Pub Date : 2025-10-01DOI: 10.1016/j.bmc.2025.118429
Peng Zhou, Yaya Peng, Gen Yang, Di Xie, Jiayin Yan, Jinliang Ma, Wenpei Dong, Chang-Po Chen
The stimulator of interferon genes (STING) pathway is pivotal component of innate immunity, playing key role in host defense against viral and bacterial infections. However, aberrant activation of the STING pathway can trigger inflammatory diseases and thus inhibition of STING signaling pathway is regarded as promising anti-inflammation strategy. In this study, we designed and synthesized a series of dimeric 1-(1H-indol-3-yl) urea compounds, derivatized from the covalent STING inhibitor H151. The representative compound 3S-12 exhibited potent STING inhibitory activity with IC50 of 0.124 μM for m-STING and 0.533 μM for h-STING. In the cisplatin-induced acute kidney injury model, 3S-12 significantly alleviated tissue injury and inflammation.
{"title":"Dimeric 1-(1H-indol-3-yl) urea as potent STING inhibitor to alleviate cisplatin-induced acute kidney injury in mice","authors":"Peng Zhou, Yaya Peng, Gen Yang, Di Xie, Jiayin Yan, Jinliang Ma, Wenpei Dong, Chang-Po Chen","doi":"10.1016/j.bmc.2025.118429","DOIUrl":"10.1016/j.bmc.2025.118429","url":null,"abstract":"<div><div>The stimulator of interferon genes (STING) pathway is pivotal component of innate immunity, playing key role in host defense against viral and bacterial infections. However, aberrant activation of the STING pathway can trigger inflammatory diseases and thus inhibition of STING signaling pathway is regarded as promising anti-inflammation strategy. In this study, we designed and synthesized a series of dimeric 1-(1<em>H</em>-indol-3-yl) urea compounds, derivatized from the covalent STING inhibitor <strong>H151</strong>. The representative compound <strong>3S-12</strong> exhibited potent STING inhibitory activity with IC<sub>50</sub> of 0.124 μM for m-STING and 0.533 μM for h-STING. In the cisplatin-induced acute kidney injury model, <strong>3S-12</strong> significantly alleviated tissue injury and inflammation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118429"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256948","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 : 2025-09-30DOI: 10.1016/j.bmc.2025.118426
Anja Kolarič , Marko Jukič , Urban Bren
Viral infections pose a significant health threat worldwide. Due to the high mutation rates of many viruses and their reliance on host cellular machinery, the development of effective antiviral therapies is particularly difficult. As a result, only a limited number of antiviral agents is currently available. In parallel to modern vaccines, traditional antiviral drug development is both time-consuming and costly, underscoring the need for faster, more efficient approaches. In recent years, particularly since the beginning of the COVID-19 pandemic, machine learning (ML) together with broader artificial intelligence (AI), have emerged as powerful methodologies for drug discovery and offer the potential to accelerate the identification and development of antiviral agents. This review examines the application of ML in the early stages of antiviral drug discovery, with a particular focus on recent studies where ML methods have successfully identified hit compounds with experimentally demonstrated activity in biological assays. By highlighting these successful case studies, the review illustrates the growing impact of ML in advancing the discovery of urgently needed novel antivirals.
