Bioorganic Chemistry最新文献

{"title":"Modular synthesis of isoxazolopyrimidine derivatives with anti-SARS-CoV-2 activity","authors":"Hui Chen ,&nbsp;Xin Wang ,&nbsp;Lianyou Zheng ,&nbsp;Lingling Shi ,&nbsp;Zhaoliang Chen ,&nbsp;Lei Zhang ,&nbsp;Yan Zhang ,&nbsp;Qiansong Gao ,&nbsp;Jie Wang ,&nbsp;Zhuoqi Zhang ,&nbsp;Zhendong Guo ,&nbsp;Jinbao Xiang","doi":"10.1016/j.bioorg.2025.108992","DOIUrl":"10.1016/j.bioorg.2025.108992","url":null,"abstract":"<div><div>A highly efficient synthetic route for the preparation of isoxazolopyrimidine derivatives has been developed, characterized by mild reaction conditions, operational simplicity and high yields. Building on this, we further functionalized the isoxazolopyrimidine scaffold to synthesize 7-morpholinoisoxazolo[4,5-<em>d</em>]pyrimidine derivatives. <em>In vitro</em> evaluations revealed that compounds <strong>5a</strong> and <strong>6</strong><strong>g</strong> demonstrated significant anti-SARS-CoV-2 activity. Mechanistic studies indicated that the antiviral effects of <strong>5a</strong> and <strong>6</strong><strong>g</strong> were mediated through the inhibition of PI3K<em>δ</em> kinase, highlighting their potential as targeted therapeutic agents. Moreover, <em>in vivo</em> experiments conducted in a golden hamster model demonstrated that compound <strong>5a</strong> effectively suppressed SARS-CoV-2 replication in lung tissue, underscoring its therapeutic potential for combating COVID-19. These findings collectively suggest that isoxazolopyrimidine derivatives, particularly <strong>5a</strong>, represent promising candidates for further development as anti-SARS-CoV-2 therapeutics.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108992"},"PeriodicalIF":4.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel flavonoid-based fluorescent probes for site-specific differentiation of human and bovine serum albumin: Visualizing quantitative research in urinary HSA","authors":"Xianfeng Ma ,&nbsp;Zixian Shen ,&nbsp;Xiaolan Liang ,&nbsp;Jiahui Wang ,&nbsp;Hua Wang ,&nbsp;Mingqi Wang ,&nbsp;Xiaofeng Yu","doi":"10.1016/j.bioorg.2025.108988","DOIUrl":"10.1016/j.bioorg.2025.108988","url":null,"abstract":"<div><div>Human serum albumin (HSA) is the most abundant protein in serum and is essential for maintaining human health. Abnormal levels have been associated with a variety of diseases, making it an important disease-diagnostic biomarker and therapeutic monitoring indicator. Due to the high structural similarity between human serum albumin (HSA) and bovine serum albumin (BSA), the detection and differentiation of these two proteins have garnered significant attention. In this study, we reported three rationally engineered flavonoid fluorescent probes capable of selectively detecting and distinguishing HSA from BSA. Among these compounds, <strong>HTN2</strong> exhibited a markedly enhanced fluorescence response to HSA with a detection limit of 4.8 nM, while <strong>HTN3</strong> demonstrated a significantly amplified fluorescence response to BSA with a detection limit of 1.4 nM. Notably, the interaction between <strong>HTN2</strong> and HSA was entropy-driven, whereas <strong>HTN3</strong> binding to BSA was enthalpy-driven. Molecular docking experiments investigated the intrinsic reasons for the differing selectivity of the nitrogen-containing six-membered heterocycles toward HSA versus BSA. Furthermore, the <strong>HTN2</strong> probes were successfully applied to detect HSA in real urine samples, offering a reliable approach for HSA analysis in biological fluids. The results showed that introducing the nitrogen heterocycle improved selectivity for HSA and BSA. <strong>HTN2</strong> entered the hydrophobic pocket of HSA effectively; however, when bound to BSA, the nitrogen heterocycle was partially exposed and formed interactions poorly. This provides an effective method for designing specific probes</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108988"},"PeriodicalIF":4.