Bioorganic Chemistry最新文献

{"title":"Design and synthesis of norsesquiterpenoid-1,2,3-triazole derivatives and investigation of their anti-influenza virus activity","authors":"Jingnan Qiu,&nbsp;Shaofen Zhou,&nbsp;Jianan Hu,&nbsp;Shixin Li,&nbsp;Shuaiqi Ma,&nbsp;Jingyan Wei,&nbsp;Jian He","doi":"10.1016/j.bioorg.2025.108819","DOIUrl":"10.1016/j.bioorg.2025.108819","url":null,"abstract":"<div><div>Influenza is a highly contagious, acute respiratory illness caused by the influenza virus. The continual emergence of drug-resistant viral strains has created an urgent need for the development of novel anti-influenza agents. In our previous study, we identified a series of nor-sesquiterpenoids with potent activity against influenza A virus, isolated from the fermentation broth of <em>Streptomyces</em> sp. XM17—an actinobacterial strain derived from fresh panda feces. Building on these findings, we synthesized the core nor-sesquiterpene scaffold and functionalized it by attaching various molecular fragments through a 1,2,3-triazole linker containing heteroatoms, utilizing a click chemistry strategy. This approach aimed to enhance antiviral potency through structural diversification. Among the resulting compounds, <strong>14d</strong> demonstrated superior antiviral activity against the influenza virus, along with a low 50 % cytotoxic concentration. Mechanistic studies indicated that compound <strong>14d</strong> exerted its antiviral effect during the later stages of viral infection. Notably, it did not inhibit neuraminidase activity. Instead, it disrupted the cellular nuclear factor kappa B signaling pathway and suppressed the virus-induced overexpression of proinflammatory cytokines. Collectively, these results highlight compound <strong>14d</strong> as a promising lead candidate for the development of novel therapeutics targeting influenza virus infection.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108819"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771372","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":"Discovery and biochemical characterization of prenyltransferases in the biosynthetic pathway of hericenones from Hericium erinaceus","authors":"Haiyan Han ,&nbsp;Shuang Peng ,&nbsp;Yuxin Yang ,&nbsp;Chao Lin ,&nbsp;Pengchao Wang ,&nbsp;Chang Li ,&nbsp;Peipei Zhao ,&nbsp;Wenbing Gong ,&nbsp;Chunliang Xie ,&nbsp;Xuekui Xia ,&nbsp;Jianzhao Qi ,&nbsp;Chengwei Liu","doi":"10.1016/j.bioorg.2025.108822","DOIUrl":"10.1016/j.bioorg.2025.108822","url":null,"abstract":"<div><div>Hericenones, neurotrophic meroterpenoids from the medicinal mushroom <em>Hericium erinaceus,</em> exhibit remarkable nerve growth factor-enhancing properties with therapeutic potential for neurodegenerative disorders. Biosynthesis of these compounds requires prenyltransferase (PT)-mediated geranylation of orsellinic acid (OA, <strong>1</strong>), though the fungal enzymes catalyzing this pivotal step remain uncharacterised. Through comprehensive genome mining of <em>H. erinaceus</em>, we identified eight putative UbiA-type prenyltransferases (HePT1–8). Heterologous expression in <em>Aspergillus oryzae</em> coupled with substrate-feeding assays revealed HePT8 as a geranyltransferase capable of <strong>1</strong> geranylation, producing cannabigerorcinic acid (<strong>2</strong>) - the committed precursor of hericenones. Notably, HePT7 demonstrated divergent specificity for dimethylallyl transfer to 4-hydroxybenzoate. Systematic mutagenesis uncovered critical catalytic residues (H40/D96/D100/D211/D218/Y158) coordinating Mg²⁺-diphosphate interactions and substrate positioning in HePT8. This work not only elucidates the foundational step in hericenone biosynthesis but significantly expands the catalytic repertoire of fungal PTs through the discovery of multifunctional enzymes with substrate plasticity. Our findings provide essential tools for bioengineering novel meroterpenoids and illuminate evolutionary convergence in fungal secondary metabolism.