Chemical Biology & Drug Design最新文献

{"title":"Using Network Pharmacology and Transcriptome Sequencing to Investigate the Mechanism of Action of Luteolin and Quercetin in Treating Obesity","authors":"Ruoshuang Liu,&nbsp;Zhaoxiang Wang,&nbsp;Kangru Shi,&nbsp;Yirong Shen,&nbsp;Xiawen Yu,&nbsp;Caiqin Cheng,&nbsp;Yue Xia,&nbsp;Guoyu Dai,&nbsp;Zhicong Zhao,&nbsp;Yuyun Xiong,&nbsp;Dong Wang,&nbsp;Ling Yang,&nbsp;Guoyue Yuan,&nbsp;Jue Jia","doi":"10.1111/cbdd.70061","DOIUrl":"https://doi.org/10.1111/cbdd.70061","url":null,"abstract":"<div>\u0000 \u0000 <p>Luteolin and quercetin, which are flavonoids, are present in various traditional Chinese medicines. Although they have been shown to improve obesity, the specific mechanisms of action remain unclear. This study aimed to determine pivotal targets and major regulatory pathways involved in their mechanisms of action using network pharmacology and transcriptome sequencing. Data on luteolin/quercetin-related targets were acquired from the PharmMapper platform, and data on known obesity-related targets were collected from the OMIM and GeneCards databases. Differentially expressed genes (DEGs) involved in luteolin and quercetin action that regulate adipogenic differentiation were identified using RNA sequencing (RNA-seq). Bioinformatic analyses were performed to identify potential target genes and pathways regulated by luteolin/quercetin during adipogenesis. Finally, key genes and pathways were validated through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Network pharmacology showed that luteolin/quercetin was closely associated with anti-obesity targets. The related pathways were metabolic, PI3K/AKT, and MAPK pathways. RNA-seq revealed 91 common DEGs involved in luteolin/quercetin regulation of adipogenic differentiation. Finally, nine potential target genes (including CIDEC, Mgll, Slc2a4, Pck1, and PNPLA3) were identified, and the AMPK and AKT signaling pathways were verified. The present study provides novel information regarding the molecular mechanism of luteolin and quercetin action in treating obesity and demonstrates their therapeutic effects through multiple targets and pathways.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248571","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":"Embelin Elevates Endoplasmic Reticulum Calcium Levels and Blocks the Sterol Regulatory Element-Binding Protein 2 Mediated Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Improves the Low-Density Lipoprotein Receptor Mediated Lipid Clearance on Hepatocytes","authors":"Mahesh Chandran,&nbsp;K. B. Rameshkumar,&nbsp;Abdul Jaleel,&nbsp;Janeesh Plakkal Ayyappan","doi":"10.1111/cbdd.70055","DOIUrl":"https://doi.org/10.1111/cbdd.70055","url":null,"abstract":"<div>\u0000 \u0000 <p>Cardiovascular diseases (CVDs) continue to be one of the leading causes of morbidity and mortality worldwide, with a significant increase in recent years. Atherosclerosis, the pathological basis and prime reason for CVDs is primarily driven by dysregulated lipid metabolism and inflammation. Recently, proprotein convertase subtilisin kexin9 (PCSK9) has been evolved to be highly implicated in the circulatory low-density lipoprotein cholesterol levels by its modulatory effects on the low-density lipoprotein receptor (LDLR) mediated clearance. Even though not economical, the therapies targeting PCSK9 demonstrated appreciable levels of efficiency in managing hyperlipidaemic conditions. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a naturally occurring para-benzoquinone isolated from dried berries of Embelia ribes, which possess several effects in maintaining the cholesterol homeostasis. In this study, we have analysed the role of embelin in sterol regulatory element-binding protein 2 (SREBP2) mediated PCSK9 expression in cultured hepatocytes. The study showed that the embelin treatment attenuates the endoplasmic reticulum (ER) stress-induced reactive oxygen species levels and ER stress markers on cultured hepatocytes. The treatment of embelin modulates the mRNA and protein level expression of SREBP2 and its downstream targets like PCSK9, LDLR, and HMG-CoA reductase (HMGCR). Interestingly the Ca2+ levels and the calcium binding protein of ER were significantly increased with embelin treatment. The work revealed a putative mechanism of embelin in lowering PCSK9 levels by boosting ER Ca2+ levels, thereby blocking SREBP2 nuclear translocation. Further, this reduces LDLR degradation and increases receptor-mediated circulatory lipid clearance. The study summarized the potential clinical applications of embelin in addressing the cardio vascular diseases.