Tomasz M Wróbel, Angelika Grudzińska, Jibira Yakubu, Therina du Toit, Katyayani Sharma, Jeremiah C Harrington, Fredrik Björkling, Flemming Steen Jørgensen, Amit V Pandey
{"title":"Pyridine indole hybrids as novel potent CYP17A1 inhibitors.","authors":"Tomasz M Wróbel, Angelika Grudzińska, Jibira Yakubu, Therina du Toit, Katyayani Sharma, Jeremiah C Harrington, Fredrik Björkling, Flemming Steen Jørgensen, Amit V Pandey","doi":"10.1080/14756366.2025.2463014","DOIUrl":"10.1080/14756366.2025.2463014","url":null,"abstract":"<p><p>Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound <b>11</b> showed the highest potency (IC<sub>50</sub> = 4 nM) and the related compound <b>14</b> presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2463014"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Design, synthesis and biological activity of novel Xuetongsu derivatives as potential anticancer agents by inducing apoptosis.","authors":"Qi Jiang, Hui Zhong, Cong Wu, Jia Li, Jingmin Chen, Xudong Zhou, Bin Li, Huanghe Yu, Wei Wang, Wenbing Sheng","doi":"10.1080/14756366.2025.2482140","DOIUrl":"10.1080/14756366.2025.2482140","url":null,"abstract":"<p><p>Xuetongsu (XTS, Schisanlactone E) is one of the main active compounds and considered as the star molecule isolated from <i>Kadsura heteroclita</i> (Roxb.) Craib. In order to improve XTS anti-tumour bioactivities, a series of novel XTS derivatives were designed and synthesised by introducing an amide bond at the parent. Anti-proliferative assays on four different human tumour cell lines (BGC-823, HepG-2, HCT-116, and MCF-7) showed that the anti-tumour activities of most derivatives increased greatly compared to the parent XTS, and especially, compounds <b>A</b>-<b>7</b>, <b>A</b>-<b>14</b>, and <b>A</b>-<b>18</b> exhibited multiple anti-tumour effects. Among them, compound <b>A</b>-<b>7</b> has the best biological activities on the four tumour cell lines with the IC<sub>50</sub> values ranging from 13.86 to 20.71 μM, which could significantly increase the fraction of apoptotic cells according to flow cytometry experience. Further study demonstrated that <b>A</b>-<b>7</b> could induce apoptosis on HepG-2 cells through influencing the key apoptotic related proteins, such as Bcl-2, Bax, and cleaved Caspase-3.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2482140"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Design, synthesis, and bioevaluation of pyrazole-containing tubulin polymerisation inhibitors based on conformational constraint strategy.","authors":"Zhongqiao Sun, Jiahao Wang, Fengwei Li, Liancheng Huang, Shide Zheng, Qi Guan, Zhaohua Wang, Weige Zhang","doi":"10.1080/14756366.2025.2545004","DOIUrl":"10.1080/14756366.2025.2545004","url":null,"abstract":"<p><p>Based on conformational preference of SMART analogues and conformational constraint strategy, two series of new tubulin polymerisation inhibitors (<b>4a </b>-<b> 4k</b> and <b>5a </b>-<b> 5h</b>/<b>6a </b>-<b> 6h</b>) were designed <i>via</i> hydrogen bonding, steric effect (for <b>4a </b>-<b> 4k</b>) and ring-closing approach by fused five- and seven-membered ring (for <b>5a </b>-<b> 5h</b>/<b>6a </b>-<b> 6h</b>) which was first adopted in the design of new SMART analogues. Among these compounds, <b>4k</b> and <b>5a</b> showed potent activities with IC<sub>50</sub> values of 15 nM and 6 nM against PC-3 cell line. Mechanism studies indicated that <b>4k</b> and <b>5a</b> could inhibit tubulin polymerisation, arrest cell cycle at G<sub>2</sub>/M phase, induce cell apoptosis, and inhibit cell migration and colony formation. Molecular docking suggested that compounds <b>4k</b> and <b>5a</b> could bind into the colchicine binding site at the pose similar to DAMA-colchicine. Western blot assays revealed that <b>4k</b> and <b>5a</b> regulated the expression of cell cycle and apoptosis-related proteins. Prediction of physicochemical properties indicated good drug-likeness of <b>4k</b> and <b>5a</b>.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2545004"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Dai, Liping Dai, Tao Su, Qin Lin, Zhiwen Lin, Shuxin Ye, Peihao Xu, Hongfeng Chen, Xilong Zheng