{"title":"Machine learning in antiviral drug design","authors":"Anja Kolarič , Marko Jukič , Urban Bren","doi":"10.1016/j.bmc.2025.118426","DOIUrl":"10.1016/j.bmc.2025.118426","url":null,"abstract":"<div><div>Viral infections pose a significant health threat worldwide. Due to the high mutation rates of many viruses and their reliance on host cellular machinery, the development of effective antiviral therapies is particularly difficult. As a result, only a limited number of antiviral agents is currently available. In parallel to modern vaccines, traditional antiviral drug development is both time-consuming and costly, underscoring the need for faster, more efficient approaches. In recent years, particularly since the beginning of the COVID-19 pandemic, machine learning (ML) together with broader artificial intelligence (AI), have emerged as powerful methodologies for drug discovery and offer the potential to accelerate the identification and development of antiviral agents. This review examines the application of ML in the early stages of antiviral drug discovery, with a particular focus on recent studies where ML methods have successfully identified hit compounds with experimentally demonstrated activity in biological assays. By highlighting these successful case studies, the review illustrates the growing impact of ML in advancing the discovery of urgently needed novel antivirals.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"132 ","pages":"Article 118426"},"PeriodicalIF":3.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247958","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 : 2025-09-29DOI: 10.1016/j.bmc.2025.118425
A.C. Kumar , Madalambika , P.M. Bharathkumar , Priyanka R. Patil , J. Rangaswamy , Ramith Ramu , K.B. Vilas Gowda , Nagaraja Naik
The inhibition of fungal biofilm formation has garnered significant attention as a promising therapeutic strategy against fungal infections. In this study, a series of N-(5-undecyl-1,3,4-oxadiazol-2-yl)benzamide derivatives 5(a–o) were synthesized as novel biofilm inhibitors targeting Candida albicans, utilizing the well-known biological activities linked with the oxadiazole nucleus. The in vitro antifungal activity of all derivatives was evaluated using the broth microdilution method, with fluconazole serving as the reference drug. Notably, compound 5e exhibited potent activity, with a minimum inhibitory concentration (MIC) of 7 μg/mL and a minimum fungicidal concentration (MFC) of 32 μg/mL, outperforming the standard drug (MIC: 8 μg/mL; MFC: 64 μg/mL). Biofilm and hyphal filament inhibition assays further revealed that compound 5e achieved 86.29 % inhibition of biofilm formation and 72.30 % inhibition of fungal filamentation. Additionally, RT-PCR analysis demonstrated that treatment with compound 5e significantly downregulated the expression of key biofilm genes, including ALS1, ALS3, and HWP1. Scanning electron microscopy (SEM) of C. albicans treated with 5e confirmed substantial inhibition of biofilm formation compared to both untreated controls and the fluconazole-treated group. Screening of compound 5e for blood compatibility by hemolytic assay revealed 4.83 % cell lysis at 1125 μg/mL, and cytotoxicity assay on human HEK293 cell line demonstrated that compound 5e was non-toxic to normal cells at the tested concentrations. Furthermore, molecular docking studies to investigate the potential binding interactions of the lead compound, along with ADMET analysis, were performed to assess pharmacokinetic and bioavailability profiles. The enhanced bioactivity of compound 5e is associated with the presence of an ortho-substituted hydroxy group, a 1,3,4-oxadiazole core, and a long hydrophobic alkyl chain, which collectively improve target binding, membrane interaction, and antifungal effectiveness. These findings suggest that compound 5e is a promising candidate for the development of next-generation antifungal agents to combat drug-resistant Candida albicans infections.
{"title":"Targeting fungal biofilms: design, synthesis, biological and in silico studies of novel N-(5-undecyl-1,3,4-oxadiazol-2-yl)benzamide derivatives against Candida albicans","authors":"A.C. Kumar , Madalambika , P.M. Bharathkumar , Priyanka R. Patil , J. Rangaswamy , Ramith Ramu , K.B. Vilas Gowda , Nagaraja Naik","doi":"10.1016/j.bmc.2025.118425","DOIUrl":"10.1016/j.bmc.2025.118425","url":null,"abstract":"<div><div>The inhibition of fungal biofilm formation has garnered significant attention as a promising therapeutic strategy against fungal infections. In this study, a series of N-(5-undecyl-1,3,4-oxadiazol-2-yl)benzamide derivatives <strong>5(a–o)</strong> were synthesized as novel biofilm inhibitors targeting <em>Candida albicans</em>, utilizing the well-known biological activities linked with the oxadiazole nucleus. The in vitro antifungal activity of all derivatives was evaluated using the broth microdilution method, with fluconazole serving as the reference drug. Notably, compound <strong>5e</strong> exhibited potent activity, with a minimum inhibitory concentration (MIC) of <strong>7</strong> μ<strong>g/mL</strong> and a minimum fungicidal concentration (MFC) of <strong>32</strong> μ<strong>g/mL</strong>, outperforming the standard drug (MIC: 8 μg/mL; MFC: 64 μg/mL). Biofilm and hyphal filament inhibition assays further revealed that compound <strong>5e</strong> achieved <strong>86.29 %</strong> inhibition of biofilm formation and <strong>72.30 %</strong> inhibition of fungal filamentation. Additionally, RT-PCR analysis demonstrated that treatment with compound <strong>5e</strong> significantly downregulated the expression of key biofilm genes, including ALS1, ALS3, and HWP1. Scanning electron microscopy (SEM) of <em>C. albicans</em> treated with <strong>5e</strong> confirmed substantial inhibition of biofilm formation compared to both untreated controls and the fluconazole-treated group. Screening of compound <strong>5e</strong> for blood compatibility by hemolytic