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111527","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":"Biochemical and Structural Studies of Protein Tyrosine Phosphatase PTP-PEST (PTPN12) in Search of Small Molecule Inhibitors","authors":"Delna Johnson,&nbsp;Madhulika Dixit,&nbsp;Sivapriya Kirubakaran","doi":"10.1111/cbdd.70058","DOIUrl":"10.1111/cbdd.70058","url":null,"abstract":"<div>\u0000 \u0000 <p>PTP-PEST (also known as PTPN12) regulates cellular signaling and transduction pathways by dephosphorylating its substrate. PTP-PEST is considered an important drug target owing to its involvement in cancer progression and myocardial injury. Till now only a few inhibitors are currently being studied in the inhibition of PTP-PEST, majorly belonging to the class of metal-based drugs. In this study, we aimed to investigate small molecules that could potentially inhibit PTP-PEST for further development of PTP-PEST inhibitors. As an approach, we used an in silico molecular docking technique to screen an in-house synthesized molecular library. Further, we validated the docking results by in vitro inhibition screening of the best molecules using the purified catalytic domain of human PTP-PEST, which was over-expressed in <i>E.coli</i>. We identified a myo-inositol based derivative, J1-65, which binds to PTP-PEST and results in the competitive inhibition of the protein. Further, we confirmed this protein-ligand binding using binding affinity studies based on protein thermal shift assay and in silico molecular dynamic simulations. Our efforts to discover a novel scaffold for inhibiting hPTP-PEST mark a crucial stride in laying the groundwork for the future development of selective PTP-PEST inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082584","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 Evaluation of Aryl Pyrazolopyrimidines as Toll-Like Receptor 7 Agonists","authors":"Ji Hwan Kim,&nbsp;Youngshim Lee,&nbsp;Seunghyun Ahn,&nbsp;Dongsoo Koh,&nbsp;Yoongho Lim,&nbsp;Young Han Lee,&nbsp;Dong-Ho Bae,&nbsp;Soon Young Shin","doi":"10.1111/cbdd.70056","DOIUrl":"10.1111/cbdd.70056","url":null,"abstract":"<div>\u0000 \u0000 <p>Compounds containing pyrazolopyrimidine scaffolds were designed and synthesized as toll-like receptor 7 (TLR7) agonists. Thirty-three compounds, including 22 novel compounds, were prepared, and their structures were identified using nuclear magnetic resonance spectroscopy and mass spectrometry. TLR7 agonist activity was determined in HEK-Blue hTLR7 reporter cells. Among the compounds tested, 2-((4-methoxyphenyl)amino)-7-(pyridin-2-yl)pyrazolo[1,5<i>-a</i>]pyrimidine-3-carbonitrile showed the highest activity, and further in vitro biological experiments were performed using this compound. Treatment with the title compound activated the TLR7-mediated NF-κB pathway, triggering the IRAK4-IKKα/β-IκBα-p65 NF-κB signaling cascade, which led to an increase in the expression of NF-κB-regulated innate cytokines such as TNFα and IL-1β in RAW264.7 macrophages. These findings suggest that the title compound acts as a TLR7 agonist and enhances the innate immune response.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070260","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 Evaluation of Novel 9H Purine Derivatives as Potent CDK9 Inhibitors","authors":"Chunlei Tang,&nbsp;Dong Wang,&nbsp;Huabing Wang,&nbsp;Shengkai Cui,&nbsp;Weizheng Fan,&nbsp;Yan Zhang","doi":"10.1111/cbdd.70062","DOIUrl":"10.1111/cbdd.70062","url":null,"abstract":"<div>\u0000 \u0000 <p>Cyclin-dependent kinase 9 (CDK9) is considered as an important target in the research of antitumor drugs. Taking the CDK2/9 inhibitor CYC065 as the positive control and an in-house library compound (<b>64</b>) as the lead compound, four classes of 22 target compounds with 9H purine as the core structure were designed to establish structure–activity relationships (SAR). In general, SAR of 9H purine CDK9 inhibitors is systematically described in this paper, resulting in the discovery of two compounds (<b>B2</b> and <b>B5</b>) with further research value. After conducting selectivity testing against CDK2/9 kinase, compound <b>B5</b> demonstrated approximately five-fold greater selectivity towards CDK9-cyclinT1 over CDK2-cyclinE2. This work also provides a reference basis for the subsequent research on CDK9 inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070256","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":"Combination of Metabolomics and Bioinformatics to Reveal the Mechanism of Luteolin in the Treatment of Cervical Cancer","authors":"Dong-min Cao,&nbsp;Yin Rao,&nbsp;Tao Liu,&nbsp;Wei-qu Yuan","doi":"10.1111/cbdd.70059","DOIUrl":"10.1111/cbdd.70059","url":null,"abstract":"<div>\u0000 \u0000 <p>The incidence of cervical cancer is high among women globally. The potential therapeutic efficacy of luteolin in the treatment of cervical cancer has been identified. Therefore, we aim to elucidate the mechanism of action of luteolin in the treatment of cervical cancer through a comprehensive approach that integrates metabolomics with bioinformatics. The first step involved the identification of differential metabolites through UHPLC-Q-Orbitrap-MS, which were then utilized for enrichment analysis of metabolic pathways and to determine the targets associated with these differential metabolites. Subsequently, the differential