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108822"},"PeriodicalIF":4.7,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763673","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":"Corrigendum to \"Designing novel tridentate iridium(III) complexes comprising functionalized benzothiazole ligands to improve anticancer activity by targeting mitochondria\" [Bioorg. Chem. 161 (2025) 108507].","authors":"Qin Zhou, Xiao-Bin Zhang, An-Li Liu, Zhi-Gang Niu, Gao-Nan Li, Fa-Biao Yu","doi":"10.1016/j.bioorg.2025.108810","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.108810","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":" ","pages":"108810"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768170","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":"Efficient immobilization of thermophilic rhamnosidase dual-network hybrid-gel with high enzymatic activity and stability","authors":"Wenli Xia ,&nbsp;Jingcong Xie ,&nbsp;Linguo Zhao ,&nbsp;Jianjun Pei","doi":"10.1016/j.bioorg.2025.108823","DOIUrl":"10.1016/j.bioorg.2025.108823","url":null,"abstract":"<div><div>Thermophilic enzymes possess numerous favorable properties for biotransformation, including high catalytic activity, exceptional thermal stability, and ease of purification and preparation. However, the challenge arises from the lack of suitable enzyme immobilization materials that exhibit both thermal tolerance and reusability, thereby hindering the effective and recurrent utilization of thermophilic enzymes. In this study, a specially designed dual-network hybrid-gel consisting of acrylamide (AM) and sodium alginate (SA) was developed to serve as a thermotolerant and reusable carrier for the efficient immobilization of a thermotolerant α-rhamnosidase IagRha. The optimal amounts of AM and SA were determined to be 5 % and 2 %, respectively. Following the step of acrylamide crosslinking to establish the skeleton of hybrid-gel, a subsequent immersion in a Ca²⁺ solution facilitated the formation of ionic bonds between SA and Ca²⁺, thereby adjusting the internal voids of the hydrogel, which effectively enhanced the thermal stability and enzyme immobilization efficiency of the hybrid-gel. This innovative approach resulted in the achievement of 93.65 % recovery of enzyme activity, along with remarkable enhancements in enzymatic properties. The immobilized α-rhamnosidase, AM-SA-IagRha, demonstrated a significant 1.34-fold increase in the <em>V_max</em> value, rising from 5.28 U/mg to 7.06 U/mg, compared to free IagRha. Furthermore, AM-SA-IagRha exhibited excellent thermostability, with a half-life of 99.0 min at 90 °C, which was 1.57-fold higher than that of free IagRha. After four cycles of reuse, the productivities of rutin and epmdin C by the immobilized enzyme were 1.91-fold and 2.53-fold that of the free enzyme, respectively. Additionally, the enzyme activity of AM-SA-IagRha remained at 90.16 % after storage at 4 °C for 30 days, and retained at 85.63 % after 20 cycles of reuse, demonstrating exceptional storage stability and reusability. The optimal expression conditions for IagRha were identified in TB medium incubated at 37 °C without IPTG, resulting in an enzyme activity of 6.32 U/mL. These significant findings underscore the potential of AM-SA-IagRha for industrial applications, particularly in high-temperature biotransformation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108823"},"PeriodicalIF":4.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766730","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":"From food waste to anti-aging solution: Harnessing the bioactive potential of pomegranate peel microparticles in skincare","authors":"Katarina Šavikin ,&nbsp;Ana Alimpić Aradski ,&nbsp;Aleksandra Jovanović ,&nbsp;Andrea Pirković ,&nbsp;Milica Radan ,&nbsp;Nada Ćujić Nikolić ,&nbsp;Jelena Živković","doi":"10.1016/j.bioorg.2025.108818","DOIUrl":"10.1016/j.bioorg.2025.108818","url":null,"abstract":"<div><div>Pomegranate peel (PP), comprising over 50 % of the fruit's weight, is often discarded as waste despite its rich composition, particularly in ellagitannins. This study explores the potential of microencapsulated PP (MPP) extract in managing skin conditions related to inflammation and enzymatic aging processes. Additionally, the impact of UV irradiation on its chemical profile was assessed to determine its suitability for skincare applications. HPLC and FT-IR analyses confirmed that UVA, UVB, and UVC irradiation did not alter the chemical composition of MPP. The major identified ellagitannins were punicalagin (118.01 mg/g dry weight) and punicalin (37.38 mg/g dry weight), alongside significant amounts of gallic and ellagic acids. <em>In vitro</em> studies demonstrated that MPP