Pub Date : 2025-12-02DOI: 10.1016/j.bmc.2025.118503
Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang
Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor C-0 (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid 9f and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid 10f exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound 10f demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds 9f and 10f had improved in vitro and in vivo pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.
{"title":"Novel indole-based indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors: design, synthesis, and antidepressant evaluation","authors":"Juan Zhang , Wen-Jing Gao , Yu-Xi Zheng , Jia-Dong Shao , Nai-Yu Zhang , Wei Guo , Shuai Wang , Qing Zhao , Kongkai Zhu , Ming Gao , Jin-Hai Yu , Ning Meng , Cheng-Shi Jiang","doi":"10.1016/j.bmc.2025.118503","DOIUrl":"10.1016/j.bmc.2025.118503","url":null,"abstract":"<div><div>Indoleamine 2,3-dioxygenase-1 (IDO1) has emerged as a promising therapeutic target for antidepressant development. The present study performed scaffold hopping-based structural optimization of a known benzimidazole-derived IDO1 inhibitor <strong>C-0</strong> (20.20 ± 2.27 nM), which yielded a series of novel indole-based IDO1 inhibitors. Among these, the 6-fluoroindole/indole-2-carboxamide hybrid <strong>9f</strong> and the 6-fluoroindole/4-bromopyrrole-2-carboxamide hybrid <strong>10f</strong> exhibited the most improved IDO1 inhibitory activity, achieving IC₅₀ values of 9.18 ± 0.84 and 6.57 ± 0.61 nM, respectively. In addition, compound <strong>10f</strong> demonstrated anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Further study revealed that compounds <strong>9f</strong> and <strong>10f</strong> had improved <em>in vitro</em> and <em>in vivo</em> pharmacokinetic properties compared to the controls, and rescued LPS-induced depressive-like behavior in mice. The present study provides indole-based IDO1 inhibitors as a promising lead compound for the development of novel and effective IDO1-targeted antidepressants.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118503"},"PeriodicalIF":3.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Malaria remains a significant cause of mortality globally; development and discovery of novel antimalarial drugs are needed to search for effective antimalarial agents due to resistance against existing drugs. Chalcones, also known as α,β-unsaturated ketones, have been studied due to their varied biological activities, including antimalarial activity. Using hybrid compounds is one helpful strategy to enhance the efficacy of antimalarial drugs and reduce treatment resistance. Hence, the current review intended to introduce various heterocycles like triazole, indole, thiophene, benzimidazole, quinoline, piperidine, pyridine, furan, coumarin, and pyrazole containing chalcone hybrids of promising antimalarial activity reported by the researchers from 2019 to 2025. The structure–activity relationship that has been discussed could provide a useful approach for possible drug design and synthesis based on hybridization between the chalcone core and heterocyclic scaffolds.
{"title":"Recent developments in synthesis and antimalarial activities of chalcone hybrids","authors":"Ravindar Lekkala , Revathi Lekkala , Fei Wen Cheong , Nurul Izzaty Hassan , Yee Ling Lau","doi":"10.1016/j.bmc.2025.118512","DOIUrl":"10.1016/j.bmc.2025.118512","url":null,"abstract":"<div><div>Malaria remains a significant cause of mortality globally; development and discovery of novel antimalarial drugs are needed to search for effective antimalarial agents due to resistance against existing drugs. Chalcones, also known as α,β-unsaturated ketones, have been studied due to their varied biological activities, including antimalarial activity. Using hybrid compounds is one helpful strategy to enhance the efficacy of antimalarial drugs and reduce treatment resistance. Hence, the current review intended to introduce various heterocycles like triazole, indole, thiophene, benzimidazole, quinoline, piperidine, pyridine, furan, coumarin, and pyrazole containing chalcone hybrids of promising antimalarial activity reported by the researchers from 2019 to 2025. The structure–activity relationship that has been discussed could provide a useful approach for possible drug design and synthesis based on hybridization between the chalcone core and heterocyclic scaffolds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118512"},"PeriodicalIF":3.