Bioorganic Chemistry最新文献

{"title":"Combined in silico and in vitro cytotoxic profiling of novel quinazoline derivatives targeting anaplastic lymphoma kinase for lung cancer therapy","authors":"Natarajan Saravanakumar ,&nbsp;Arunagiri Sivanesan Aruna Poorani ,&nbsp;Pandeeshwaran Santhoshkumar ,&nbsp;Anantha Krishnan Dhanabalan ,&nbsp;Santhalingam Gayathri ,&nbsp;Balasubramaniem Ashokkumar ,&nbsp;Srimari Srikanth ,&nbsp;Venkatasubramanian Ulaganathan ,&nbsp;Palaniswamy Suresh","doi":"10.1016/j.bioorg.2025.109450","DOIUrl":"10.1016/j.bioorg.2025.109450","url":null,"abstract":"<div><div>Lung cancer is one of the most common cancers globally, and targeting specific molecular pathways, such as the anaplastic lymphoma kinase (ALK), has shown great potential in developing effective treatments. From the X-ray crystal structure analysis of ALK, its binding interactions have highlighted the critical role of the pyrimidine moiety in ALK inhibition. Building on this insight, a series of novel N,4-diaryl-5,6-dihydrobenzo[<em>h</em>]quinazolin-2-amines was designed by incorporating 2-aminopyrimidine and tetralin frameworks via a hybridisation strategy. The library of eleven novel N,4-diaryl-5,6-dihydrobenzo[<em>h</em>]quinazolin-2-amines has been synthesised through the optimised Buchwald-Hartwig reaction. The synthesised compounds were evaluated for</div><div><em>in vitro</em> antiproliferative activity against lung cancer cell lines Karpas 299, H2228, A549, and gastric adenocarcinoma cell line AGS. And its ALK-selective inhibition was analyzed experimentally using an enzyme inhibition assay. Parallelly, molecular docking studies and molecular mechanics/generalized Born surface area (MM/GBSA) calculations have been conducted to assess their binding affinities with Anaplastic Lymphoma Kinase (ALK). Both the biological assay and computational studies revealed that the synthesised compounds exhibited significant cytotoxic activity. In particular, compound <strong>8c</strong>, featuring a 4-methoxybenzene moiety, showed significant potency, emphasizing the therapeutic potential of pyrimidine-based scaffolds in the development of novel anti-lung cancer agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109450"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897941","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":"Sialylated porphyrins optimized as anti-infective agents against SARS-CoV-2 variants","authors":"Vivian Lioret ,&nbsp;Constant Gillot ,&nbsp;Marie Hologne ,&nbsp;Jenny Ha ,&nbsp;Dmytro Strilets ,&nbsp;Laurent Lubrano Di Scampamorte ,&nbsp;Laurent Gillet ,&nbsp;Jonathan Douxfils ,&nbsp;Stéphane P. Vincent","doi":"10.1016/j.bioorg.2026.109519","DOIUrl":"10.1016/j.bioorg.2026.109519","url":null,"abstract":"<div><div>Anti-adhesion strategies based on multivalent glycosylated molecules have emerged as promising antiviral tools to block early stages of viral infection. Herein, we report the design, synthesis, and evaluation of a series of porphyrin-based glycoclusters bearing sialic acid (SA) or 9-<em>O</em>-acetyl SA units, connected via linkers of varying length, polarity and rigidity. Their ability to inhibit virus-host cell interaction was assessed against wild-type, Alpha, Delta, JN.1 and KP.3 pseudotyped SARS-CoV-2 variants spanning the virus's evolutionary trajectory. The same inhibition pattern was measured with lived SARS-CoV-2 Delta variant. Although a small erosion of the SA affinity for the spike protein could be observed over the variants, all glycoclusters displayed robust and broad-spectrum neutralizing activity, highlighting the conserved role of SA-mediated recognition. Porphyrins bearing 9Ac-SA always displayed slightly better anti-effective properties than their SA counterparts. The engineering of the linkers distributing the SA ligands to the porphyrin central core proved successful as it could decrease the IC₅₀'s up to 4 times. The best optimized tetrameric inhibitors displayed a 60-fold enhanced activity compared to their monomers (15-fold per ligand). This work contributes both to the development and the improvement of antiviral agents and to a better understanding of viral evolution that drives SARS-CoV-2 infection.