Pub Date : 2025-12-24DOI: 10.1016/j.bmcl.2025.130523
Renan Augusto Gomes , Leonardo Luiz Gomes Ferreira , Witor Ribeiro Ferraz , Rodrigo Alves Heleno , Fernando Moura Gatti , Mariana Laureano de Souza , Cleydson Breno Rodrigues dos Santos , Adriano Defini Andricopulo , Gustavo Henrique Goulart Trossini
Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was synthesized and tested against Leishmania donovani and Trypanosoma cruzi. Four compounds showed promising antileishmanial activity (from 1.27 to 19.53 μM), with two analogues displaying superior potency compared to some current first-line treatments, such as sodium stibogluconate and paromomycin. Computational analyses revealed that activity is driven by specific electronic properties rather than steric factors, while a methyl group consistently reduced potency. The compounds demonstrated favorable predicted ADME properties and were not flagged as aggregators. This research identifies cinnamoyl aryl hydrazones as a promising scaffold for leishmanicidal drug discovery, providing a rational basis for future optimization efforts.
{"title":"Cinnamoyl aryl hydrazones as potent leishmanicidal agents: design, synthesis, and structure–activity relationships","authors":"Renan Augusto Gomes , Leonardo Luiz Gomes Ferreira , Witor Ribeiro Ferraz , Rodrigo Alves Heleno , Fernando Moura Gatti , Mariana Laureano de Souza , Cleydson Breno Rodrigues dos Santos , Adriano Defini Andricopulo , Gustavo Henrique Goulart Trossini","doi":"10.1016/j.bmcl.2025.130523","DOIUrl":"10.1016/j.bmcl.2025.130523","url":null,"abstract":"<div><div>Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was synthesized and tested against <em>Leishmania donovani</em> and <em>Trypanosoma cruzi</em>. Four compounds showed promising antileishmanial activity (from 1.27 to 19.53 μM), with two analogues displaying superior potency compared to some current first-line treatments, such as sodium stibogluconate and paromomycin. Computational analyses revealed that activity is driven by specific electronic properties rather than steric factors, while a methyl group consistently reduced potency. The compounds demonstrated favorable predicted ADME properties and were not flagged as aggregators. This research identifies cinnamoyl aryl hydrazones as a promising scaffold for leishmanicidal drug discovery, providing a rational basis for future optimization efforts.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130523"},"PeriodicalIF":2.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives with pyridine congeners at C-1 position. Notably, 13c and 14c exhibited the GI50 of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that 14c shares a similar binding mode with abiraterone at the CYP17A1 active site.
{"title":"Design and synthesis of Tetrahydroindeno[4,5-c]chromen-4(3H)-one derivatives as antiproliferative agents for prostate Cancer cells","authors":"Hui-Yu Chan , Pin-Shuo Huang , Pei-Fang Chiu , Tzung-Sheng Lin , Li-Jou Huang , Pi-Hui Liang , Jih-Hwa Guh , Mei-Hsiang Lin","doi":"10.1016/j.bmcl.2025.130515","DOIUrl":"10.1016/j.bmcl.2025.130515","url":null,"abstract":"<div><div>Abiraterone, a CYP17A1 inhibitor, is approved by the FDA for castration-resistance prostate cancer. To mimic the structure of abiraterone, we designed and synthesized nine tetrahydroindeno[4,5-<em>c</em>]chromen-4(3<em>H</em>)-one derivatives with pyridine congeners at C-1 position. Notably, <strong>13c</strong> and <strong>14c</strong> exhibited the GI<sub>50</sub> of 10 nM against PC-3 cells compared to 21.4 μM for abiraterone. The docking studies further revealed that <strong>14c</strong> shares a similar binding mode with abiraterone at the CYP17A1 active site.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130515"},"PeriodicalIF":2.2,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.bmcl.2025.130513
Yanlin He , Yuwan Zhang , Wei Wang , Chaoyong Cui , Qianyun Hao , Hongguan Xie , Rui Yang