analysis and WGCNA were employed to identify DEGs and functional module genes respectively. The common targets were obtained by intersecting the results from the aforementioned three analyses, followed by conducting GO and KEGG pathway enrichment analysis on these targets. Subsequently, PPI networks were constructed using these common targets, and key targets were identified utilizing the MCC, EPC, Degree, Closeness Centrality, Betweenness Centrality, and Bottleneck algorithms in the CytoHubba plug-in. The subsequent steps involved the analysis of key genes for constructing a nomogram, conducting a ROC curve, examining content expression and survival analysis, and ultimately employing molecular docking to investigate the interaction between luteolin and crucial targets. The metabolomics analysis revealed the identification of a total of 45 distinct metabolites in this study, primarily associated with amino acid and nucleotide metabolism. The intersection of 773 differential metabolite targets, 3493 cervical cancer differential genes, and 3245 WGCNA-associated module genes yielded a set of 32 target genes associated with luteolin therapy for cervical cancer. The GO and KEGG pathway enrichment analysis also revealed that these targets were primarily associated with amino acid metabolism and nucleotide metabolism. The CytoHubba plug-in was utilized to identify three key genes (DMNT1, EZH2, and GMPS) through the application of multiple algorithms. Additionally, the datasets GSE63514, GSE67522, and GEPIA2 revealed a significant upregulation of all three genes in tumor tissue. ROC analysis demonstrated the good predictive ability of these three hub genes. Finally, the molecular docking results demonstrated the high binding affinity of luteolin towards DMNT1, EZH2, and GMPS. In conclusion, this study has unveiled the potential of luteolin in modulating amino acid and nucleotide metabolism for the treatment of cervical cancer, thereby providing a theoretical foundation for further investigation into the intricate association between luteolin and cervical cancer.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070253","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":"Polyphyllin VII Enhances the Sensitivity of Prostate Cancer Cells to Docetaxel by Promoting Mitochondrial Dysfunction and Inducing Ferroptosis","authors":"Yun-Yi Chen,&nbsp;Wen-Xi Hua,&nbsp;Yu-Hua Huang,&nbsp;Xiang Ding","doi":"10.1111/cbdd.70053","DOIUrl":"10.1111/cbdd.70053","url":null,"abstract":"<div>\u0000 \u0000 <p>Docetaxel (DTX) is the preferred chemotherapeutic drug for prostate cancer (Pca), but the emergence of resistance has significantly reduced its efficacy. Polyphyllin VII (PPVII), a small molecule natural product derived from the traditional herb Paris polyphylla, has shown anticancer potential. This study aims to investigate the effects and mechanisms of PPVII combined with DTX in treating Pca. DTX-sensitive DU-145 cells and DTX-resistant DU145/DTX cells were utilized for experiments in this study. Cell viability was assessed using MTT assays, while apoptosis, cell cycles, and ferroptosis were analyzed through flow cytometry and Western blot. Mitochondrial function was evaluated using immunofluorescence. Additionally, the expression of proteins related to the AMP-activated protein kinase/mammalian target of the rapamycin/S6 kinase (AMPK/mTOR/S6K) signaling pathway was also examined to further investigate the underlying mechanisms. PPVII significantly enhanced the inhibitory effect of DTX, reduced cell viability (<i>p</i> &lt; 0.05), and promoted apoptosis (<i>p</i> &lt; 0.05) and cell cycle arrest (<i>p</i> &lt; 0.05). Specifically, PPVII increased the sensitivity of Pca cells to DTX by inducing ferroptosis and affecting mitochondrial function. Notably, the activation of the AMPK/mTOR/S6K signaling pathway played a crucial role in this process. This study revealed the synergistic effects and potential mechanisms of PPVII combined with DTX in Pca cells, and provided a reference for effectively overcoming DTX resistance in the clinical treatment of Pca.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 2","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054582","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":"N-Substituted-5- [(2,5-Dihydroxybenzyl)amino]salicylamides as Lavendustin Analogs: Antiproliferative Activity, COMPARE Analyses, Mechanistic, Docking, ADMET and Toxicity Studies","authors":"Hajjaj H. M. Abdu-Allah,&nbsp;Mohamed K. S. El-Nagar,&nbsp;Wesam S. Qayed,&nbsp;Ola I. A. Salem,&nbsp;Abdel-Hamid N. Kafafy,&nbsp;Raafat El-Awady,&nbsp;Mariam A. Nicola","doi":"10.1111/cbdd.70052","DOIUrl":"10.1111/cbdd.70052","url":null,"abstract":"<div>\u0000 \u0000 <p>Target cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors; 5-([2,5-Dihydroxybenzyl]amino)salicylamides (Compounds <b>1</b>–<b>11</b>) were examined for potential anticancer activity, with a trial to assess the underlying possible mechanisms. Compounds were assessed at a