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109519"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073893","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":"Engineered N-terminal modified α/β-hybrid peptides with enhanced selectivity and stability: Multi-target antibacterials for combating MRSA","authors":"Jyoti Kumari ,&nbsp;Aminur Rahman Sarkar ,&nbsp;Beenish Rashid ,&nbsp;Arti Rathore ,&nbsp;Shifa Firdous ,&nbsp;Rubina Chowdhary ,&nbsp;Biplab Sarkar ,&nbsp;Rakshit Manhas ,&nbsp;Rajkishor Rai ,&nbsp;Avisek Mahapa","doi":"10.1016/j.bioorg.2026.109495","DOIUrl":"10.1016/j.bioorg.2026.109495","url":null,"abstract":"<div><div>Cytotoxicity, hemolytic effects, poor enzymatic stability and high manufacturing costs are the major challenges associated with the clinical development of antibacterial peptides. We designed and synthesized a new series of short cationic α/β-hybrid peptides (TH-01, TH-02, and TH-03) by incorporating a urea bond in place of a traditional amide bond and an N-terminal THPA moiety. These modifications were strategically incorporated to enhance antibacterial activity, structural stability, and cellular selectivity, also allowing detailed mechanistic investigation. Remarkably, the synthesized peptides retained antimicrobial activity, achieving an MIC of 1.5–12.5 μM (0.9–7.5 μg/ml) against MRSA, along with enhanced selectivity and stability. The subsequent mechanistic studies revealed that these peptides showed bactericidal activity by utilizing multi-targeted mechanisms, including lysis of the cell membrane, interaction with genomic DNA and induction of reactive oxygen species. Overall, this class of α/β-hybrid peptides represents a promising advancement toward the development of short, stable, and selective antimicrobial agents, offering valuable new strategies for combating antimicrobial resistance.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109495"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035064","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":"Cascade biocatalysis for pyridoxal 5′-phosphate synthesis with ATP autonomy via polyphosphate kinase","authors":"Jinnian Wang ,&nbsp;Haoming Zhao ,&nbsp;Shijun Tong ,&nbsp;Xingjian Zhang ,&nbsp;Shuyu Ding ,&nbsp;Han Zhang ,&nbsp;Zhong-Hua Yang","doi":"10.1016/j.bioorg.2026.109518","DOIUrl":"10.1016/j.bioorg.2026.109518","url":null,"abstract":"<div><div>The industrial production of pyridoxal 5′-phosphate (PLP)—an indispensable enzymatic cofactor—is hampered by inefficient multistep chemical syntheses and the economic infeasibility of ATP-dependent biocatalytic routes. To address these challenges, we report an ATP-autonomous biocatalytic cascade that couples pyridoxal kinase (PLK) with polyphosphate kinase (PPK) for sustainable PLP synthesis. This system harnesses inexpensive sodium hexametaphosphate (SHMP) as a phosphoryl donor to drive continuous ATP regeneration, thereby enabling efficient phosphorylation of pyridoxal to PLP without exogenous ATP input. Recombinant PLK and PPK were co-expressed in <em>E. coli</em> BL21(DE3), yielding specific activities of 50 and 145 U/g_cell, respectively. The whole-cell biocatalyst achieved only about 25% conversion yield due to mass transfer limitations and intracellular PLP degradation. Notably, while the optimized cell-free system (45 °C, pH 6.5, PLK:PPK = 1:3, 25 mM SHMP) attained a remarkable 95% PLP yield. This 3.8-fold enhancement demonstrates the critical advantage of eliminating cellular barriers in complex multi-enzyme cascades. Our work establishes a robust, ATP-independent platform for high-efficiency PLP biosynthesis that seamlessly integrates cofactor regeneration with cascade catalysis, offering a scalable and economically viable route for industrial biomanufacturing. Moreover, it demonstrates the broader utility of polyphosphate-driven energy recycling in sustainable biocatalysis.