The endophytic fungus Alternaria sp. S4, derived from Ruta graveolens, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation, alternariol (1) and alternariol-5-O-methyl ether (2) were isolated from the ethyl acetate fraction of Alternaria sp. S4 and characterized spectroscopically. Compound 1 exhibited potent bactericidal activity against Staphylococcus aureus (MIC = 4 μg/mL, MBC = 16 μg/mL), whereas compound 2 was inactive. Time-growth assays confirmed concentration-dependent bacterial eradication, with 2× MIC of compound 1 achieving complete growth inhibition. Mechanistic investigations revealed that compound 1 targets the bacterial membrane, inducing depolarization, compromising permeability (evidenced by ion leakage and release of intracellular constituents), and causing ultrastructural damage visualized via SEM. Furthermore, compound 1 prevented biofilm formation via bacterial eradication and disrupted preformed biofilms. Checkerboard assays indicated additive effects when combined with conventional antibiotics. Notably, compound 1 displayed no hemolytic activity even at 1024 μg/mL, highlighting its membrane selectivity. This work identifies alternariol as a promising membrane-targeting bactericidal agent from an endophytic source, capable of preventing biofilm establishment, with potential for combinatorial therapy against S. aureus.
从芦笋中提取的内生真菌Alternaria sp. S4显示出显著的抗菌潜力，但其有效成分和作用方式尚不清楚。采用生物测定引导分离的方法，从Alternaria sp. S4的乙酸乙酯部位分离得到交替蒿醇(1)和交替蒿醇-5- o -甲基醚(2)，并对其进行了光谱表征。化合物1对金黄色葡萄球菌具有较强的杀菌活性（MIC = 4 μg/mL, MBC = 16 μg/mL），而化合物2对金黄色葡萄球菌无活性。时间生长试验证实了浓度依赖的细菌根除，化合物1的2倍MIC达到完全生长抑制。机制研究表明，化合物1靶向细菌膜，诱导去极化，损害渗透性（通过离子泄漏和细胞内成分释放证明），并通过扫描电镜观察造成超微结构损伤。此外，化合物1通过细菌根除阻止生物膜的形成，并破坏预先形成的生物膜。棋盘试验表明，当与常规抗生素联合使用时，会产生叠加效应。值得注意的是，化合物1即使在1024 μg/mL浓度下也没有溶血活性，表明其具有膜选择性。这项工作确定了交替蒿醇是一种有前途的内生膜靶向杀菌剂，能够阻止生物膜的形成，具有联合治疗金黄色葡萄球菌的潜力。
{"title":"Alternariol from the endophytic fungus Alternaria sp. S4 acts as a membrane-targeting bactericidal agent against Staphylococcus aureus","authors":"Yanlin He , Yuwan Zhang , Wei Wang , Chaoyong Cui , Qianyun Hao , Hongguan Xie , Rui Yang","doi":"10.1016/j.bmcl.2025.130513","DOIUrl":"10.1016/j.bmcl.2025.130513","url":null,"abstract":"<div><div>The endophytic fungus <em>Alternaria</em> sp. S4, derived from <em>Ruta graveolens</em>, shows significant antimicrobial potential, but its active components and mode of action require clarification. Through bioassay-guided fractionation, alternariol (<strong>1</strong>) and alternariol-5-<em>O</em>-methyl ether (<strong>2</strong>) were isolated from the ethyl acetate fraction of <em>Alternaria</em> sp. S4 and characterized spectroscopically. Compound <strong>1</strong> exhibited potent bactericidal activity against <em>Staphylococcus aureus</em> (MIC = 4 μg/mL, MBC = 16 μg/mL), whereas compound <strong>2</strong> was inactive. Time-growth assays confirmed concentration-dependent bacterial eradication, with 2× MIC of compound <strong>1</strong> achieving complete growth inhibition. Mechanistic investigations revealed that compound <strong>1</strong> targets the bacterial membrane, inducing depolarization, compromising permeability (evidenced by ion leakage and release of intracellular constituents), and causing ultrastructural damage visualized via SEM. Furthermore, compound <strong>1</strong> prevented biofilm formation via bacterial eradication and disrupted preformed biofilms. Checkerboard assays indicated additive effects when combined with conventional antibiotics. Notably, compound <strong>1</strong> displayed no hemolytic activity even at 1024 μg/mL, highlighting its membrane selectivity. This work identifies alternariol as a promising membrane-targeting bactericidal agent from an endophytic source, capable of preventing biofilm establishment, with potential for combinatorial therapy against <em>S. aureus</em>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130513"},"PeriodicalIF":2.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.bmcl.2025.130514
