconazole showed a positive synergy (δ = 29.58) resulting in 80% inhibition of microbial growth. BS was able to reduce the MIC of FLC from 2 mg/L to 0.5 mg/L when used in combination. Additionally, in murine systemic <i>Candida</i> infection, BS reduced fungal load by 83% in mice kidneys at a dose of 100 mg/kg/day. The findings demonstrated the antifungal potential of BS, proposing its use in combination therapy with fluconazole to combat resistance through alternative mechanisms.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213876","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":"Kisspeptin-54 Restores Blood–Brain Barrier Integrity via GATA-4 in Ischemic Stroke","authors":"Weifeng Shan,&nbsp;Haiyan Lan,&nbsp;Yini Wu,&nbsp;Qiaomin Xu,&nbsp;Minji You,&nbsp;Ruijun Ma","doi":"10.1111/cbdd.70134","DOIUrl":"https://doi.org/10.1111/cbdd.70134","url":null,"abstract":"<div>\u0000 \u0000 <p>Ischemic stroke damages the blood–brain barrier (BBB), worsening neuronal injury. Treatments to protect the BBB are limited. We evaluated the neurovascular protective capacity of Kisspeptin-54 in ischemic stroke using in vivo and in vitro models. In vivo, mice underwent middle cerebral artery occlusion (MCAO), and cerebral infarct volume, neurological function, and blood–brain barrier (BBB) permeability were evaluated. In vitro, human brain microvascular endothelial cells (HBMVECs) were exposed to oxygen–glucose deprivation/reperfusion (OGD/R) to assess the effects of Kisspeptin-54 on paracellular flux and transendothelial electrical resistance (TEER). Additionally, GATA-4 was silenced to investigate its role in mediating protection. Our results showed that cortical ischemia downregulated KISS-1 metastasis-suppressor (KISS1, 59% mRNA; 55% protein) and G protein-coupled receptor 54 (GPR54, 54% mRNA; 48% protein), with a 32% decline in circulating Kisspeptin-54. Prophylactic Kisspeptin-54 reduced cerebral infarct volume by 42%, enhanced neurological performance by 49%, and decreased BBB leakage by 26%, with near-complete occludin recovery. In vitro: Kisspeptin-54 treatment reduced paracellular flux by 48% and increased transendothelial resistance by 60%. GATA-4 silencing abolished Kisspeptin-54-induced occludin restoration, increasing permeability by 65% and diminishing barrier resistance by 28%. This study reveals Kisspeptin-54 modulates BBB stability via GATA-4-driven occludin expression, highlighting the KISS1/GPR54 pathway as a potential therapeutic target for ischemic stroke.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190666","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":"Discovery of 1-(Cyclopropylmethyl)-2-(Dibenzo[b,d]Thiophen-2-yl)-1H-Benzo[d]Imidazole-5-Carboxylic Acid as Orally Bioavailable EP4 Receptor Antagonist","authors":"Sanjay Kumar,&nbsp;Rajib Chakraborty,&nbsp;Chandreyee Roy,&nbsp;Sohini Basu,&nbsp;Arun K. Hajra,&nbsp;Priyam Sen,&nbsp;Debajyoti Paul,&nbsp;Karabi Phukan,&nbsp;Subhasis Roy,&nbsp;Rammohan Bera,&nbsp;Trisha Mondal,&nbsp;Sabyasachi Chakraborty,&nbsp;Manish Banerjee,&nbsp;Susanta K. Mondal,&nbsp;Sonali Das,&nbsp;Pradip Malik,&nbsp;Surajit De Mandal,&nbsp;Enketeswara Subudhi,&nbsp;Mrinalkanti Kundu","doi":"10.1111/cbdd.70132","DOIUrl":"https://doi.org/10.1111/cbdd.70132","url":null,"abstract":"<div>\u0000 \u0000 <p>The prostaglandin E₂ (PGE₂) regulates several biological processes via interaction with 1 of 4 E-type prostanoid receptors (EP1–EP4). The E-type prostanoid receptor 4 (EP4) is expressed primarily on myeloid cells, T lymphocytes, and tumor cells, and has emerged as a major contributor to PGE₂-mediated enhancement of tumor survival pathways and as a suppressor of innate and adaptive antitumor immune responses. To date, significant work on the discovery of EP4 receptor antagonists has been carried out, but no compound has been approved for use in humans yet. Toward our aim of discovering potential EP4 antagonists, a pharmacophore-based scaffold-hopping approach combined with docking studies has been envisaged. As a result, compound 4 was found to be a non-toxic, potent EP4 antagonist binding in the orthosteric site. This compound exhibited good aqueous solubility, with acceptable in vitro metabolic stability and permeability. Albeit high protein binding, it displayed sustained exposure and significant oral bioavailability in mice and can thus have the potential for further optimization to yield next-generation EP4 antagonists.