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Since the outbreak of COVID-19, one key strategy has been to screen inhibitors of the SARS-CoV-2 main protease (Mpro). Mpro is critical for viral replication and a key target for therapeutic development. In this work, we report the design and synthesis of 29 thiosemicarbazone derivatives. Enzymatic inhibition assays showed that 27 compounds exhibited inhibitory activity against Mpro, among which 4 compounds (1e, 2c, 2f, 3a) demonstrated significant inhibitory potency, with IC50 values of 5.97 ± 0.98 μM, 4.43 ± 1.67 μM, 10.99 ± 2.39 μM, and 28.88 ± 3.57 μM, respectively. Fluorescence spectroscopy, molecular docking, microscale thermophoresis and molecular dynamics simulations were used to analyze the interaction mechanisms between thiosemicarbazone derivatives and Mpro. Fluorescence results indicated that the fluorescence quenching mechanism of the compounds on Mpro was predominantly static quenching. Hydrogen bonding and hydrophobic interactions were observed in the binding process. Microscale thermophoresis results confirmed that compounds 1e, 2c and 2f exhibit significant binding affinity for Mpro, with Kd values of 4.21 ± 0.35 μM, 3.24 ± 0.28 μM, and 24.26 ± 1.82 μM, respectively. This study provides valuable information for understanding the interaction mechanism between thiosemicarbazone derivatives and Mpro and offers insights into novel Mpro inhibitors.
{"title":"Discovery of thiosemicarbazone derivatives as promising SARS-CoV-2 Mpro inhibitors by spectroscopy and microscale thermophoresis","authors":"Xing Xue , Leyao Chen , Miao Zhang , Xiaoyu Chang , Ruiyong Wang","doi":"10.1016/j.bmc.2025.118501","DOIUrl":"10.1016/j.bmc.2025.118501","url":null,"abstract":"<div><div>Since the outbreak of COVID-19, one key strategy has been to screen inhibitors of the SARS-CoV-2 main protease (Mpro). Mpro is critical for viral replication and a key target for therapeutic development. In this work, we report the design and synthesis of 29 thiosemicarbazone derivatives. Enzymatic inhibition assays showed that 27 compounds exhibited inhibitory activity against Mpro, among which 4 compounds (<strong>1e</strong>, <strong>2c</strong>, <strong>2f</strong>, <strong>3a</strong>) demonstrated significant inhibitory potency, with IC<sub>50</sub> values of 5.97 ± 0.98 μM, 4.43 ± 1.67 μM, 10.99 ± 2.39 μM, and 28.88 ± 3.57 μM, respectively. Fluorescence spectroscopy, molecular docking, microscale thermophoresis and molecular dynamics simulations were used to analyze the interaction mechanisms between thiosemicarbazone derivatives and Mpro. Fluorescence results indicated that the fluorescence quenching mechanism of the compounds on Mpro was predominantly static quenching. Hydrogen bonding and hydrophobic interactions were observed in the binding process. Microscale thermophoresis results confirmed that compounds <strong>1e</strong>, <strong>2c</strong> and <strong>2f</strong> exhibit significant binding affinity for Mpro, with K<sub>d</sub> values of 4.21 ± 0.35 μM, 3.24 ± 0.28 μM, and 24.26 ± 1.82 μM, respectively. This study provides valuable information for understanding the interaction mechanism between thiosemicarbazone derivatives and Mpro and offers insights into novel Mpro inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118501"},"PeriodicalIF":3.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bmc.2025.118499
Shun Li , Xinrui Li , Shuanglong Li, Daoyuan Chen, Chunli Xia
The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.