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted protein degradation in pancreatic cancer: advances and challenges of PROTAC-based therapeutics","authors":"Mingyao Huang ,&nbsp;Fang Wei ,&nbsp;Jilong Cao ,&nbsp;Hongzhou Jiang","doi":"10.1016/j.bioorg.2025.108985","DOIUrl":"10.1016/j.bioorg.2025.108985","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the deadliest malignancies, with limited therapeutic options and a dismal prognosis<strong>.</strong> Traditional treatment modalities, including chemotherapy and molecular targeted therapies, often face challenges such as drug resistance, limited targetability, and systemic toxicity. The emergence of proteolysis-targeting chimeras (PROTACs) has opened a new frontier in targeted protein degradation, offering a promising approach to overcome these limitations by hijacking the ubiquitin–proteasome system to selectively degrade disease-related proteins. This review provides a comprehensive overview of the design principles and molecular components of PROTACs, including POI ligands, E3 ligase ligands, and linker strategies. We further highlight recent progress in the application of PROTACs in pancreatic cancer therapy, focusing on their ability to target oncogenic kinases, epigenetic regulators, antiapoptotic proteins, metabolic regulators, and transcription factors. Despite significant advances, the clinical translation of PROTACs faces multiple challenges, including poor cell permeability, off-target effects, tissue toxicity, and acquired resistance. Finally, we discuss future perspectives on rational design, tissue-specific delivery systems, and combination strategies to fully realize the therapeutic potential of PROTACs in pancreatic cancer treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108985"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of novel 2, 6-Di-substituted Imidazo[1,2-a]pyridine derivatives as potent METTL3 inhibitors","authors":"Ruoyang Miao ,&nbsp;Xiaohan Wu ,&nbsp;Ning Wang ,&nbsp;Linnan Zhao ,&nbsp;Guanghe Zhu ,&nbsp;Ruiying Zhu ,&nbsp;Han Wei ,&nbsp;Chunxia Liu ,&nbsp;Weiyan Cheng ,&nbsp;Xin Tian","doi":"10.1016/j.bioorg.2025.108980","DOIUrl":"10.1016/j.bioorg.2025.108980","url":null,"abstract":"<div><div>METTL3, the core catalytic subunit of the <em>N</em>⁶-methyladenosine (m⁶A) methyltransferase complex, aberrantly overexpressed in various cancers and emerged as a potential target for cancer treatment. Here, we report the discovery of a series of 2, 6-di-substituted imidazo[1,2-<em>a</em>]pyridine derivatives as novel, potent, and selective METTL3 inhibitors. Compound <strong>30t</strong> exhibited excellent inhibitory activity against METTL3 with an IC₅₀ value of 45.31 nM and good antiproliferation ability in ovarian cancer SKOV3 and acute myeloid leukemia MOLM-13 cells with IC₅₀ values of 6.42 μM and 12.34 μM, respectively. Compound <strong>30t</strong> exhibited high selectivity towards METTL3 compared to DNMT1, EZH1, MLL1, and PRMT1. In addition, <strong>30t</strong> reduced the m⁶A level of total RNA in MOLM-13 and SKOV3 cells, induced cell apoptosis, and inhibited cell migration. Western blot assay demonstrated that <strong>30</strong>t could reduce the expression of m⁶A downstream target genes (c-MYC and BCL2). Meanwhile, compound <strong>30t</strong> displayed good pharmacokinetic properties and favorable antitumor activity <em>in vivo</em>. Collectively, this study provides a novel compound for further development of anticancer drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108980"},"PeriodicalIF":4.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rapid-response red-emitting probe for peroxynitrite fluctuation and silymarin protection in drug-induced hepatotoxicity","authors":"Pengcheng Zhang,&nbsp;Xiaoyu Wang,&nbsp;Zhipeng Sai,&nbsp;Conghui Lu,&nbsp;Yan Yang,&nbsp;Zhijun Yang,&nbsp;Chunpo Ge","doi":"10.1016/j.bioorg.2025.108986","DOIUrl":"10.1016/j.bioorg.2025.108986","url":null,"abstract":"<div><div>Drug-induced liver injury (DILI) is a clinically important condition caused by hepatotoxic drugs or their reactive metabolites, frequently linked to excessive reactive oxygen species (ROS) generation. Given the pivotal role of peroxynitrite (ONOO⁻) in oxidative stress-mediated DILI progression, real-time tracking of its spatial-temporal dynamics is critical for mechanistic