single dose against 60 cancer cell lines panel and those with the highest activity were tested in the five-dose assay. COMPARE analysis was conducted to explore potential mechanisms underlying their biological activity. In vitro epidermal growth factor receptor (EGFR) inhibitory activity was performed, as well as cell cycle and apoptosis assays, in addition to molecular docking to rationalize the potential of these compounds as potent EGFR inhibitors. The compounds revealed broad-spectrum anticancer activity against most cancer cell lines, particularly those of leukemia. Compound <b>9</b> showed the maximum growth inhibition (99.65%) against <i>leukemia HL-60</i> (<i>TB</i>) cell line. Compound <b>5</b> produced the uppermost cytotoxic activity (62.28%) against <i>non-small cell lung cancer cell line</i> (<i>NCI-H522</i>), and the most potent antiproliferative and cytotoxic activities against the same cell line in the five-dose assay. Flow cytometry of cell cycle distribution on <i>NCI-H522</i> showed arrest of cells at different phases of the cycle by Compounds <b>4</b>, <b>5</b>, <b>9</b>–<b>11</b>. These compounds induced apoptosis in <i>NCI-H522</i>, particularly Compounds <b>4</b> and <b>5</b>. They showed a remarkable in vitro EGFR inhibitory activity that was comparable to erlotinib, and a predicted ADME pharmacokinetic profile. In conclusion, the <i>N</i>-substituted aminosalicylamides exhibited considerable anticancer activity. The pattern of <i>N</i>-substitution is important in their activity. The compounds exhibited polypharmacology; one of the targets is the EGFR, as supported by molecular docking.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048483","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":"Coumarin Analogues as Promising Anti-Obesity Agents: In Silico Design, Synthesis, and In Vitro Pancreatic Lipase Inhibitory Activity","authors":"Nisha Yadav,&nbsp;Atish T. Paul","doi":"10.1111/cbdd.70046","DOIUrl":"10.1111/cbdd.70046","url":null,"abstract":"<div>\u0000 \u0000 <p>A set of coumarin-3-carboxamide analogues were designed, synthesized, and evaluated for their ability to impede pancreatic lipase (PL) activity. Out of all the analogues, <b>5dh</b> and <b>5de</b> demonstrated promising inhibitory activity against PL, as indicated by their respective IC₅₀ values of 9.20 and 11.4 μM, as compared to Orlistat (IC₅₀ = 0.97 μM). It was found that analogue <b>5dh</b> inhibited PL in a competitive manner with an inhibition constant (<i>K</i>_i) of 4.504 μM. Additionally, the docking analysis validated the interactions between the analogue <b>5dh</b> (MolDock score of −140.251 kcal/mol) and key amino acids in the active site, including Leu 153, Gly 76, Arg 256, His 151, Phe 77, and His 263. The inhibitory activity of these analogues was significantly correlated with their MolDock scores (Pearson's <i>r</i> = 0.6586). Finally, molecular dynamics simulation was also performed for 100 ns in order to elucidate the stability, confirmation and intermolecular interactions of the active analogue <b>5dh</b>. The results of this investigation suggested that the complex maintained its stability despite the dynamic conditions exhibiting interactions with important amino acids. In summary, the outcomes indicated that the synthesized analogues exhibited the potential to inhibit PL activity.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048288","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":"The Significance of Mono- and Dual-Effective Agents in the Development of New Antifungal Strategies","authors":"Cengiz Zobi,&nbsp;Oztekin Algul","doi":"10.1111/cbdd.70045","DOIUrl":"10.1111/cbdd.70045","url":null,"abstract":"<p>Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current antifungal drugs target the fungal cell membrane, cell wall, or intracellular components, but resistance mechanisms such as altered drug-target interactions, enhanced efflux, and adaptive cellular responses have diminished their efficacy. Recent research has highlighted the potential of dual inhibitors that simultaneously target multiple pathways or enzymes involved in fungal growth and survival. Combining pharmacophores, such as lanosterol 14α-demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), and squalene epoxidase (SE) inhibitors, has led to the development of compounds with enhanced antifungal activity and reduced resistance. This dual-target approach, along with novel chemical scaffolds, not only represents a promising strategy for combating antifungal resistance but is also being utilized in the development of anticancer agents. This review explores the development of new antifungal agents that employ mono-, dual-, or multi-target strategies to combat IFIs. We discuss emerging antifungal targets, resistance mechanisms, and innovative therapeutic approaches that offer hope in managing these challenging infections.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025785","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}