{"title":"Discovery of novel hybrids of coumarin and quinoline as potential anti-Alzheimer's disease agent","authors":"Shun Li , Xinrui Li , Shuanglong Li, Daoyuan Chen, Chunli Xia","doi":"10.1016/j.bmc.2025.118499","DOIUrl":"10.1016/j.bmc.2025.118499","url":null,"abstract":"<div><div>The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound <strong>B8</strong> as a promising lead compound. <strong>B8</strong> exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, <strong>B8</strong> demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of <strong>B8</strong> to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with <strong>B8</strong> emerging as a promising lead candidate warranting further investigation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118499"},"PeriodicalIF":3.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bmc.2025.118502
Maxwell Ampomah-Wireko , Yuequan Wu , Ye Qu , Daran Li , Ruirui Li , Yuanbo Li , Hongtao Kong , Zhi-Hao Li , Cedric Dzidzor Kodjo Amengor , Ya-Na Wang , En Zhang
Drug-resistant bacteria and biofilm-associated infections remain major challenges in anti-infective therapy, contributing to high morbidity and mortality and emphasizing the need to develop novel antimicrobial agents with a low potential to induce resistance. Toward this, quaternization of compounds has become a viable molecular design approach for developing antibacterial agents. In this study, we report the design, synthesis, and antibacterial evaluation of a series of novel ring-C-modified quaternary ammonium oxazolidinone derivatives bearing various lipophilic substituents (alkyl- and aryl-moieties). The structure-activity relationship (SAR) exploration showed that the introduction of longer alkyl chains had a good effect on the antibacterial activity. Compound 4i with longest carbon chain exhibited potent antibacterial activity against E. faecalis with a MIC of 4 μg/mL. Furthermore, this pyridinium oxazolidinone not only exhibited a rapid bactericidal effect but also demonstrated a strong activity against E. faecalis biofilms, with no observable tendency for bacteria to develop resistance to 4i after 20 consecutive passages. Mechanistic studies revealed that 4i disrupted glutathione (GSH)/reactive oxygen species (ROS) homeostasis, thereby inducing lethal oxidative stress, leading to ROS accumulation and bacterial death. Compound 4i also showed low toxicity toward mammalian cells. Overall, our results suggest that incorporating quaternary ammonium salts into oxazolidinones will provide promising strategy for designing novel oxazolidinone derivatives with potent antimicrobial activity and low toxicity against mammalian cells.
{"title":"Development of cationic Pyridinium-Oxazolidinone derivatives as antibacterial agents","authors":"Maxwell Ampomah-Wireko , Yuequan Wu , Ye Qu , Daran Li , Ruirui Li , Yuanbo Li , Hongtao Kong , Zhi-Hao Li , Cedric Dzidzor Kodjo Amengor , Ya-Na Wang , En Zhang","doi":"10.1016/j.bmc.2025.118502","DOIUrl":"10.1016/j.bmc.2025.118502","url":null,"abstract":"<div><div>Drug-resistant bacteria and biofilm-associated infections remain major challenges in anti-infective therapy, contributing to high morbidity and mortality and emphasizing the need to develop novel antimicrobial agents with a low potential to induce resistance. Toward this, quaternization of compounds has become a viable molecular design approach for developing antibacterial agents. In this study, we report the design, synthesis, and antibacterial evaluation of a series of novel ring-C-modified quaternary ammonium oxazolidinone derivatives bearing various lipophilic substituents (alkyl- and aryl-moieties). The structure-activity relationship (SAR) exploration showed that the introduction of longer alkyl chains had a good effect on the antibacterial activity. Compound <strong>4i</strong> with longest carbon chain exhibited potent antibacterial activity against <em>E. faecalis</em> with a MIC of 4 μg/mL. Furthermore, this pyridinium oxazolidinone not only exhibited