{"title":"Green ultrasound‑assisted deep eutectic solvent extraction of flavonoid enzyme inhibitors from <i>Blumea aromatica</i>: process optimization, characterization, and mechanistic insights into <i>α</i>‑glucosidase and tyrosinase inhibition.","authors":"Wei Dai, Liping Dai, Tao Su, Qin Lin, Zhiwen Lin, Shuxin Ye, Peihao Xu, Hongfeng Chen, Xilong Zheng","doi":"10.1080/14756366.2025.2552445","DOIUrl":"10.1080/14756366.2025.2552445","url":null,"abstract":"<p><p>A green ultrasound-assisted deep eutectic solvent (UAE<b>-</b>DES) method was optimised for extracting flavonoid enzyme inhibitors from <i>Blumea aromatica</i>. Optimal conditions (choline chloride-1,4-butanediol 1:3 molar ratio, 43% water content, 50 mL/g liquid-to-solid ratio, 80 °C ultrasound for 48 min) yielded 3.15% total flavonoids, 45.2% higher than 50% ethanol extraction. Scanning electron microscopy confirmed cell wall disruption. The UAE-DES extract showed the strongest enzyme inhibition among all extracts tested (IC<sub>50</sub> 35.872 ± 0.294 µg/mL for <i>α</i>-glucosidase, 9.126 ± 0.285 μg/mL for tyrosinase), though the <i>α</i>-glucosidase inhibition was much weaker than acarbose, while tyrosinase inhibition was comparable to kojic acid. Six flavonoids were identified via UPLC-Q-Orbitrap HRMS, including scutellarein and corylin. Molecular docking revealed strong binding affinities (≤ -5 kcal/mol), with corylin showing the highest binding to both enzymes through hydrogen bonds and van der Waals interactions. This approach supports sustainable discovery of natural enzyme inhibitors for antidiabetic and skin-whitening applications.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2552445"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12412317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yucheng Lu, Daniel Partleton, Filibus M Gugu, Ahmed Y G Alhejaili, Samuel Norris, J Jonathan Harburn, Jason H Gill, Jonathan D Sellars, Alistair K Brown
{"title":"Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts.","authors":"Yucheng Lu, Daniel Partleton, Filibus M Gugu, Ahmed Y G Alhejaili, Samuel Norris, J Jonathan Harburn, Jason H Gill, Jonathan D Sellars, Alistair K Brown","doi":"10.1080/14756366.2025.2502600","DOIUrl":"10.1080/14756366.2025.2502600","url":null,"abstract":"<p><p>Despite efforts to discover effective treatments to eradicate tuberculosis (TB), it remains a global threat. The increase in drug-resistant bacterial species has made the discovery of new drugs highly coveted. The utilisation of previous efficacious structures is one approach that can be employed to developing novel series of compounds to combat this ever-growing problem. This study sought to re-examine two such compounds, isoxyl (ISO) and SQ109, previously shown to be efficacious in TB treatment. SQ109-ISO hybrid compounds were shown to have demonstrable activity against both drug-sensitive and drug-resistant <i>Mtb</i> whilst displaying limited toxicity <i>in vitro</i> in comparison to other antitubercular agents. Indications from our genetic and biochemical studies suggest that these structurally similar pharmacophores bind to different proteins within <i>Mtb</i>, highlighting the need for careful consideration when producing regioisomeric analogues and that the utilisation of previous efficacious structures is a valid approach to developing promising novel drugs against <i>Mtb</i>.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2502600"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Design and synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives as novel mitochondrial permeability transition pore inhibitors.","authors":"Valentina Albanese, Gaia Pedriali, Martina Fabbri, Antonella Ciancetta, Silvia Ravagli, Chiara Roccatello, Remo Guerrini, Giampaolo Morciano, Delia Preti, Paolo Pinton, Salvatore Pacifico","doi":"10.1080/14756366.2025.2505907","DOIUrl":"10.1080/14756366.2025.2505907","url":null,"abstract":"<p><p>Ischaemia/reperfusion injury (IRI) is a condition that occurs when tissues from different organs undergo reperfusion following an ischaemic event. The mitochondrial permeability transition pore (mPTP), a multiprotein platform including structural components of ATP synthase with putative gate function, is an emerging pharmacological target that could be modulated to facilitate the restoration of organ function after a hypoxic insult. Herein, we reported the synthesis and biological characterisation of new molecules with a 1,4,8-triaza-spiro[4.5]decan-2-one framework of potential interest for the treatment of IRI able to inhibit the opening of mPTP in a cardiac model in vitro. Modelling studies were useful to rationalise the observed structure-activity relationship detecting a binding site for the investigated molecules at the interface between the c<sub>8</sub>-ring and subunit a of ATP synthase. Compound <b>14e</b> was shown to display high potency as mPTP inhibitor combined with the capability to counteract cardiomyocytes death in an in vitro model of hypoxia/reoxygenation.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2505907"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid
{"title":"Ligand-based discovery of novel N-arylpyrrole derivatives as broad-spectrum antimicrobial agents with antibiofilm and anti-virulence activity.","authors":"Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid","doi":"10.1080/14756366.2025.2523970","DOIUrl":"10.1080/14756366.2025.2523970","url":null,"abstract":"<p><p>The escalating threat of antimicrobial resistance calls for novel therapeutic agents. This study employed a ligand-based design approach to develop three series of N-arylpyrrole derivatives (<b>Va-e</b>, <b>VIa-e</b>, and <b>VIIa-e</b>), refined through molecular modeling. Synthesized compounds were evaluated against ESKAPE pathogens, MRSA, and <i>Mycobacterium phlei</i>. Series <b>Va-e</b> showed the most promise, with compounds <b>Vb</b>, <b>Vc</b>, and <b>Ve</b> outperforming levofloxacin against MRSA (MIC = 4 μg/mL vs. 8 μg/mL). <b>Vc</b> also exhibited activity against <i>E. coli, K. pneumoniae</i>, and <i>A. baumannii</i>, and showed significant inhibition against <i>M. phlei</i> (MIC = 8 μg/mL). Compounds were evaluated for antibiofilm and antivirulence properties, targeting resistance mechanisms linked to infection persistence and dissemination. Most exhibited broad-spectrum biofilm inhibition and antivirulence activity. Cytotoxicity studies revealed selectivity for bacterial cells. ADMET studies supported drug-like properties. Docking studies suggested UPPP inhibition as the potential mechanism. SAR analysis was conducted to support future optimizations.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2523970"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction.","authors":"","doi":"10.1080/14756366.2025.2537523","DOIUrl":"10.1080/14756366.2025.2537523","url":null,"abstract":"","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2537523"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tiankuang Liu, Cheuk Hei Kan, Yingbo Zheng, Tsz Fung Tsang, Yanpeng Liu, Man Wai Tsang, Hantian Fang, Long Yin Lam, Xiao Yang, Cong Ma
{"title":"Development of triaryl antimicrobials by scaffold hopping from an aminopropanol hit targeting bacterial RNA polymerase-NusG interactions.","authors":"Tiankuang Liu, Cheuk Hei Kan, Yingbo Zheng, Tsz Fung Tsang, Yanpeng Liu, Man Wai Tsang, Hantian Fang, Long Yin Lam, Xiao Yang, Cong Ma","doi":"10.1080/14756366.2025.2543923","DOIUrl":"10.1080/14756366.2025.2543923","url":null,"abstract":"<p><p>Bacterial RNA polymerase (RNAP) requires the NusG factor to facilitate transcription, with the RNAP clamp-helix domain (CH) serving as the primary binding site for NusG and representing a promising target for antimicrobial intervention. In previous work, we unprecedentedly developed a pharmacophore model based on key clamp-helix residues (R270, R278, R281) at RNAP CH essential for NusG binding, which led to the identification of a hit compound exhibiting modest antimicrobial activity against <i>Streptococcus pneumoniae</i>. In this study, we designed a new class of triaryl inhibitors via scaffold hopping, substituting the linear structure of the hit compound with a benzene ring. Antimicrobial testing showed that several newly synthesised lead compounds achieved the minimum inhibitory concentration of 1 µg/mL against drug-resistant <i>S. pneumoniae</i>, superior to some marketed antibiotics. The following inhibitory and cell-based assays demonstrated the potential of these triaryl compounds as promising candidates for further development as novel antimicrobial agents.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2543923"},"PeriodicalIF":5.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Study on the synthesis and biological activity of kojic acid triazol thiosemicarbazide Schiff base derivatives.","authors":"Yayuan Luo, Zhiyong Peng, Junyuan Tang, Dahan Wang, Sheng Tao, Jinbing Liu","doi":"10.1080/14756366.2025.2475071","DOIUrl":"10.1080/14756366.2025.2475071","url":null,"abstract":"<p><p>A series of kojic acid triazol thiosemicarbazide Schiff base derivatives were designed and synthesised. Evaluation on the inhibition of tyrosinase activity showed that these compounds possessed potent inhibit tyrosinase activity, and the compound <b>6w</b> (IC<sub>50</sub> = 0.94 μM) exhibited the best inhibitory effect. Preliminary structure-activity relationships indicate that steric hindrance, halogen atom radius, and electron donating ability of functional groups have some impact on the inhibition of tyrosinase activity. Inhibition mechanism showed that compound <b>6w</b> is a non-competitive mixed inhibitor, and this result was further confirmed by molecular docking. The fluorescence quenching mode of compound <b>6w</b> is dynamic quenching, and interacts with tyrosinase by changing the amide structure of tyrosinase. Compound <b>6w</b> has some anti-browning effect. Compound <b>6p</b> had the strongest DPPH radical scavenging activity (IC<sub>50</sub> = 10.53 ± 0.014 μM), and compound <b>6w</b> showed the best ABTS scavenging activity (IC<sub>50</sub> = 3.03 ± 0.009 μM).</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2475071"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}