assay revealed <strong>4.83 %</strong> cell lysis at <strong>1125</strong> μ<strong>g/mL</strong>, and cytotoxicity assay on human HEK293 cell line demonstrated that compound <strong>5e</strong> was non-toxic to normal cells at the tested concentrations. Furthermore, molecular docking studies to investigate the potential binding interactions of the lead compound, along with ADMET analysis, were performed to assess pharmacokinetic and bioavailability profiles. The enhanced bioactivity of compound <strong>5e</strong> is associated with the presence of an ortho-substituted hydroxy group, a 1,3,4-oxadiazole core, and a long hydrophobic alkyl chain, which collectively improve target binding, membrane interaction, and antifungal effectiveness. These findings suggest that compound <strong>5e</strong> is a promising candidate for the development of next-generation antifungal agents to combat drug-resistant <em>Candida albicans</em> infections.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118425"},"PeriodicalIF":3.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217875","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}
Kinetoplastids are parasites which cause various neglected tropical diseases. A hallmark feature of their genomic composition is the presence of polycistronic transcription, a phenomenon that involves the transcription of multiple genes into a single mRNA molecule, along with unconventional modes of gene regulation. In these organisms, histone variants and post-translational modifications play pivotal roles in modulating chromatin structure and transcriptional activity. This review provides a comprehensive overview of histone variants and post-translational modifications identified across Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei, detailing both the diversity of modifications and their known functional roles. This review also focuses on the writers, erasers, and readers proteins, including available three-dimensional structural data, to better understand their contribution to chromatin regulation, cell cycle progression, and parasite adaptation. Concurrently, this review offers a synopsis of therapeutic endeavors that have targeted these pathways, emphasizing the outcomes of in silico, in vitro and in vivo studies. This comprehensive review underscores the potential of unraveling kinetoplastid epigenetic mechanisms as a promising avenue for developing innovative treatments against these major human pathogens.
{"title":"The epigenetic landscape of kinetoplastid parasites: From histone post-translational modifications to emerging therapeutic strategies","authors":"Inès Jacquet , Romain Paoli-Lombardo , Patrice Vanelle , Nicolas Primas","doi":"10.1016/j.bmc.2025.118377","DOIUrl":"10.1016/j.bmc.2025.118377","url":null,"abstract":"<div><div>Kinetoplastids are parasites which cause various neglected tropical diseases. A hallmark feature of their genomic composition is the presence of polycistronic transcription, a phenomenon that involves the transcription of multiple genes into a single mRNA molecule, along with unconventional modes of gene regulation. In these organisms, histone variants and post-translational modifications play pivotal roles in modulating chromatin structure and transcriptional activity. This review provides a comprehensive overview of histone variants and post-translational modifications identified across <em>Leishmania</em> spp., <em>Trypanosoma cruzi</em>, and <em>Trypanosoma brucei</em>, detailing both the diversity of modifications and their known functional roles. This review also focuses on the writers, erasers, and readers proteins, including available three-dimensional structural data, to better understand their contribution to chromatin regulation, cell cycle progression, and parasite adaptation. Concurrently, this review offers a synopsis of therapeutic endeavors that have targeted these pathways, emphasizing the outcomes of <em>in silico</em>, <em>in vitro</em> and <em>in vivo</em> studies. This comprehensive review underscores the potential of unraveling kinetoplastid epigenetic mechanisms as a promising avenue for developing innovative treatments against these major human pathogens.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118377"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211076","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 : 2025-09-27DOI: 10.1016/j.bmc.2025.118423
Jiayuan Ye , Nan Chen , Yixiang Zhu , Yana Xu , Chenghao Pan , Yaojiang Xu
Aurora B, a subtype of Aurora kinases that functions as a serine/threonine kinase, playing a vital role in the process of mitosis, is often overexpressed in certain tumor cells leading to tumorigenesis and progression. Therefore, the development of small molecule inhibitors targeting Aurora B holds promise for providing new options for some cancer patients. In this study, we efficiently screened 4 compounds from MCE compound database using a combination of machine learning-based screening and structure-based screening. The results showed that 2 compounds exhibited strong Aurora B inhibitory activity in a homogeneous time-resolved fluorescence (HTRF) assay, indicating a high hit rate for this screening method. Among them, compound 4 demonstrated optimal inhibitory activity against Aurora B, with an IC50 value of 15.54 nM, comparable to Aurora B inhibitors that have entered clinical trials. In vitro experiments indicated that compound 4 effectively inhibited Huh-7 and Huh-6 cells, with IC50 values of 0.9 μM and 1.8 μM, respectively. Molecular dynamics simulation results revealed that the compound binds to the ATP binding pocket of Aurora B, forming hydrogen bond interactions with Glu171 and Glu220, salt bridges with Asp234 and Glu177, and a pi-cation interaction with Arg97. In summary, by integrating multi-modal screening approaches, we successfully identified a potent Aurora B inhibitor with in vitro antitumor activity, providing lead compounds for subsequent drug development.