a rapid bactericidal effect but also demonstrated a strong activity against <em>E. faecalis</em> biofilms, with no observable tendency for bacteria to develop resistance to <strong>4i</strong> after 20 consecutive passages. Mechanistic studies revealed that <strong>4i</strong> disrupted glutathione (GSH)/reactive oxygen species (ROS) homeostasis, thereby inducing lethal oxidative stress, leading to ROS accumulation and bacterial death. Compound <strong>4i</strong> also showed low toxicity toward mammalian cells. Overall, our results suggest that incorporating quaternary ammonium salts into oxazolidinones will provide promising strategy for designing novel oxazolidinone derivatives with potent antimicrobial activity and low toxicity against mammalian cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118502"},"PeriodicalIF":3.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.bmc.2025.118500
Phoebe R. Rubio , Gavin A. Clausen , Zachary D. Ruighaver , Abigail F. Dalton, John P. Blobe, Amanda L. Moore, Christopher R. Shugrue
We report the development of a new benzothiazole sulfone (BTS) tool for peptide modification and cleavage. Benzothiazole sulfones are electrophiles that rapidly react with thiols in nucleophilic aromatic substitution (SNAr) reactions. Alkyne-containing BTS compounds were incorporated onto azidolysine-containing peptides through copper-catalyzed azide-alkyne cycloadditions (CuAACs). BTS-containing peptides were found to react rapidly with two equivalents of thiol nucleophiles at room temperature in 30 min or less. BTS-containing peptides were conjugated to a variety of different compounds, including small molecules, fluorophores, and peptides. Alternatively, a BTS-based cleavable linker could also be synthesized with small molecule cargo, such as biotin, and attached to peptides through CuAAC. This linker enabled the capture and release of a peptide with immobilized streptavidin. The BTS motif is a versatile tool for various applications in peptide science.
{"title":"Benzothiazole sulfones as a tool for peptide modification and cleavage","authors":"Phoebe R. Rubio , Gavin A. Clausen , Zachary D. Ruighaver , Abigail F. Dalton, John P. Blobe, Amanda L. Moore, Christopher R. Shugrue","doi":"10.1016/j.bmc.2025.118500","DOIUrl":"10.1016/j.bmc.2025.118500","url":null,"abstract":"<div><div>We report the development of a new benzothiazole sulfone (BTS) tool for peptide modification and cleavage. Benzothiazole sulfones are electrophiles that rapidly react with thiols in nucleophilic aromatic substitution (S<sub><em>N</em></sub>Ar) reactions. Alkyne-containing BTS compounds were incorporated onto azidolysine-containing peptides through copper-catalyzed azide-alkyne cycloadditions (CuAACs). BTS-containing peptides were found to react rapidly with two equivalents of thiol nucleophiles at room temperature in 30 min or less. BTS-containing peptides were conjugated to a variety of different compounds, including small molecules, fluorophores, and peptides. Alternatively, a BTS-based cleavable linker could also be synthesized with small molecule cargo, such as biotin, and attached to peptides through CuAAC. This linker enabled the capture and release of a peptide with immobilized streptavidin. The BTS motif is a versatile tool for various applications in peptide science.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118500"},"PeriodicalIF":3.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.bmc.2025.118498
Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin
Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound 5l exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC50) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC50 of human embryonic lung fibroblast MRC-5 cells/IC50 of A549 cells) of 15.39. Mechanistic studies further revealed that compound 5l is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound 5l demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound 5l holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).