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109518"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016739","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":"Comparative study of 47Sc and 177Lu-labeled albumin binder-conjugated FAPI radiopharmaceuticals","authors":"Yuxiao Xia ,&nbsp;Jianpeng Cao ,&nbsp;Dongkun Xu ,&nbsp;Xue Jiang ,&nbsp;Qian Liu ,&nbsp;Lina Liu ,&nbsp;Wenling Tu ,&nbsp;Ying Huang ,&nbsp;Quanyu Zhou ,&nbsp;Yuhong Shi ,&nbsp;Hua Pang","doi":"10.1016/j.bioorg.2026.109527","DOIUrl":"10.1016/j.bioorg.2026.109527","url":null,"abstract":"<div><h3>Objective</h3><div>Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with ⁶⁸Ga, ¹⁷⁷Lu and the emerging ⁴⁷Sc.</div></div><div><h3>Methods</h3><div>FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with ⁶⁸Ga, ¹⁷⁷Lu or ⁴⁷Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5–55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.</div></div><div><h3>Results</h3><div>All conjugates showed &gt;95% radiochemical purity and &gt; 40% albumin binding. ⁶⁸Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. ¹⁷⁷Lu- and ⁴⁷Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for ⁴⁷Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses &gt;30 Gy. ⁴⁷Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35–60% higher than the ¹⁷⁷Lu analogue. Therapy studies showed only cytostatic effects (T/C 36–43%) accompanied by dose-dependent hepatogastrointestinal toxicity.</div></div><div><h3>Conclusion</h3><div>While ⁶⁸Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of ⁴⁷Sc-FAPI-X5 preclude its clinical translation. Future ⁴⁷Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109527"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016708","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":"2-Aminothiophene and 2-aminothiazole scaffolds as potent antimicrobial agents: Design, synthesis, biological evaluation, and computational insights","authors":"Munugala Chandrakanth ,&nbsp;Jyothi Kumari ,&nbsp;Paramita Pakhira ,&nbsp;Dharmarajan Sriram ,&nbsp;Siddhardha Busi ,&nbsp;Sampathkumar Ranganathan ,&nbsp;Chandni Kumari ,&nbsp;Sonam Bisla ,&nbsp;Mukesh Pasupuleti ,&nbsp;Ramesh Gondru ,&nbsp;Jesu Arockiaraj ,&nbsp;Janardhan Banothu","doi":"10.1016/j.bioorg.2026.109511","DOIUrl":"10.1016/j.bioorg.2026.109511","url":null,"abstract":"<div><div>The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of <em>Mycobacterium tuberculosis (Mtb)</em>, underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared <em>via</em> the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against <em>Mtb H37Rv</em>, with <strong>4</strong><strong>h</strong>, <strong>4</strong><strong>k</strong>, and <strong>4</strong><strong>l</strong> showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds <strong>4q</strong>, <strong>4</strong><strong>s</strong>, <strong>7</strong><strong>g, 7o</strong>, and <strong>9e</strong> emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against <em>Mtb</em>. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound <strong>4</strong><strong>k</strong> as a promising lead candidate against <em>Mtb</em>, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109511"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035019","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, and antitumor activity of novel Flavokawain A derivatives by suppressing LRPPRC-YBX1-RPN1 cascade","authors":"Rui Wu ,&nbsp;Yong Wang ,&nbsp;Yanyan Li ,&nbsp;Honghui Lian ,&nbsp;Pan Li ,&nbsp;Hangrui Liu ,&nbsp;Lin Tang ,&nbsp;Yuanying Li ,&nbsp;Yubing Zhou ,&nbsp;Yunxiao Ge ,&nbsp;Yushu Li ,&nbsp;Shuting Gong ,&nbsp;Haohan Zhang ,&nbsp;Bin Yu ,&nbsp;Zigang Dong ,&nbsp;Hui Liu","doi":"10.1016/j.bioorg.2025.109425","DOIUrl":"10.1016/j.bioorg.2025.109425","url":null,"abstract":"<div><div>Natural Flavokawain A (FKA) demonstrates notable anti-tumor activity. In this study, a novel sulfonamide derivative, designated as <strong>FKA-9i</strong>, was meticulously designed and synthesized. This compound effectively inhibits cancer cell proliferation and tumor growth by inducing cancer cell cycle arrest, apoptosis, and mitochondrial dysfunction, manifested as the inhibition of oxidative phosphorylation and the accumulation of reactive oxygen species, without discernible toxicity. Mechanistic studies integrating small molecule pull-down coupled with proteomics and surface plasmon resonance techniques initially verified that <strong>FKA-9i</strong> directly binds to the target proteins leucine-rich PPR motif-containing protein (LRPPRC), Y-box binding protein 1 (YBX1), and ribophorin I (RPN1), reducing their interactions and stability. Further experiments confirmed that these are <strong>FKA-9i</strong> direct targets, as the anti-tumor activity of <strong>FKA-9i</strong> was significantly attenuated following LRPPRC, YBX1, and RPN1 knockdown. RNA sequencing and pathway analysis revealed that <strong>FKA-9i</strong> impede cancer progression via LRPPRC-YBX1-RPN1 mediated MAPK signaling pathway. Moreover, <strong>FKA-9i</strong> exhibits a synergistic enhancement effect when combined with chemotherapeutic drugs, YBX1 and RPN1 inhibitors, as well as drugs targeting the glycolysis pathway. This study firmly establishes <strong>FKA-9i</strong> as an anti-tumor leading compound by targeting the LRPPRC-YBX1-RPN1 mediated MAPK regulatory network, offering a novel strategy to surmount the clinical translation hurdles of natural flavonoids.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109425"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964914","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":"Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene","authors":"Xia-Zhen Bao ,&nbsp;Xiao-Rong Ren ,&nbsp;Wei Tang ,&nbsp;Yu Zhang ,&nbsp;Zheng-Kai Deng ,&nbsp;Fang Dai ,&nbsp;Bo Zhou","doi":"10.1016/j.bioorg.2026.109505","DOIUrl":"10.1016/j.bioorg.2026.109505","url":null,"abstract":"<div><div>To effectively trigger an energy crisis within cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit <em>via</em> a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC₅₀ = 0.25 μM) as opposed to normal L02 cells (IC₅₀ = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate reactive oxygen species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within cancer cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109505"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974455","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, and antidiabetic evaluation of triazolopyrimidine thioacetamides as potent and selective α-glucosidase inhibitors","authors":"Fariba Peytam ,&nbsp;Maryam Norouzbahari ,&nbsp;Bahareh Bayati ,&nbsp;Hayrettin Ozan Gülcan ,&nbsp;Vahid Sheibani ,&nbsp;Maliheh Barazandeh Tehrani ,&nbsp;Somayeh Mojtabavi ,&nbsp;Mohammad Ali Faramarzi ,&nbsp;Fahimeh Ghasemi ,&nbsp;Mohammadreza Torabi ,&nbsp;Meghdad Payab ,&nbsp;Fatemeh Safari ,&nbsp;Loghman Firoozpour ,&nbsp;Alireza Foroumadi","doi":"10.1016/j.bioorg.2026.109482","DOIUrl":"10.1016/j.bioorg.2026.109482","url":null,"abstract":"<div><div>Diabetes mellitus is a global health challenge characterized by chronic hyperglycemia. <em>α</em>-Glucosidase inhibitors, like acarbose, are pivotal in managing postprandial blood glucose levels but are often associated with gastrointestinal side effects. This study aimed to rationally design and synthesize a library of 2-((6-amino-5,7-diaryl-[1,2,4]triazolo[1,5-<em>a</em>]pyrimidin-2-yl)thio)-<em>N</em>-arylacetamide derivatives (<strong>15a-15ae</strong>) as