{"title":"Identification of a novel Aurora B inhibitor using the AI-driven drug screening and docking-based traditional screening","authors":"Jiayuan Ye , Nan Chen , Yixiang Zhu , Yana Xu , Chenghao Pan , Yaojiang Xu","doi":"10.1016/j.bmc.2025.118423","DOIUrl":"10.1016/j.bmc.2025.118423","url":null,"abstract":"<div><div>Aurora B, a subtype of Aurora kinases that functions as a serine/threonine kinase, playing a vital role in the process of mitosis, is often overexpressed in certain tumor cells leading to tumorigenesis and progression. Therefore, the development of small molecule inhibitors targeting Aurora B holds promise for providing new options for some cancer patients. In this study, we efficiently screened 4 compounds from MCE compound database using a combination of machine learning-based screening and structure-based screening. The results showed that 2 compounds exhibited strong Aurora B inhibitory activity in a homogeneous time-resolved fluorescence (HTRF) assay, indicating a high hit rate for this screening method. Among them, compound <strong>4</strong> demonstrated optimal inhibitory activity against Aurora B, with an IC<sub>50</sub> value of 15.54 nM, comparable to Aurora B inhibitors that have entered clinical trials. <em>In vitro</em> experiments indicated that compound <strong>4</strong> effectively inhibited Huh-7 and Huh-6 cells, with IC<sub>50</sub> values of 0.9 μM and 1.8 μM, respectively. Molecular dynamics simulation results revealed that the compound binds to the ATP binding pocket of Aurora B, forming hydrogen bond interactions with Glu171 and Glu220, salt bridges with Asp234 and Glu177, and a pi-cation interaction with Arg97. In summary, by integrating multi-modal screening approaches, we successfully identified a potent Aurora B inhibitor with <em>in vitro</em> antitumor activity, providing lead compounds for subsequent drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118423"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205043","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 : 2025-09-27DOI: 10.1016/j.bmc.2025.118422
Anjali Saxena , Noimul Hasan Siddiquee , Mohammad Hasan Shahariar , Subhrajit Biswas , Andrew M.Lynn , Biswajit Saha
Quinoline and chromene scaffold are recognized to possess anticancer activities but their synergistic potential has never been studied extensively. Our present work investigated a selectively designed series of quinoline-chromene hybrids using an integrative approach combining computational and experimental evaluations. Molecular docking experiments performed on topoisomerase I (3QX3) and II (4FM9) showed high binding affinities with lead molecules 6c, 6l, and 6j having greater efficacy in comparison to standard agents camptothecin and amsacrine. Moreover, molecular dynamics simulations confirmed the stability of the complexes of the ligand and the protein with low RMSD values and positive MM-GBSA binding free energies. ADMET profiling predicted high oral bioavailability, metabolic stability, and tolerable levels of toxicity with encouraging drug-like behavior. Seven of these hybrids were experimentally assessed for cytotoxicity in several cancer cell lines (HepG2, Hep3B, HCT-116, and MCF-7) and showed selective behavior in relation to normal cells (HEK-293 cells). Notably, the compounds 6c and 6l showed sub-micromolar IC₅₀ values and strong dual topoisomerase I/II inhibition and verified their mode of action. Structure-activity relationship (SAR) analysis showed that substituents with an electron-donating effect increased π–π stacking and hydrogen bonding and associated well with enhanced potency and selectivity. Collectively, these results position quinoline–chromene hybrids as important leads in anticancer treatment and emphasize the advantages of scaffold hybridization in attaining efficient, selective, and mechanistically established inhibition of the topoisomerase.