exhibited inhibitory activity against collagenase, elastase, hyaluronidase, and tyrosinase, suggesting promising anti-aging potential. These findings were further supported by a molecular docking study, which revealed key interactions between MPP bioactives and enzyme active sites. MPP showed dose-dependent UVA and UVB absorption comparable to zinc oxide. In human keratinocytes (HaCaT), MPP reduced reactive oxygen species production in the presence of H₂O₂, and IL-1β and MIF expressions, confirming the anti-inflammatory effect against lipopolysaccharide challenge. Additionally, MPP in all tested concentrations (50–200 μg/mL), protected erythrocyte membranes from heat- and hypotonic-induced lysis, demonstrating concentration-dependent anti-inflammatory (membrane stability) effects. Lower MPP concentrations did not significantly affect keratinocyte viability. These findings highlight MPP's potential for use in cosmetic and pharmaceutical skincare formulations targeting inflammation, oxidative stress, and aging-related concerns.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108818"},"PeriodicalIF":4.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749267","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":"Exploring therapeutic strategies for candidiasis: From current treatments to future perspectives","authors":"Hadiya Amin Kantroo ,&nbsp;Mohamad Mosa Mubarak ,&nbsp;Zahoor Ahmad","doi":"10.1016/j.bioorg.2025.108797","DOIUrl":"10.1016/j.bioorg.2025.108797","url":null,"abstract":"<div><div>The rising prevalence of antifungal resistance in <em>Candida</em> species poses a significant challenge to public health, necessitating the exploration of novel therapeutic strategies. This review highlights advancements in molecular innovations targeting <em>Candida</em> infections, emphasizing novel drug discovery approaches, including high-throughput screening, structure-based drug design, and synthetic modifications of existing molecules. We discuss emerging drug candidates in preclinical and clinical development, targeting key fungal pathways such as ergosterol biosynthesis, β-(1,3)-D-glucan synthesis, and novel metabolic regulators. Furthermore, drug repurposing strategies, leveraging known pharmacokinetics and pharmacodynamics of existing drugs, provide accelerated routes to new antifungal treatments. Collaborative efforts integrating pharmaceutical research, clinical insights, and technological advancements are imperative for the development of next-generation antifungal therapeutics. This review underscores the need for an interdisciplinary approach to antifungal drug discovery, ensuring effective and sustainable treatment options against resistant <em>Candida</em> strains.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108797"},"PeriodicalIF":4.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757973","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":"Synthesis, insecticidal activity against Aedes aegypti and acetylcholinesterase inhibition of new N-arylmethyl-1,2,3,4-tetrahydroquinoline derivatives containing an N-arylmethylpiperidine scaffold inspired on donepezil structure","authors":"Fabián L. Monares Bueno ,&nbsp;Sergio A. Gómez ,&nbsp;Aurora L. Carreño Otero ,&nbsp;Marlyn S. Rada ,&nbsp;Jonny E. Duque ,&nbsp;Yorley Duarte ,&nbsp;Arnold R. Romero Bohórquez","doi":"10.1016/j.bioorg.2025.108816","DOIUrl":"10.1016/j.bioorg.2025.108816","url":null,"abstract":"<div><div>Reducing <em>Aedes aegypti</em> population using natural or synthetic insecticides remains one of the main strategies for controlling diseases such as dengue, Zika or Chikungunya, as this mosquito is their primary vector. Traditionally, some organic compounds -mainly carbamates or organophosphates derivatives- have been employed for this purpose. These insecticides act as irreversible inhibitors of the acetylcholinesterase enzyme (AChE), which results in high nonspecific toxicity. Moreover, the eventual development of resistance highlights the need to explore new alternatives. In this study a series of sixteen (16) new <em>N</em>-arylmethyl-1,2,3,4-tetrahydroquinoline derivatives containing an <em>N</em>-arylmethylpiperidine scaffold inspired by the structure of donepezil structure, were designed and synthesized, using a mild and efficient methodology via cationic Povarov reaction. This approach enabled access to the <em>N</em>-arylmethyl tetrahydroquinoline core with good to high yields (61–94 %).