{"title":"Development of lupeol derivatives based on tubulin-targeting strategy: structural modification and correlation analysis of antitumor activity","authors":"Yinxu Zhao , Liman Hou , Shuang Tian , Mengxin Zhu , Jiale Wu , Yukun Ma , Ming Bu , Yu Lin","doi":"10.1016/j.bmc.2025.118498","DOIUrl":"10.1016/j.bmc.2025.118498","url":null,"abstract":"<div><div>Lupeol is a natural pentacyclic triterpenoid compound and exhibits great potential as a lead compound for the development of novel antitumor drugs. To further enhance its antitumor activity and targeting ability, two series of new lupeol derivatives were designed and synthesized in this study, and their antiproliferative activities against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated. Among these derivatives, compound <strong>5l</strong> exhibited more potent in vitro antiproliferative activity against A549 cells, with a half-maximal inhibitory concentration (IC<sub>50</sub>) of 1.84 ± 0.53 μmol/L and a selectivity index (SI; IC<sub>50</sub> of human embryonic lung fibroblast MRC-5 cells/IC<sub>50</sub> of A549 cells) of 15.39. Mechanistic studies further revealed that compound <strong>5l</strong> is a novel tubulin inhibitor: it can specifically bind to the colchicine-binding site of β-tubulin with a binding energy of −13.40 kcal/mol, effectively inhibit tubulin polymerization, arrest the cell cycle at the G2/M phase, and simultaneously trigger a series of apoptosis-related responses, thereby significantly inducing apoptosis of tumour cells. In the mouse lung cancer model, compound <strong>5l</strong> demonstrated significant antitumor activity and a favorable safety profile. Based on these results, compound <strong>5l</strong> holds promise as a new tubulin inhibitor for the treatment of non-small cell lung cancer (NSCLC).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118498"},"PeriodicalIF":3.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1016/j.bmc.2025.118497
Hao-Zhe Long , Meng-Jie Fu , Xin-Qian Ji , Cong-Jun Liu , Bo Wang , Ya Gao , Hui-Min Liu , Yi-Chao Zheng , Hong-Min Liu , Xing-Jie Dai
Quinazoline-based scaffolds represent a class of nitrogen-containing heterocycles distinguished by their structural versatility and broad-spectrum anticancer activities, positioning them as key elements in targeted cancer therapy. This review highlights the role of quinazoline derivatives as potent small-molecule inhibitors targeting diverse oncogenic drivers. They effectively modulate critical receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and cellular-mesenchymal epithelial transition factor (c-Met); non-receptor serine/threonine kinases including cyclin-dependent kinases (CDKs), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Aurora kinases, and hematopoietic progenitor kinase 1 (HPK1); as well as epigenetic, cytoskeletal, and DNA-interacting proteins. Recent advances in structure-activity relationship (SAR) studies, binding analyses, and preclinical evaluations have facilitated scaffold optimization to counter resistance mutations and improve pharmacokinetic properties. Collectively, clinical and experimental evidence underscores quinazoline derivatives as a robust platform for developing next-generation targeted anticancer agents.
{"title":"Unveiling the power of quinazoline derivatives: a new frontier in targeted cancer therapy","authors":"Hao-Zhe Long , Meng-Jie Fu , Xin-Qian Ji , Cong-Jun Liu , Bo Wang , Ya Gao , Hui-Min Liu , Yi-Chao Zheng , Hong-Min Liu , Xing-Jie Dai","doi":"10.1016/j.bmc.2025.118497","DOIUrl":"10.1016/j.bmc.2025.118497","url":null,"abstract":"<div><div>Quinazoline-based scaffolds represent a class of nitrogen-containing heterocycles distinguished by their structural versatility and broad-spectrum anticancer activities, positioning them as key elements in targeted cancer therapy. This review highlights the role of quinazoline derivatives as potent small-molecule inhibitors targeting diverse oncogenic drivers. They effectively modulate critical receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and cellular-mesenchymal epithelial transition factor (c-Met); non-receptor serine/threonine kinases including cyclin-dependent kinases (CDKs), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Aurora kinases, and hematopoietic progenitor kinase 1 (HPK1); as well as epigenetic, cytoskeletal, and DNA-interacting proteins. Recent advances in structure-activity relationship (SAR) studies, binding analyses, and preclinical evaluations have facilitated scaffold optimization to counter resistance mutations and improve pharmacokinetic properties. Collectively, clinical and experimental evidence underscores quinazoline derivatives as a robust platform for developing next-generation targeted anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118497"},"PeriodicalIF":3.0,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1016/j.bmc.2025.118496
Mo Ahamad Khan , Lechen Zhu , Hu Zhu
The rise of antimicrobial resistance (AMR) has outpaced the development of new antibiotics, necessitating alternative therapeutic strategies that do not rely on conventional bactericidal approaches. Quorum-sensing (QS), a bacterial communication system that regulates virulence, biofilm formation and genetic competence, has emerged as a promising non-lethal target. Peptide-based quorum-sensing inhibitors (QSIs) including antimicrobial peptides (AMPs), cyclic dipeptides, and synthetic analogs are gaining recognition for their ability to disrupt QS pathways and attenuate pathogenicity without promoting resistance. This review summarizes recent advancements in peptide-mediated QS interference, covering mechanistic insights, molecular design strategies, and application domains. Natural AMPs such as LL-37 and GH12 modulate QS by altering gene expression or blocking receptor function, while marine-derived cyclic dipeptides act as competitive inhibitors of QS receptors like LasR and CviR. Engineered peptides and peptide-nanocomposite systems have demonstrated improved stability and target specificity, particularly against multidrug-resistant pathogens. Applications span wound healing, prevention of dental biofilms, and prevention of infectious diseases development. However, challenges remain, including peptide instability, low bioavailability, off-target effects, and potential resistance development. Peptide-based QSIs represent a paradigm shift in antimicrobial therapy by disabling bacterial virulence without directly killing cells. Advances in peptide engineering, delivery systems, and synthetic biology are accelerating their clinical and environmental translation. With continued innovation and adapted regulatory frameworks, peptide-based QS inhibition may become a cornerstone of next-generation anti-virulence therapeutics.