{"title":"Synthesis, in-silico and in-vitro evaluation of quinoline-chromene hybrids as dual topoisomerase inhibitors","authors":"Anjali Saxena , Noimul Hasan Siddiquee , Mohammad Hasan Shahariar , Subhrajit Biswas , Andrew M.Lynn , Biswajit Saha","doi":"10.1016/j.bmc.2025.118422","DOIUrl":"10.1016/j.bmc.2025.118422","url":null,"abstract":"<div><div>Quinoline and chromene scaffold are recognized to possess anticancer activities but their synergistic potential has never been studied extensively. Our present work investigated a selectively designed series of quinoline-chromene hybrids using an integrative approach combining computational and experimental evaluations. Molecular docking experiments performed on topoisomerase I (3QX3) and II (4FM9) showed high binding affinities with lead molecules 6c, 6l, and 6j having greater efficacy in comparison to standard agents camptothecin and amsacrine. Moreover, molecular dynamics simulations confirmed the stability of the complexes of the ligand and the protein with low RMSD values and positive MM-GBSA binding free energies. ADMET profiling predicted high oral bioavailability, metabolic stability, and tolerable levels of toxicity with encouraging drug-like behavior. Seven of these hybrids were experimentally assessed for cytotoxicity in several cancer cell lines (HepG2, Hep3B, HCT-116, and MCF-7) and showed selective behavior in relation to normal cells (HEK-293 cells). Notably, the compounds 6c and 6l showed sub-micromolar IC₅₀ values and strong dual topoisomerase I/II inhibition and verified their mode of action. Structure-activity relationship (SAR) analysis showed that substituents with an electron-donating effect increased π–π stacking and hydrogen bonding and associated well with enhanced potency and selectivity. Collectively, these results position quinoline–chromene hybrids as important leads in anticancer treatment and emphasize the advantages of scaffold hybridization in attaining efficient, selective, and mechanistically established inhibition of the topoisomerase.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118422"},"PeriodicalIF":3.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205093","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 : 2025-09-26DOI: 10.1016/j.bmc.2025.118414
Wenpei Zhang , Huagong Zeng , Meng Xu , Ziqing Zhang , Xinyue Pan , Jiaqi Li , Tianzi Xu , Jie He , Qiuyuan Duan , Shujun Huang , Yirong Lin , Fengyang Zhang , Yeran Li , Jieqing Liu
This study developed a novel light-switchable proteolysis-targeting chimera (PROTAC) by integrating azobenzene-modified combretastatin A4 (Azo-CA4) as a photocontrollable tubulin ligand. In contrast to conventional light-regulated PROTACs that modulate linker conformation, our strategy embeds the photoswitch directly within the target protein ligand (Azo-CA4). Under 365 nm UV light, Azo-CA4 isomerizes to its cis-configuration, enabling high-affinity tubulin binding and subsequent ubiquitin-proteasome-dependent degradation. The lead compound AC2 exhibited pronounced light-dependent antitumor activity against triple-negative breast cancer (MDA-MB-231 cells), with a 15-fold enhancement in potency (IC₅₀ = 4.05 ± 0.13 μM under UV vs. 63.64 μM in the dark). Furthermore, AC2 exhibited minimal toxicity in normal breast epithelial cells (MCF-10A) under both light and dark conditions (IC₅₀ > 100 μM), highlighting its favorable selectivity. Mechanistic analyses established reversible β-tubulin degradation, ubiquitin-proteasome system (UPS) dependency (inhibited by MG132), and robust ternary complex formation (binding energy: −5.96 kcal/mol). ADMET profiling indicated moderate membrane permeability (Log Po/w = 3.19) but this permeability limited oral bioavailability, attributable to its high-molecular-weight (645 Da) and poor solubility. This ligand-embedded approach enhances spatiotemporal precision while mitigating off-target toxicity, establishing a novel therapeutic paradigm for targeted cancer therapy.