Jing Du , Wei Wang , Yanni Ma , Chaoyong Cui , Yuwan Zhang , Jian Yang , Rui Yang
This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (1–21 and their demethylated analogs 1′–16′). These compounds were synthesized via cyclization in POCl3, amine substitution, and BBr3-mediated demethylation, with structures confirmed by NMR and HRMS. Antifungal evaluation showed that while most compounds were weakly active (MICs ≥128 μg/mL), several—particularly those with 6-position hydroxy or methoxy substituents (14, 16, and 14′–16′)—displayed notable activity (MICs = 4–32 μg/mL) against Candida albicans, Candida tropicalis, and Cryptococcus neoformans. Compound 14′ exhibited potent fungicidal action against C. albicans (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (>90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to fungal cells. Importantly, 14′ showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight 14′ as a promising lead compound with membrane-targeting antifungal mechanisms and an improved safety profile relative to amphotericin B.
{"title":"Design, synthesis, and biological evaluation of novel 4-aminoquinoline derivatives as potent membrane-targeting antifungal agents","authors":"Jing Du , Wei Wang , Yanni Ma , Chaoyong Cui , Yuwan Zhang , Jian Yang , Rui Yang","doi":"10.1016/j.bmcl.2025.130514","DOIUrl":"10.1016/j.bmcl.2025.130514","url":null,"abstract":"<div><div>This study aimed to develop novel antifungal agents through the design and synthesis of two series of 4-aminoquinoline derivatives (<strong>1</strong>–<strong>21</strong> and their demethylated analogs <strong>1′</strong>–<strong>16′</strong>). These compounds were synthesized via cyclization in POCl<sub>3</sub>, amine substitution, and BBr<sub>3</sub>-mediated demethylation, with structures confirmed by NMR and HRMS. Antifungal evaluation showed that while most compounds were weakly active (MICs ≥128 μg/mL), several—particularly those with 6-position hydroxy or methoxy substituents (<strong>14</strong>, <strong>16</strong>, and <strong>14′</strong>–<strong>16′</strong>)—displayed notable activity (MICs = 4–32 μg/mL) against <em>Candida albicans</em>, <em>Candida tropicalis</em>, and <em>Cryptococcus neoformans</em>. Compound <strong>14′</strong> exhibited potent fungicidal action against <em>C. albicans</em> (MIC = MFC = 4 μg/mL), rapid time-kill kinetics, membrane disruption evidenced by PI/DAPI staining, and strong biofilm inhibition (>90 % at ≥16 μg/mL). SEM imaging revealed extensive ultrastructural damage to fungal cells. Importantly, <strong>14′</strong> showed low cytotoxicity toward human epithelial cells and favorable in silico predicted ADMET profiles. These findings highlight <strong>14′</strong> as a promising lead compound with membrane-targeting antifungal mechanisms and an improved safety profile relative to amphotericin B.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130514"},"PeriodicalIF":2.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-21DOI: 10.1016/j.bmcl.2025.130512
Sungwoo Cho , Renjie Zhu , Katarzyna Kuncewicz , Hongliang Duan , Moustafa Gabr
Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1500 peptide–target complexes, prioritizing four candidates that met structural and energetic criteria. Subsequent biophysical evaluation identified TP4 as a weak but reproducible TREM2 binder, demonstrating consistent binding in spectral shift, microscale thermophoresis, and surface plasmon resonance. Pharmacokinetic profiling indicated that TP4 possesses favorable plasma stability and moderate metabolic stability, supporting its potential for further optimization. This study establishes a generalizable framework for AI-driven cyclic peptide discovery and provides the first proof-of-concept demonstration of TREM2-targeted cyclic peptide binders.