studies. We present a red-emitting fluorescent probe, LD-ONOO, engineered with a naphthylamide-based fluorophore and a phenylboronic acid pinacol ester as the ONOO⁻-specific trigger. This probe demonstrates ultrafast response kinetics (&lt;30 s), a remarkably large Stokes shift (163 nm), and exceptional selectivity and sensitivity for ONOO⁻ over competing ROS. LD-ONOO enabled real-time monitoring of endogenous ONOO⁻ fluctuations in both cellular and zebrafish models. In vivo imaging in a DILI mouse model revealed pronounced ONOO⁻ upregulation, directly implicating its pathological role. Notably, silymarin treatment effectively normalized ONOO⁻ levels, demonstrating the therapeutic potential of this traditional Chinese medicine-derived compound in mitigating DILI. Our study not only delivers a versatile molecular imaging tool for investigating ONOO⁻-associated hepatotoxicity but also provides experimental validation for the application of natural compounds in DILI intervention strategies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108986"},"PeriodicalIF":4.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating molecular imaging with near-infrared theranostics to improve early detection and therapy of Alzheimer's disease","authors":"Gaurav Mahajan ,&nbsp;Kalpana Pandya ,&nbsp;Avanish Tripathi ,&nbsp;Devendra Kumar","doi":"10.1016/j.bioorg.2025.108949","DOIUrl":"10.1016/j.bioorg.2025.108949","url":null,"abstract":"<div><div>Alzheimer's disease (AD) remains a significant unmet clinical need due to its asymptomatic prodromal phase and multifaceted pathophysiology, which comprises amyloid-β (Aβ) plaques characterized by neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Conventional diagnostic methods, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), detect AD only after extensive neuronal loss. Recent progress in chemical biology has enabled the creation of multifunctional small-molecule theranostic probes that integrate diagnostic imaging with therapeutic intervention. This review emphasizes the design and molecular engineering of new probes in particular, near-infrared (NIR) dyes, aryl quinolines, cyanine-based fluorophores, and curcumin derivatives, which are highly specific for Aβ and tau aggregates, penetrate the blood-brain barrier (BBB) effectively, and are amenable to multimodal imaging including near-infrared imaging (NIR) fluorescence, MRI, PET. These probes commonly contain donor-acceptor motifs and exhibit environment-sensitive fluorescence, allowing for the real-time imaging of pathological protein aggregation. Furthermore, we consider dual-mode probes, such as PiB-C and BTTA, which combine metal chelation therapy with imaging, providing a targeted approach to disaggregate Aβ plaques concurrently visualizing therapeutic effectiveness. Through the combination of synthetic chemistry, molecular imaging, and neurotherapeutics, this transdisciplinary approach outlines a promising new paradigm for early AD detection and treatment. The development of these small-molecule theranostics presents new opportunities for personalized medicine in treating neurodegenerative diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108949"},"PeriodicalIF":4.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bis-quaternary ammonium BODIPY derivatives: Photophysical, antimicrobial, and antitumor photodynamic applications","authors":"Mingjie Wang ,&nbsp;Feng Xiao ,&nbsp;Le Mi ,&nbsp;Han Qian ,&nbsp;Yijing Zhang ,&nbsp;Sandra Kalil Bussadori ,&nbsp;Vanderlei S. Bagnato ,&nbsp;Muthumuni Managa ,&nbsp;Mohamed Elagawany ,&nbsp;Tebello Nyokong ,&nbsp;Yingyuan Peng ,&nbsp;Yijia Yan ,&nbsp;Zhi Long Chen","doi":"10.1016/j.bioorg.2025.108982","DOIUrl":"10.1016/j.bioorg.2025.108982","url":null,"abstract":"<div><div>Although Boron-dipyrromethene (BODIPY) derivatives have been explored for photodynamic antibacterial or antitumor applications, respectively, dual-activity cationic BODIPY photosensitizers have received much less attention. In addition, traditional quaternary ammonium compounds (QACs) are primarily studied as antibacterial agents, with systematic reports on their direct antitumor activity