{"title":"Ligand-embedded photoswitching PROTAC for spatiotemporal tubulin degradation","authors":"Wenpei Zhang , Huagong Zeng , Meng Xu , Ziqing Zhang , Xinyue Pan , Jiaqi Li , Tianzi Xu , Jie He , Qiuyuan Duan , Shujun Huang , Yirong Lin , Fengyang Zhang , Yeran Li , Jieqing Liu","doi":"10.1016/j.bmc.2025.118414","DOIUrl":"10.1016/j.bmc.2025.118414","url":null,"abstract":"<div><div>This study developed a novel light-switchable proteolysis-targeting chimera (PROTAC) by integrating azobenzene-modified combretastatin A4 (Azo-CA4) as a photocontrollable tubulin ligand. In contrast to conventional light-regulated PROTACs that modulate linker conformation, our strategy embeds the photoswitch directly within the target protein ligand (Azo-CA4). Under 365 nm UV light, Azo-CA4 isomerizes to its cis-configuration, enabling high-affinity tubulin binding and subsequent ubiquitin-proteasome-dependent degradation. The lead compound AC2 exhibited pronounced light-dependent antitumor activity against triple-negative breast cancer (MDA-MB-231 cells), with a 15-fold enhancement in potency (IC₅₀ = 4.05 ± 0.13 μM under UV vs. 63.64 μM in the dark). Furthermore, AC2 exhibited minimal toxicity in normal breast epithelial cells (MCF-10A) under both light and dark conditions (IC₅₀ > 100 μM), highlighting its favorable selectivity. Mechanistic analyses established reversible β-tubulin degradation, ubiquitin-proteasome system (UPS) dependency (inhibited by MG132), and robust ternary complex formation (binding energy: −5.96 kcal/mol). ADMET profiling indicated moderate membrane permeability (Log <em>P</em><sub>o/w</sub> = 3.19) but this permeability limited oral bioavailability, attributable to its high-molecular-weight (645 Da) and poor solubility. This ligand-embedded approach enhances spatiotemporal precision while mitigating off-target toxicity, establishing a novel therapeutic paradigm for targeted cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118414"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205107","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 : 2025-09-26DOI: 10.1016/j.bmc.2025.118419
Catarina A. Montargil , Mariana Pinto , Rosa Resende , Elisabete P. Carreiro , Alfonso T. García-Sosa , Armanda E. Santos , Anthony J. Burke
Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60–70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules – some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules 12a underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (3a, 3b, 3i and 12a) have shown moderate BuChE inhibitory activity.
{"title":"Exploring the potential of new acetylated unsaturated Oxindole derivatives as multi-target inhibitors for BACE1 and BuChE","authors":"Catarina A. Montargil , Mariana Pinto , Rosa Resende , Elisabete P. Carreiro , Alfonso T. García-Sosa , Armanda E. Santos , Anthony J. Burke","doi":"10.1016/j.bmc.2025.118419","DOIUrl":"10.1016/j.bmc.2025.118419","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60–70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules – some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules <strong>12a</strong> underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (<strong>3a</strong>, <strong>3b</strong>, <strong>3i</strong> and <strong>12a</strong>) have shown moderate BuChE inhibitory activity.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118419"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218317","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 : 2025-09-26DOI: 10.1016/j.bmc.2025.118424
Sandip Patra , Hari K. Namballa , Ashok R. Gudipally , Li Xie , Lei Xie , Wayne W. Harding
We undertook the rational design and synthesis of a novel series of ligands intended to function as selective dual dopamine D1 receptor (D1R) partial agonists and D3 receptor (D3R) antagonists. The molecular architecture of these compounds was derived by integrating key pharmacophoric features from established D1R partial agonists and D3R antagonists. Specifically, the 6-(2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione scaffold was employed as the core “tail” region associated with D1R partial agonism, while various substituted phenyl piperazine moieties were introduced as “head” groups to confer D3R antagonistic activity. A pyridine ring was utilized as a central linker across the series.