{"title":"Peptide-based approaches to quorum-sensing disruption: emerging trends and applications in antimicrobial therapy","authors":"Mo Ahamad Khan , Lechen Zhu , Hu Zhu","doi":"10.1016/j.bmc.2025.118496","DOIUrl":"10.1016/j.bmc.2025.118496","url":null,"abstract":"<div><div>The rise of antimicrobial resistance (AMR) has outpaced the development of new antibiotics, necessitating alternative therapeutic strategies that do not rely on conventional bactericidal approaches<em>.</em> Quorum-sensing (QS), a bacterial communication system that regulates virulence, biofilm formation and genetic competence, has emerged as a promising non-lethal target. Peptide-based quorum-sensing inhibitors (QSIs) including antimicrobial peptides (AMPs), cyclic dipeptides, and synthetic analogs are gaining recognition for their ability to disrupt QS pathways and attenuate pathogenicity without promoting resistance. This review summarizes recent advancements in peptide-mediated QS interference, covering mechanistic insights, molecular design strategies, and application domains. Natural AMPs such as LL-37 and GH12 modulate QS by altering gene expression or blocking receptor function, while marine-derived cyclic dipeptides act as competitive inhibitors of QS receptors like <em>LasR and CviR.</em> Engineered peptides and peptide-nanocomposite systems have demonstrated improved stability and target specificity, particularly against multidrug-resistant pathogens. Applications span wound healing, prevention of dental biofilms, and prevention of infectious diseases development. However, challenges remain, including peptide instability, low bioavailability, off-target effects, and potential resistance development. Peptide-based QSIs represent a paradigm shift in antimicrobial therapy by disabling bacterial virulence without directly killing cells. Advances in peptide engineering, delivery systems, and synthetic biology are accelerating their clinical and environmental translation. With continued innovation and adapted regulatory frameworks, peptide-based QS inhibition may become a cornerstone of next-generation anti-virulence therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118496"},"PeriodicalIF":3.0,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.bmc.2025.118493
Suzanne Chamberland , Audrey Larose , Guillaume Millette , Jean-Philippe Langlois , Julie Côté-Gravel , Eric Brouillette , Daniela Droppa Almeida , Renaud Binette , Julien A. Delbrouck , Iryna Diachenko , Abdelkhalek Ben Jamaa , Chad Normandin , Alexandre Murza , François Malouin , Pierre-Luc Boudreault
Tomatidine (TO), a natural steroidal alkaloid derived from Solanaceae (e.g., tomato), is recognized for its narrow-spectrum antibiotic activity, particularly against persistent forms of Staphylococcus aureus, such as small-colony variants (SCVs). Previous studies have shown that TO exerts its effect by inhibiting S. aureus ATP synthase. In earlier work, we synthesized nearly 100 TO analogs featuring an ethylenediamine linker branched with aromatic substituents at the C3 position, and demonstrated that several of these analogs possess notable antibacterial activity against typical (non-SCV) S. aureus strains, including methicillin-resistant S. aureus (MRSA), with minimum inhibitory concentrations (MICs) ranging from 1 to 4 μg/mL. Among these, analogs incorporating an indole (TM-247) or para-substituted aryl moiety (TM-184, -I; TM-218, -Br; TM-220, -Cl; TM-303, -CF₃) emerged as lead candidates, exhibiting potent antibacterial