</div><div>The biological activity of these compounds was then evaluated through insecticidal activity and acetylcholinesterase inhibition assays, as indicators of their potential as insecticidal agents. In preliminary insecticidal activity assay, compounds <strong>4d</strong>, <strong>4e</strong>, <strong>4f</strong> and <strong>4j</strong> were identified as the most active, with LC₅₀ of 42, 21, 88 and 65 μg/mL after 24 h of treatment. Enzymatic assays showed that compounds <strong>4a</strong>, <strong>4e</strong> and <strong>4</strong> <strong>m</strong> exhibited the highest inhibitory activity, with IC₅₀ values of 8.32 ± 0.32, 16.43 ± 1.13, and 13.23 ± 1.42 μM, respectively. Among them, compound <strong>4e</strong> emerged as the most promising candidate. Finally, <em>silico</em> studies, including molecular dynamics simulations and binding free energy calculations, revealed the stability and strong binding interactions of the three most active compounds (<strong>4a</strong>, <strong>4e</strong>, and <strong>4</strong> <strong>m</strong>) against <em>A. aegypti</em> AChE.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108816"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739091","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":"Synthesis, biological screening and computational analysis of Thiazole linked Thiazolidinone Schiff bases as anti-Alzheimer's drug candidates","authors":"Thoraya A. Farghaly ,&nbsp;Wajid Rehman ,&nbsp;Yousaf Khan ,&nbsp;Hina Sarfraz","doi":"10.1016/j.bioorg.2025.108812","DOIUrl":"10.1016/j.bioorg.2025.108812","url":null,"abstract":"<div><div>This study unveils the rational design and stepwise synthesis of new thiazole-based thiazolidinone Schiff base derivatives <strong>(1–15)</strong>, harnessing 2-amino-5-nitrothiazole as a crucial precursor. These newly synthesized derivatives were structurally characterized through spectroscopic techniques ¹HNMR, ¹³CNMR and HREI-MS. Moreover, consider the crucial role of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition in Alzheimer's disease (AD) therapy, the synthesized compounds were evaluated for their cholinergic enzyme inhibitory potential against AChE and BuChE, with Donepezil (IC₅₀ = 5.10 ± 0.10 μM) as the reference drug. Among all the derivatives, the compounds <strong>2, 3, 5,</strong> and <strong>7</strong> has shown the best biological inhibition potency with the values of (IC₅₀ = 2.98 ± 0.19 and 3.22 ± 0.51 μM), (IC₅₀ = 2.80 ± 1.23 and 3.11 ± 0.78 μM), (IC₅₀ = 4.34 ± 0.86 and 5.55 ± 0.91 μM) and (IC₅₀ = 3.90 ± 1.42 and 3.75 ± 0.98 μM) respectively as compared to the standard drug. Additionally, molecular docking studies were conducted against AChE and BuChE enzymes, with docking validation confirming accuracy via RMSD values of 1.15 Å and 0.19 Å, respectively, indicating reliable binding predictions. Among the screened compounds, compound-<strong>5</strong> showed the strongest binding affinity and was further investigated through <em>in-silico</em> techniques. Similarly, density Functional Theory (DFT) analysis revealed that compound-<strong>5</strong> had the lowest HOMO-LUMO gap (2.36 eV), indicating high reactivity, while compound-<strong>2</strong> exhibited the highest energy gap (3.39 eV), suggesting greater stability. Furthermore, molecular electrostatic potential (MESP) maps supported these findings by highlighting distinct charge distribution patterns. Similarly, ADMET predictions showed that compound-<strong>5</strong> possessed favorable drug-like properties, including membrane permeability and optimal lipophilicity. Moreover, toxicity analysis confirmed that all selected compounds were non-carcinogenic, moderately toxic (LD₅₀ ≥ 1000 mg/kg) and non-cytotoxic, with compound-<strong>3</strong> having the highest LD₅₀ (2604 mg/kg) and lowest toxicity class. None of the compounds were predicted to cross the blood-brain barrier or inhibit major cytochrome P450 enzymes. Hence, these findings highlight the potential of these newly synthesized thiazole-thiazolidinone Schiff base derivatives as promising therapeutic targets for Alzheimer's disease that were contributing to the development of next-generation cholinesterase inhibitors with promising efficacy and selectivity.