remaining scarce. We developed bis-quaternary ammonium cationic BODIPY derivatives as photosensitizers to investigate dual photodynamic antibacterial/antitumor action. All synthesized new compounds demonstrated notable UV-vis absorption in the range of 646-659 nm, intense fluorescence emission (665, 670, and 675 nm), and capabilities for reactive oxygen species (ROS) generation. Among these, brominated BODIPYs <strong>II</strong>_{<strong>3</strong>} and <strong>II</strong>_{<strong>5</strong>} exhibited high ROS generation efficiency and significant photodynamic antitumor activity against Eca-109 cells <em>in vitro</em> (IC₅₀ = 0.22 μM and 0.36 μM) and <em>in vivo</em>, comparable to the control drug <em>m</em>-THPC. Compounds <strong>I</strong>_{<strong>5</strong>} and <strong>II</strong>_{<strong>5</strong>} demonstrated substantial photodynamic antibacterial activities against pathogenic <em>Staphylococcus aureus</em> (<em>S. aureus</em>), with minimum inhibitory concentrations (MIC) of 0.5 μg/mL for both compounds. Furthermore, they achieved effective biofilm inhibition efficiencies of 86.74% and 85.23%, respectively, through the disruption of membrane integrity. These findings hold significant promise for pioneering new multifunctional photosensitizers that enable combined or sequential antimicrobial and antitumor photodynamic therapies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108982"},"PeriodicalIF":4.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 potential anti-nontuberculous mycobacterial drug candidate targeting a mycothiol disulfide reductase","authors":"Tianyu Liu ,&nbsp;Yong Nian ,&nbsp;Ying Liu ,&nbsp;Simin Xu ,&nbsp;Chujie Lu ,&nbsp;Wei Yang ,&nbsp;Wei Chen ,&nbsp;Wei Lin","doi":"10.1016/j.bioorg.2025.108981","DOIUrl":"10.1016/j.bioorg.2025.108981","url":null,"abstract":"<div><div>The resistance of nontuberculous mycobacteria (NTM) to conventional anti-tuberculosis drugs and its growing infection rate year by year urgently require new treatment strategies. Structure-based virtual screening, which can greatly improve efficiency and reduce costs in the early stage of drug development, is an indispensable part of modern drug discovery. In this study, the crystal structure of the mycothiol disulfide reductase from <em>Mycobacterium abscessus</em> (<em>Mab</em>Mtr) was determined. Through virtual screening, compound AK-968/11492032 was identified as a promising candidate capable of fitting well into the potential MSSM-binding pocket of <em>Mab</em>Mtr. It was discovered that AK-968/11492032 and its derivatives (<strong>Y6B</strong> and <strong>Y6C</strong>) could produce antimicrobial effects on the <em>Mycobacterial</em> type strain <em>Mycobacterium smegmatis</em>. Moreover, microscale thermophoresis analysis was employed to evaluate the high binding affinity of the compounds to <em>Mab</em>Mtr. Furthermore, the key residues (S14, I47, H451) of <em>Mab</em>Mtr involved in the interaction with AK-968/11492032 were predicted and confirmed through molecular docking and mutational analysis, <em>Mab</em>Mtr was verified as the target for it to exert antibacterial effects through <em>in vitro</em> enzyme activity and <em>in vivo</em> gene knockout, complementation, and overexpression. These findings provide a potential development target to develop effective and specific anti-NTM drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108981"},"PeriodicalIF":4.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design of tirabrutinib derivatives as inhibitors of bacterial tryptophanyl-tRNA synthetase","authors":"Kaijiang Xia ,&nbsp;Xiaoying Peng ,&nbsp;Lingzhen Xiao ,&nbsp;Qingting Huang ,&nbsp;Jingyi Xu ,&nbsp;Bingyi Chen ,&nbsp;Huihao Zhou","doi":"10.1016/j.bioorg.2025.108978","DOIUrl":"10.1016/j.bioorg.2025.108978","url":null,"abstract":"<div><div>The escalating threat of antibiotic resistance poses a critical challenge to global public health, necessitating the urgent development of novel therapeutic agents with distinct mechanisms of action and unique structural scaffolds. Tryptophanyl-tRNA synthetase (TrpRS) has emerged as a promising antibacterial target. Our previous study