{"title":"AI-guided design of cyclic peptide binders targeting TREM2 using CycleRFdiffusion and experimental validation","authors":"Sungwoo Cho , Renjie Zhu , Katarzyna Kuncewicz , Hongliang Duan , Moustafa Gabr","doi":"10.1016/j.bmcl.2025.130512","DOIUrl":"10.1016/j.bmcl.2025.130512","url":null,"abstract":"<div><div>Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimer's disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1500 peptide–target complexes, prioritizing four candidates that met structural and energetic criteria. Subsequent biophysical evaluation identified <strong>TP4</strong> as a weak but reproducible TREM2 binder, demonstrating consistent binding in spectral shift, microscale thermophoresis, and surface plasmon resonance. Pharmacokinetic profiling indicated that <strong>TP4</strong> possesses favorable plasma stability and moderate metabolic stability, supporting its potential for further optimization. This study establishes a generalizable framework for AI-driven cyclic peptide discovery and provides the first proof-of-concept demonstration of TREM2-targeted cyclic peptide binders.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130512"},"PeriodicalIF":2.2,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound 8a, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, 8a markedly reduced lactate dehydrogenase (LDH) release (IC₅₀ = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16–C17 double bond afforded compound 8b, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between 8a and NLRP3. We also conducted structure–activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify 8a as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure–activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.
作为一个关键的细胞内模式识别受体，NLRP3感知多种病原体和损伤相关的分子模式（PAMPs和DAMPs），启动炎症小体组装和焦亡细胞死亡。异常的NLRP3激活有助于多种慢性炎症性疾病，包括动脉粥样硬化、阿尔茨海默病和类风湿性关节炎，强调其治疗相关性。在本研究中，我们设计并合成了一种结构优化的二萜类生物碱松果碱衍生物8a。在脂多糖（LPS）和尼日利亚菌素刺激的巨噬细胞模型中，8a显着降低了乳酸脱氢酶（LDH）的释放（在THP-1细胞中IC₅0 = 2.69 μM，在J774A.1细胞中IC₅0 = 1.75 μM），并有效抑制了gasdermin D （GSDMD）的裂解和白细胞介素-1β (IL-1β)的分泌，显示出对焦亡的有效抑制。C16-C17双键加氢后，化合物8b失去了抑制活性，这表明α，β-不饱和羰基部分对功能至关重要，可能是通过NLRP3上半胱氨酸残基的共价修饰。药物亲和力反应靶稳定性（dart）和质谱分析进一步证实了这一机制，证实了8a与NLRP3之间的直接结合。我们还通过修改C1位置进行了构效关系研究，发现这种修改对化合物的活性没有明显影响。综上所述，这些发现确定了8a是一种新型的songorin衍生的共价NLRP3抑制剂，并首次阐明了其构效关系和分子机制，为合理设计安全有效的靶向NLRP3的抗炎药提供了有价值的见解。
{"title":"Identification of a novel Songorine derivative as a potent NLRP3 inflammasome inhibitor","authors":"Runqin Liu , Qiang Zhang , Miao Xian , Qifeng Chen","doi":"10.1016/j.bmcl.2025.130511","DOIUrl":"10.1016/j.bmcl.2025.130511","url":null,"abstract":"<div><div>As a key intracellular pattern-recognition receptor, NLRP3 senses diverse pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), initiating inflammasome assembly and pyroptotic cell death. Aberrant NLRP3 activation contributes to various chronic inflammatory diseases, including atherosclerosis, Alzheimer's disease, and rheumatoid arthritis, underscoring its therapeutic relevance. In this study, we designed and synthesized compound <strong>8a</strong>, a structurally optimized derivative of the diterpenoid alkaloid songorine. In lipopolysaccharide (LPS)- and nigericin-stimulated macrophage models, <strong>8a</strong> markedly reduced lactate dehydrogenase (LDH) release (IC₅₀ = 2.69 μM in THP-1 cells and 1.75 μM in J774A.1 cells) and effectively inhibited gasdermin D (GSDMD) cleavage and interleukin-1β (IL-1β) secretion, demonstrating potent suppression of pyroptosis. Hydrogenation of the C16–C17 double bond afforded compound <strong>8b</strong>, which lost inhibitory activity, indicating that the α,β-unsaturated carbonyl moiety is essential for function, likely via covalent modification of cysteine residues on NLRP3. This mechanism was further substantiated by Drug Affinity Responsive Target Stability (DARTS) assays and mass spectrometry, confirming direct binding between <strong>8a</strong> and NLRP3. We also conducted structure–activity relationship studies by modifying the C1 position and found that such modifications did not significantly impact the compound's activity. Collectively, these findings identify <strong>8a</strong> as a novel songorine-derived covalent NLRP3 inhibitor and provide the first elucidation of its structure–activity relationship and molecular mechanism, offering valuable insights for the rational design of safe and effective anti-inflammatory agents targeting NLRP3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130511"},"PeriodicalIF":2.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.bmcl.2025.130510