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108812"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757972","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":"γ-aminobutyric methyl ester-derived sulfamides as carbonic anhydrase inhibitors","authors":"Federico M. Garofalo ,&nbsp;Karen A. Terrazas ,&nbsp;Simone Giovannuzzi ,&nbsp;Evelyn L. Bonifazi ,&nbsp;Fabrizio Carta ,&nbsp;Claudiu T. Supuran ,&nbsp;Luciana Gavernet ,&nbsp;Melisa E. Gantner","doi":"10.1016/j.bioorg.2025.108814","DOIUrl":"10.1016/j.bioorg.2025.108814","url":null,"abstract":"<div><div>Catalytically active α‑carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes that primarily regulate the physiological concentration of proton and bicarbonate ions by means of the reversible hydration of CO₂. Since such species are all essential in many biochemical processes, CAs are important molecular targets in medicinal chemistry. Here we report the microwave-assisted synthesis of new asymmetric <em>N,N′</em>-disubstituted sulfamides bearing the γ-aminobutyric methyl ester scaffold. The compounds were screened <em>in vitro</em> for their inhibition features against the human CA VII isoform (hCA VII), predominantly expressed in the Central Nervous System (CNS), and the ubiquitous isoforms hCA I and II. Overall, the sulfamides showed inhibition potencies (Ki) in the low micromolar range, with moderate selectivity towards hCA VII. These results point to this family of sulfamides as potentially useful for the treatment of CA-based CNS-related pathologies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108814"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771373","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":"Design, synthesis, antibacterial evaluation, and molecular modelling studies of 1,2,3-triazole-linked coumarin-vanillin hybrids as potential DNA gyrase and topoisomerase IV inhibitors","authors":"Aanchal Khanna ,&nbsp;Anmol Narang ,&nbsp;Vishakha Thakur ,&nbsp;Karanvir Singh ,&nbsp;Nitish Kumar ,&nbsp;Rubaldeep Kaur ,&nbsp;Megha ,&nbsp;Alok Raj ,&nbsp;Meenakshi Devi ,&nbsp;Jyoti ,&nbsp;Rupali Rana ,&nbsp;Anchal Sharma ,&nbsp;Harmandeep Kaur ,&nbsp;Prabhpreet Singh ,&nbsp;Sukhraj Kaur ,&nbsp;Preet Mohinder Singh Bedi","doi":"10.1016/j.bioorg.2025.108815","DOIUrl":"10.1016/j.bioorg.2025.108815","url":null,"abstract":"<div><div>The escalating threat of antimicrobial resistance necessitates the urgent development of novel therapeutic agents targeting essential bacterial enzymes. In this study, a new series of 1,2,3-triazole-linked coumarin-vanillin hybrids was rationally designed and synthesized, integrating the bioactive moieties of coumarin and vanillin derivatives via the click chemistry technique. The synthesized compounds (AK1-AK30) were thoroughly characterized by ¹H, ¹³C NMR, FT-IR, and HR-MS spectroscopic techniques. All the compounds exhibited broad-spectrum antibacterial efficacy against both gram-positive and gram-negative pathogens. <strong>AK19</strong> demonstrated minimum inhibitory concentrations (MIC) of 1.9 μM against <em>Bacillus subtilis</em> and clinical isolates of methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), and superior efficacy compared to ciprofloxacin against <em>Pseudomonas aeruginosa</em> and <em>Shigella boydii.</em> Additionally, it exhibited significant biofilm inhibition against <em>B. subtilis</em> and MRSA. Mechanistically, <strong>AK19</strong> showed strong inhibition against <em>Escherichia coli</em> DNA gyrase and <em>E. coli</em> topoisomerase with IC₅₀ values of 0.783 ± 0.04 μM and 7.136 ± 1.03 μM, respectively. Molecular docking and molecular dynamics simulations further substantiated these results by demonstrating stable binding of <strong>AK19</strong> within the active sites of the targeted enzymes, with favourable binding free energies (ΔG = − 48 KJ/Mol and - 29 KJ/Mol, respectively). Additionally, bovine serum albumin (BSA) binding studies and ADME profiling indicated desirable pharmacokinetic characteristics. The overall results underscore the <strong>AK19</strong> as a promising lead compound for the development of next-generation antibacterial agents targeting DNA gyrase and topoisomerase IV</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"164 ","pages":"Article 108815"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722292","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}