demonstrated that the clinically utilized Bruton's tyrosine kinase (BTK) inhibitor tirabrutinib, along with several of its analogues, can simultaneously occupy both the substrates <span>l</span>-Trp and tRNA^Trp A76 binding sites of <em>Escherichia coli</em> tryptophanyl-tRNA synthetase (<em>Ec</em>TrpRS), thereby effectively inhibiting its catalytic activity. Building on this finding, we employed structure-based drug design to systematically optimize the interactions of tirabrutinib analogues with the <span>l</span>-Trp and tRNA^Trp binding sites, as well as to further extend the structure to the adjacent ATP binding site within the catalytic pocket of <em>Ec</em>TrpRS to establish additional interactions, leading to the design and synthesis of 22 new derivatives. Among these, <strong>WRS22</strong> (a racemic mixture) demonstrated the best binding to <em>Ec</em>TrpRS, with a Δ<em>T</em>_m value of 33.2 °C and 90 % inhibition rate at 10 μM concentration. Its binding affinity for <em>Ec</em>TrpRS (<em>K</em>_d = 0.33 ± 0.03 μM) is superior to that of the positive control, indolmycin (<em>K</em>_d = 0.71 ± 0.1 μM). Notably, <strong>WRS22</strong> displayed no affinity to human cytoplasmic TrpRS (<em>Hc</em>TrpRS) and its interaction with human BTK is likely to be disrupted, indicating high degree of target selectivity. Therefore, the structure-guided design successfully developed new tirabrutinib analogues as inhibitors of bacterial TrpRS, presenting a promising lead compound for the development of AARS-based antibacterial agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108978"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of pyrazole and pyrazolopyrimidine derivatives as promising anti-MRSA agents targeting penicillin-binding protein (PBP2a) and mecA gene","authors":"Ahmed Ragab ,&nbsp;Moustafa S. Abusaif ,&nbsp;Heba Mohammed Refat M. Selim ,&nbsp;Omnia Karem M. Riad ,&nbsp;Mohamed H. Helal ,&nbsp;Abeer M. Ali ,&nbsp;Yousry A. Ammar ,&nbsp;Ghada E. Ahmed","doi":"10.1016/j.bioorg.2025.108977","DOIUrl":"10.1016/j.bioorg.2025.108977","url":null,"abstract":"<div><div>Global health is threatened by methicillin-resistant <em>S. aureus</em> (MRSA). The rising prevalence of MRSA complicates anti-infective treatment strategies, highlighting the urgent need for novel therapeutics targeting MRSA. In this study, novel pyrazole and pyrazolopyrimidine derivatives were synthesized and comprehensively characterized using IR, ¹H/¹³C NMR, and elemental analysis. Significant anti-microbial activity of these derivatives was demonstrated (using MIC test) against both Gram-positive (<em>S. aureus</em> ATCC 25923 and MRSA ATCC 43300) and Gram-negative bacteria (<em>E. coli</em> ATCC 25922 and <em>K. pneumoniae</em> ATCC 700603), in addition to exhibiting antifungal activity against <em>C. albicans</em> ATCC 10231. Notably, the Schiff bases pyrazoles <strong>6b</strong> and <strong>6c</strong> represent the most promising derivatives in comparison to the positive control drugs (neomycin sulfate and fluconazole). Additionally, MBC/MFC tests exhibited bactericidal and fungicidal activity, except for pyrazole derivative <strong>3a</strong>, which demonstrated bacteriostatic efficacy specifically against MRSA. The promising compounds <strong>6b</strong> and <strong>6c</strong> showed strong antibiofilm activity against MRSA, resulting in a reduction of biofilm formation by 74.1 % and 71.36 %, respectively, at ½ MIC. Schiff base pyrazoles (<strong>6b</strong> and <strong>6c</strong>) showed specific activity against MRSA, by revealing a reduction in expression of PBP2a protein levels using Western blotting. Additionally, polymerase chain reaction and sequencing of the <em>mec</em>A gene confirmed induced mutations following exposure to these compounds, suggesting a dual mechanism of action at both phenotypic and genotypic levels. Finally, the <em>in-silico</em> ADME studies for the promising derivatives were successful in predicting their oral bioavailability, drug-likeness, and pharmacokinetic features.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108977"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}