Contrary to the intended dopaminergic profile, these compounds exhibited markedly higher binding affinities for α2-adrenergic receptors (α2-ARs) relative to their activity at dopamine receptor subtypes. Several analogues demonstrated potent α2C-AR binding affinities in the low nanomolar range (Ki = 7–30 nM), with moderate selectivity (up to 17-fold) over other α2-AR subtypes. Notably, compounds bearing ortho-substituted aryl groups within the “head” domain generally displayed enhanced α2C-AR binding compared to their para-substituted counterparts.
Molecular docking studies conducted at both α2A-AR and α2C-AR suggested that multiple receptor-ligand interactions contribute to the observed binding profiles. In particular, an anion–pi interaction between Asp131 of α2C-AR and the phenyl ring of the phenyl piperazine “head” moiety was identified as a possible determinant of the increased α2C-AR affinity observed in ortho-substituted analogues.
Given the therapeutic potential of selective α2C-AR targeting in treating various disorders, coupled with the limited availability of clinically approved selective α2C-AR ligands, the discovery of this new scaffold offers new prospects for drug discovery targeting α2C-ARs.
{"title":"Discovery of a selective α2C-AR scaffold from a molecular hybridization approach","authors":"Sandip Patra , Hari K. Namballa , Ashok R. Gudipally , Li Xie , Lei Xie , Wayne W. Harding","doi":"10.1016/j.bmc.2025.118424","DOIUrl":"10.1016/j.bmc.2025.118424","url":null,"abstract":"<div><div>We undertook the rational design and synthesis of a novel series of ligands intended to function as selective dual dopamine D1 receptor (D1R) partial agonists and D3 receptor (D3R) antagonists. The molecular architecture of these compounds was derived by integrating key pharmacophoric features from established D1R partial agonists and D3R antagonists. Specifically, the 6-(2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione scaffold was employed as the core “tail” region associated with D1R partial agonism, while various substituted phenyl piperazine moieties were introduced as “head” groups to confer D3R antagonistic activity. A pyridine ring was utilized as a central linker across the series.</div><div>Contrary to the intended dopaminergic profile, these compounds exhibited markedly higher binding affinities for α2-adrenergic receptors (α2-ARs) relative to their activity at dopamine receptor subtypes. Several analogues demonstrated potent α2C-AR binding affinities in the low nanomolar range (K<sub>i</sub> = 7–30 nM), with moderate selectivity (up to 17-fold) over other α2-AR subtypes. Notably, compounds bearing <em>ortho</em>-substituted aryl groups within the “head” domain generally displayed enhanced α2C-AR binding compared to their <em>para</em>-substituted counterparts.</div><div>Molecular docking studies conducted at both α2A-AR and α2C-AR suggested that multiple receptor-ligand interactions contribute to the observed binding profiles. In particular, an anion–pi interaction between Asp131 of α2C-AR and the phenyl ring of the phenyl piperazine “head” moiety was identified as a possible determinant of the increased α2C-AR affinity observed in <em>ortho</em>-substituted analogues.</div><div>Given the therapeutic potential of selective α2C-AR targeting in treating various disorders, coupled with the limited availability of clinically approved selective α2C-AR ligands, the discovery of this new scaffold offers new prospects for drug discovery targeting α2C-ARs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118424"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217900","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}
Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids (5a–5m) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative 5d emerging as the top hit (KI = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB 4JIR), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. In silico ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting in vivo evaluation and SAR-guided optimization.
{"title":"Phthalimide–benzoic acid hybrids as potent aldose reductase inhibitors: Synthesis, enzymatic kinetics, and in silico characterization","authors":"Dafina Hoti , Arleta Rifati Nixha , Hatice Esra Duran , Mustafa Arslan , Gizem Yıldıztekin , Abdulilah Ece , Cüneyt Türkeş","doi":"10.1016/j.bmc.2025.118416","DOIUrl":"10.1016/j.bmc.2025.118416","url":null,"abstract":"<div><div>Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids (<strong>5a</strong>–<strong>5m</strong>) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative <strong>5d</strong> emerging as the top hit (<em>K</em><sub>I</sub> = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB <span><span>4JIR</span><svg><path></path></svg></span>), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. <em>In silico</em> ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting <em>in vivo</em> evaluation and SAR-guided optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118416"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197714","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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