Wenwen Nie , Baoli Ding , Xiaotong Chen , Li Jiang , Qiaojun He , Ji Cao , Cheng-Liang Zhu
Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.
{"title":"Multifaceted roles of HDAC7 in disease and the evolving chemical toolkit for its modulation","authors":"Wenwen Nie , Baoli Ding , Xiaotong Chen , Li Jiang , Qiaojun He , Ji Cao , Cheng-Liang Zhu","doi":"10.1016/j.bmcl.2025.130510","DOIUrl":"10.1016/j.bmcl.2025.130510","url":null,"abstract":"<div><div>Histone deacetylase 7 (HDAC7) is a key member of the class IIa HDAC subfamily (HDAC4, 5, 7, and 9) that is characterized by a key tyrosine-to-histidine substitution in its active site, a feature that renders these HDACs catalytically inefficient and underscores their versatile roles beyond intrinsic deacetylation. Structurally, HDAC7 is distinguished from its paralogs by its lack of the conserved N-terminal glutamine-rich domain. This combination of functional duality and a unique structural context enables HDAC7 to regulate a vast array of cellular processes. Consequently, its dysregulation is implicated in numerous pathologies, including cancer and autoimmune disorders, establishing it as a compelling therapeutic target. However, effectively and selectively targeting HDAC7 is complicated by its context-dependent biological modes of actions and the high structural homology it shares with other class IIa isoforms. This review first provides a current overview of the multifaceted roles of HDAC7 in human diseases and discusses how its contributions are dictated by the complex interplay between its catalytic and diverse scaffolding functions. We then summarize the recent medicinal chemistry efforts, from the class-selective deacetylase inhibitors to the recently emerged targeted protein degraders that not only achieve superior isoform selectivity but also modulate HDAC7's deacetylase-independent functions. By bridging the functional complexity of HDAC7 with the latest advances in chemical biology tools, we aim to provide a timely summary of the current status of HDAC7 as a druggable target and offer a perspective on strategies guiding the development of next-generation modulators.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130510"},"PeriodicalIF":2.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145797624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.bmcl.2025.130509
Le Thi Thao , Hwa Kyung Kim , Nguyen Phuong Ngan , Bui Quang Cuong , Dao Thi Kim Oanh , Do Thi Mai Dung , Da Hyeon Kang , Ha Young Kim , Eun Hye Song , Jong Soon Kang , Duong Tien Anh , Truong Thanh Tung , Sang-Bae Han , Nguyen-Hai Nam
Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (4a-e, 7a-i, and 10a-e) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The 4a-e series emerged as the most potent HDAC inhibitors, with IC50 values of 0.33–0.87 μM, led by 4a (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that 4b (6-CH3) and 4c (7-CH3) were the most effective, achieving IC50 values of 0.93–1.34 μM in HCT116 and 1.79–2.08 μM in SW620. In the 7a-i series, compounds 7b (6-CH3), 7d (6-Cl), and particularly 7f (7-F) demonstrated notable cytotoxicity with IC50 values of 1.14–3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (7g, 7i) or the unsubstituted analog 7a led to markedly reduced activity (> 4.5 μM). The 10a-e series was significantly less active, and 10e (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC50 = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that 4c and 7f induced G2/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight 4a-c and 7f as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.