activity in vitro against both Gram-positive and Gram-negative bacteria, including S. aureus SCVs. In the present study, we conducted a comprehensive antibacterial profiling of this compound series, including the predecessor compound TM-02, against a panel comprising 16 Gram-positive strains, 16 antibiotic-resistant Escherichia coli isolates, and two multidrug-resistant Acinetobacter baumannii strains. TM-184 emerged as the most promising candidate and was subsequently subjected to an expanded in vitro evaluation across 24 clinically relevant Gram-negative bacterial species. Furthermore, TM-184 was assessed in vivo using a neutropenic mouse thigh infection model against E. coli, demonstrating significant efficacy and resulting in a substantial reduction in bacterial burden.
{"title":"In vitro and in vivo activity profiles of broad-spectrum bacterial ATP synthase inhibitors","authors":"Suzanne Chamberland , Audrey Larose , Guillaume Millette , Jean-Philippe Langlois , Julie Côté-Gravel , Eric Brouillette , Daniela Droppa Almeida , Renaud Binette , Julien A. Delbrouck , Iryna Diachenko , Abdelkhalek Ben Jamaa , Chad Normandin , Alexandre Murza , François Malouin , Pierre-Luc Boudreault","doi":"10.1016/j.bmc.2025.118493","DOIUrl":"10.1016/j.bmc.2025.118493","url":null,"abstract":"<div><div>Tomatidine (<strong>TO</strong>), a natural steroidal alkaloid derived from Solanaceae (<em>e.g.</em>, tomato), is recognized for its narrow-spectrum antibiotic activity, particularly against persistent forms of <em>Staphylococcus aureus</em>, such as small-colony variants (SCVs). Previous studies have shown that <strong>TO</strong> exerts its effect by inhibiting <em>S. aureus</em> ATP synthase. In earlier work, we synthesized nearly 100 <strong>TO</strong> analogs featuring an ethylenediamine linker branched with aromatic substituents at the C3 position, and demonstrated that several of these analogs possess notable antibacterial activity against typical (non-SCV) <em>S. aureus</em> strains, including methicillin-resistant <em>S. aureus</em> (MRSA), with minimum inhibitory concentrations (MICs) ranging from 1 to 4 μg/mL. Among these, analogs incorporating an indole (<strong>TM-247</strong>) or para-substituted aryl moiety (<strong>TM-184</strong>, -I; <strong>TM-218</strong>, -Br; <strong>TM-220</strong>, -Cl; <strong>TM-303</strong>, -CF₃) emerged as lead candidates, exhibiting potent antibacterial activity <em>in vitro</em> against both Gram-positive and Gram-negative bacteria, including <em>S. aureus</em> SCVs. In the present study, we conducted a comprehensive antibacterial profiling of this compound series, including the predecessor compound <strong>TM-02</strong>, against a panel comprising 16 Gram-positive strains, 16 antibiotic-resistant <em>Escherichia coli</em> isolates, and two multidrug-resistant <em>Acinetobacter baumannii</em> strains. <strong>TM-184</strong> emerged as the most promising candidate and was subsequently subjected to an expanded <em>in vitro</em> evaluation across 24 clinically relevant Gram-negative bacterial species. Furthermore, <strong>TM-184</strong> was assessed <em>in vivo</em> using a neutropenic mouse thigh infection model against <em>E. coli</em>, demonstrating significant efficacy and resulting in a substantial reduction in bacterial burden.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"133 ","pages":"Article 118493"},"PeriodicalIF":3.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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