potent and selective <em>α</em>-glucosidase inhibitors. All 31 target compounds exhibited inhibitory activity (IC₅₀ ranging from 7.09 μM to 245.57 μM) under assay conditions where the reference drug, acarbose, exhibited an IC₅₀ value of 750.67 μM. The most potent compound, <strong>15o</strong> (IC₅₀ = 7.09 ± 0.2 μM), demonstrated approximately 106-fold higher potency than acarbose under the identical assay conditions. Kinetic analysis indicated that <strong>15o</strong> acted as a competitive inhibitor (Kᵢ = 6.9 μM). Moreover, this compound did not show <em>α</em>-amylase inhibitory activity and cytotoxicity at concentration of 100 μM, showing preliminary indications of favorable safety and selectivity. Spectroscopic studies (CD, fluorescence) and computational analyses (model performance and augmentation, docking, and MD simulations) confirmed the strong binding affinity and stabilization of compound <strong>15o</strong> within the enzyme's active site. <em>In vivo</em> evaluation in a diabetic rat model demonstrated that <strong>15o</strong> (30 mg/kg BW) significantly reduced fasting blood glucose, improved glucose tolerance in OGTT, reduced HbA₁c levels to near-normal ranges, and restored hepatic and pancreatic histology, with effects better than those observed with acarbose in this model. Compound <strong>15o</strong> also exhibited acceptable acute toxicity profiles. These findings introduced compound <strong>15o</strong> as a promising lead candidate for further structural development of anti-diabetic agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109482"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923488","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":"Characterization of bridged guaiane-type sesquiterpenoids from Stellera chamaejasme and their antifungal activities against phytopathogenic fungi","authors":"Sheng-Yun Wei ,&nbsp;Yan Huang ,&nbsp;Jiao Yao ,&nbsp;Ping Zhao ,&nbsp;Jun-Cheng Su ,&nbsp;Luo-Sheng Wan ,&nbsp;Guo-Lei Zhu","doi":"10.1016/j.bioorg.2026.109475","DOIUrl":"10.1016/j.bioorg.2026.109475","url":null,"abstract":"<div><div>Plant pathogenic fungi pose a serious threat to global agricultural productivity, driving the need for novel and eco-friendly antifungal agents. An investigation into the antifungal constituents from the roots of <em>Stellera chamaejasme</em> led to the isolation of nine new guaiane-type sesquiterpenoids, named stelleroids D–L (<strong>1–3</strong> and <strong>8–13</strong>), along with eight known analogues. Their structures, featuring extensively modified bridged scaffolds and diverse oxidative patterns, were elucidated by comprehensive spectroscopic analysis and X-ray crystallography. Antifungal evaluation against five agriculturally significant phytopathogenic fungi identified compound <strong>11</strong> as the most potent and broad-spectrum agent, exhibiting exceptional activity against <em>Phytophthora infestans</em> (MIC = 3.1 μg/mL). Subsequent mechanistic studies revealed that compound <strong>11</strong> disrupted the cell membrane integrity of <em>P. infestans</em>, leading to increased permeability, leakage of cellular contents, and severe ultrastructural damage. Molecular docking simulations suggested that <strong>11</strong> could effectively bind to the putative targets CYP51 and SDH. Importantly, <em>in vivo</em> experiments on tomato fruits confirmed the significant protective and curative efficacy of <strong>11</strong> against late blight. This work not only expands the structural diversity of bioactive sesquiterpenoids but also provides a highly promising natural lead compound (<strong>11</strong>) with validated in planta efficacy for further development as a new antifungal agrochemical.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109475"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145923487","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}