{"title":"Novel 2-mercaptoquinazolinone N-hydroxycinnamamides as histone deacetylase inhibitors: design, synthesis, and anticancer evaluation","authors":"Le Thi Thao , Hwa Kyung Kim , Nguyen Phuong Ngan , Bui Quang Cuong , Dao Thi Kim Oanh , Do Thi Mai Dung , Da Hyeon Kang , Ha Young Kim , Eun Hye Song , Jong Soon Kang , Duong Tien Anh , Truong Thanh Tung , Sang-Bae Han , Nguyen-Hai Nam","doi":"10.1016/j.bmcl.2025.130509","DOIUrl":"10.1016/j.bmcl.2025.130509","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (<strong>4a-e</strong>, <strong>7a-i</strong>, and <strong>10a-e</strong>) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The <strong>4a-e</strong> series emerged as the most potent HDAC inhibitors, with IC<sub>50</sub> values of 0.33–0.87 μM, led by <strong>4a</strong> (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that <strong>4b</strong> (6-CH<sub>3</sub>) and <strong>4c</strong> (7-CH<sub>3</sub>) were the most effective, achieving IC<sub>50</sub> values of 0.93–1.34 μM in HCT116 and 1.79–2.08 μM in SW620. In the <strong>7a-i</strong> series, compounds <strong>7b</strong> (6-CH<sub>3</sub>), <strong>7d</strong> (6-Cl), and particularly <strong>7f</strong> (7-F) demonstrated notable cytotoxicity with IC<sub>50</sub> values of 1.14–3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (<strong>7g</strong>, <strong>7i</strong>) or the unsubstituted analog <strong>7a</strong> led to markedly reduced activity (> 4.5 μM). The <strong>10a-e</strong> series was significantly less active, and <strong>10e</strong> (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC<sub>50</sub> = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that <strong>4c</strong> and <strong>7f</strong> induced G<sub>2</sub>/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight <strong>4a-c</strong> and <strong>7f</strong> as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130509"},"PeriodicalIF":2.2,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.bmcl.2025.130508
Ying Liu , Jing Wu , Ni Gao , Lin Zheng , Wenbo Zhang , Fabao Zhao , Bairu Meng , Xinyong Liu , Lanyu Liu , Huajun Zhao , Dongwei Kang
STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mimetics. Although compounds such as C53 and NVS-STG2 have been reported as TMD-targeting agonists, their therapeutic potential is restricted by insufficient potency. In this work, compound LA24 was identified as a novel potent STING allosteric agonist through structure-based multilevel virtual screening combined with rational optimization. It exhibited an EC₅₀ value of 0.82 μM, being superior to that of the reference C53 (EC50 = 2.80 μM). Molecular modeling studies revealed that LA24 exhibited enhanced STING agonistic activity by forming hydrogen bonds with key transmembrane domain residues G114 and Y106, as well as π–π stacking interactions with H50. These findings suggested that LA24 holds promise as a novel lead compound for the development of STING-targeted immunomodulatory therapies.