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179190","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":"Design, Synthesis, and Biological Activity of 8-Hydroxyurolithin A Class PDE2 Inhibitors","authors":"Qiulin Hu,&nbsp;Long Tang,&nbsp;Zhongqiu Xu,&nbsp;Fen Yan,&nbsp;Guoqiang Song,&nbsp;Xiaoqing Feng","doi":"10.1111/cbdd.70119","DOIUrl":"https://doi.org/10.1111/cbdd.70119","url":null,"abstract":"<div>\u0000 \u0000 <p>Urolithin A (UA) is a dibenzo[<i>b,d</i>]pyran-6-one polyhydroxy derivative produced as intestinal microbe metabolize ellagitannin and ellagic acid. Because of its superior anti-inflammatory and antioxidant effects, it can cure neuronal damage in a variety of ways and play a neuroprotective role. More and more research has revealed that UA is a potential medicine for the treatment of neurodegenerative diseases. Due to UA source limitations, it is insufficient to achieve disease treatment concentrations, and the activity of UA inhibiting PDE2 needs further enhancement. As a result, we used UA as the parent nucleus structure, independently designed and used Discovery Studio software to assist in the structural design and molecular docking screening of the compounds, and tested the in vitro enzyme activity of the synthesized compounds, hoping to obtain UA-based PDE2 inhibitors. The IC₅₀ of 6–18, 6–19, 6–20, 6–22, and 6–29 were 0.62, 0.85, 1.51, 1.09, and 1.58 μM, respectively. In this study, UA derivatives that can bind to the crystal structure of PDE2 protein 4HTX were proposed, which laid a groundwork for further structural modification, lead design, and development of small molecule inhibitors with inhibitory activity of PDE2.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148354","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 of Novel Thiazole/Thiadiazole Conjugates of Fluoroquinolones as Potent Antibacterial and Antimycobacterial Agents","authors":"Pınar Poyraz Yılmaz,&nbsp;Necla Kulabaş,&nbsp;Arif Bozdeveci,&nbsp;Siva Krishna Vagolu,&nbsp;Mohd Imran,&nbsp;Esra Tatar,&nbsp;Şengül Alpay Karaoğlu,&nbsp;Dharmarajan Sriram,&nbsp;Ammar A. Razzak Mahmood,&nbsp;İlkay Küçükgüzel","doi":"10.1111/cbdd.70126","DOIUrl":"https://doi.org/10.1111/cbdd.70126","url":null,"abstract":"<p>Twenty azole-fluoroquinolone hybrids were designed and synthesized by conjugating thiazole and thiadiazole structures to ciprofloxacin and norfloxacin via a 2-oxoethyl bridge. The structures and purities of the synthesized compounds were proven by spectral techniques. The antimycobacterial effects of target compounds <b>21–40</b> were tested against <i>Mycobacterium tuberculosis</i> H37Rv strain. Among the 20 synthesized compounds, 12 exhibited minimal inhibition concentration (MIC) values in the range of 1.56–25 μg/mL. Among the molecules screened for antimycobacterial effects, the most effective was compound <b>35</b>, a thiadiazole-ciprofloxacin hybrid. The cytotoxic effect of this molecule was found to be lower than the reference drugs, and it was also determined to be a more effective inhibitor than ciprofloxacin and norfloxacin in the DNA-gyrase supercoiling test. The antimicrobial effects of compounds <b>21–40</b> were screened by agar-well diffusion and microdilution tests against Gram-positive/negative bacteria, a fast-growing mycobacterium, and two yeast strains. While most of the compounds tested showed antibacterial effects, the most effective fluoroquinolone derivative appeared to be compound <b>31</b> with an MIC value of &lt; 0.63 μg/mL against all Gram-negative bacteria tested. Azole-fluoroquinolone hybrids <b>21–40</b> did not show any activity against non-pathogenic <i>Lactobacillus</i> species and yeast-like fungi, indicating that they have selective antibacterial and antimycobacterial activity, particularly against Gram-negative bacteria. <i>In silico</i> molecular docking studies were conducted to uncover the interactions between lead compound <b>35</b> and the DNA gyrase proteins of <i>M. tuberculosis</i> and <i>S. aureus</i>. Additionally, a 100 ns molecular dynamics simulation was carried out to assess the stability of the complexes formed between compound <b>35</b> and both proteins.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135680","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}