{"title":"Discovery and optimization of 2,3-Dihydroindole derivatives as STING receptor allosteric agonists","authors":"Ying Liu , Jing Wu , Ni Gao , Lin Zheng , Wenbo Zhang , Fabao Zhao , Bairu Meng , Xinyong Liu , Lanyu Liu , Huajun Zhao , Dongwei Kang","doi":"10.1016/j.bmcl.2025.130508","DOIUrl":"10.1016/j.bmcl.2025.130508","url":null,"abstract":"<div><div>STING allosteric agonists targeting the cryptic pocket in the transmembrane domain (TMD) could overcome the limitations of membrane permeability and oligomerization instability that are inherent to conventional cGAMP mimetics. Although compounds such as C53 and NVS-STG2 have been reported as TMD-targeting agonists, their therapeutic potential is restricted by insufficient potency. In this work, compound <strong>LA24</strong> was identified as a novel potent STING allosteric agonist through structure-based multilevel virtual screening combined with rational optimization. It exhibited an EC₅₀ value of 0.82 μM, being superior to that of the reference C53 (EC<sub>50</sub> = 2.80 μM). Molecular modeling studies revealed that <strong>LA24</strong> exhibited enhanced STING agonistic activity by forming hydrogen bonds with key transmembrane domain residues G114 and Y106, as well as π–π stacking interactions with H50. These findings suggested that <strong>LA24</strong> holds promise as a novel lead compound for the development of STING-targeted immunomodulatory therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130508"},"PeriodicalIF":2.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145779668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.bmcl.2025.130505
Kelsey R. Latterell , Evan Keil , Benjamin R. Kraemer , Joe B. Huisken , Ben A. Thomas , Noah Daniels , Amit Kaushik , Maria Lillian Olson , Pamela Meléndez Noriega , Maria Alejandra Pizarro Daniels , Daron E. Janzen , Gyanu Lamichhane , Monica Campo , J. Thomas Ippoliti
Oxazolidinones are a class of antibiotics used to treat bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the class display poor safety profiles, and improved, next-generation drugs are urgently needed. Here we report the synthesis of two novel oxazolidinones: T504 and its regioisomer T542. Alongside the previously reported compound T145, we evaluate their inhibitory activity against the causative agent of tuberculosis, Mycobacterium tuberculosis. We also explore their antimycobacterial activity in a human monocyte-derived macrophage model of infection. Both T145 and T504 demonstrate potent activity and low cellular toxicity in human macrophages. The investigation reveals vast discrepancies in activities between the two regioisomers (T504 and T542), offering insights into the structure-activity relationship of substitutions on the oxanthrene scaffold.
{"title":"Synthesis and evaluation of novel oxanthrene scaffold-derived oxazolidinone antibiotics with potent antitubercular activity and low cellular toxicity","authors":"Kelsey R. Latterell , Evan Keil , Benjamin R. Kraemer , Joe B. Huisken , Ben A. Thomas , Noah Daniels , Amit Kaushik , Maria Lillian Olson , Pamela Meléndez Noriega , Maria Alejandra Pizarro Daniels , Daron E. Janzen , Gyanu Lamichhane , Monica Campo , J. Thomas Ippoliti","doi":"10.1016/j.bmcl.2025.130505","DOIUrl":"10.1016/j.bmcl.2025.130505","url":null,"abstract":"<div><div>Oxazolidinones are a class of antibiotics used to treat bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the class display poor safety profiles, and improved, next-generation drugs are urgently needed. Here we report the synthesis of two novel oxazolidinones: T504 and its regioisomer T542. Alongside the previously reported compound T145, we evaluate their inhibitory activity against the causative agent of tuberculosis, <em>Mycobacterium tuberculosis</em>. We also explore their antimycobacterial activity in a human monocyte-derived macrophage model of infection. Both T145 and T504 demonstrate potent activity and low cellular toxicity in human macrophages. The investigation reveals vast discrepancies in activities between the two regioisomers (T504 and T542), offering insights into the structure-activity relationship of substitutions on the oxanthrene scaffold.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130505"},"PeriodicalIF":2.2,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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