Pub Date : 2025-12-11DOI: 10.1016/j.bmcl.2025.130495
Ye Kong , Shunda Li , Xintong Xue , Huiping Liu , Ruiwei Fu , Yan Gao , Yingjie Zhang , Xia Xue
Dual inhibition of ALK and HDACs might be an effective cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assays, compound 19b showed dual inhibitory activity against ALK (ALK WT IC50 = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC50 = 1.18 ± 0.22 μM). Notably, 19b exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, 19b demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, 19b treatment led to increased apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by 19b. These findings support the promise of 19b as a dual ALK/HDAC inhibitor for managing neuroblastoma, especially ALK-positive cancer.
{"title":"Design, synthesis and biological evaluation of ALK/HDAC dual-targeting agents","authors":"Ye Kong , Shunda Li , Xintong Xue , Huiping Liu , Ruiwei Fu , Yan Gao , Yingjie Zhang , Xia Xue","doi":"10.1016/j.bmcl.2025.130495","DOIUrl":"10.1016/j.bmcl.2025.130495","url":null,"abstract":"<div><div>Dual inhibition of ALK and HDACs might be an effective cancer treatment approach. We designed and synthesized novel dual ALK and HDAC inhibitors using molecular hybridization and pharmacophore merging. In enzymatic assays, compound <strong>19b</strong> showed dual inhibitory activity against ALK (ALK WT IC<sub>50</sub> = 8.0 ± 1.2 nM) and HDACs (HeLa cell nuclear extract IC<sub>50</sub> = 1.18 ± 0.22 μM). Notably, <strong>19b</strong> exhibited ~5-fold greater inhibition than Staurosporine and approved ALK inhibitor Brigatinib against the ALK G1202R mutant. Additionally, <strong>19b</strong> demonstrated strong activity in ALK-related neuroblastoma SK-N-BE2 cells, comparable to controls SAHA, MS275, and Brigatinib. In SK-N-BE2 cells, <strong>19b</strong> treatment led to increased apoptosis and G2/M arrest. Docking studies explained the potent dual inhibition by <strong>19b</strong>. These findings support the promise of <strong>19b</strong> as a dual ALK/HDAC inhibitor for managing neuroblastoma, especially ALK-positive cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130495"},"PeriodicalIF":2.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751442","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 : 2025-12-10DOI: 10.1016/j.bmcl.2025.130500
Xiang Qiu , Lingling Dong , Hongzhen Shu , Guangxing Yu , Yuling Tong , Hengfan Ni , Shunjie Zhang
Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound 24 emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC50 value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound 24 efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC50 value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound 24 effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound 24 was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.
{"title":"Design, synthesis and biological evaluation of coumarin-based HDAC6 inhibitors for the treatment of ulcerative colitis","authors":"Xiang Qiu , Lingling Dong , Hongzhen Shu , Guangxing Yu , Yuling Tong , Hengfan Ni , Shunjie Zhang","doi":"10.1016/j.bmcl.2025.130500","DOIUrl":"10.1016/j.bmcl.2025.130500","url":null,"abstract":"<div><div>Novel selective histone deacetylase 6 (HDAC6) inhibitors using coumarin moiety as the cap were designed, synthesized and evaluated for HDAC enzymatic assays and anti-inflammatory tests. Among them, compound <strong>24</strong> emerged as the most promising candidate, demonstrating potent HDAC6 inhibition with an IC<sub>50</sub> value of 17 nM and exhibiting 32.39-fold selectivity over HDAC1. In vitro studies revealed that compound <strong>24</strong> efficiently suppressed nitric oxide production in RAW264.7 mouse macrophages, with an IC<sub>50</sub> value of 2.31 μM. Furthermore, human liver microsome tests confirmed its excellent metabolic stability, with a half-life of 59.74 min. Following administration at 30 mg/kg, compound <strong>24</strong> effectively maintain the integrity of colon tissue of DSS-induced ulcerative colitis mice model. Notably, its therapeutic efficacy was comparable to that of tofacitinib. These findings suggested that compound <strong>24</strong> was a promising anti-inflammatory candidate for selective HDAC6 inhibitor and deserves further investigation.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130500"},"PeriodicalIF":2.2,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740259","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 : 2025-12-08DOI: 10.1016/j.bmcl.2025.130496
Jinyu Bai , Huaihuai Shi , Jitun Chen , Hui Tian , Jiaxin Liang , Bichun Chen , Jiazhong Li , Lijing Fang
Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.
{"title":"Bicyclic peptide-based CPPTACs for extracellular and cell membrane protein degradation","authors":"Jinyu Bai , Huaihuai Shi , Jitun Chen , Hui Tian , Jiaxin Liang , Bichun Chen , Jiazhong Li , Lijing Fang","doi":"10.1016/j.bmcl.2025.130496","DOIUrl":"10.1016/j.bmcl.2025.130496","url":null,"abstract":"<div><div>Extracellular and cell membrane proteins are critical for maintaining physiological homeostasis and the abnormal expression of these proteins cause various diseases. Consequently, the development of targeted degradation strategy for these proteins represents a significant therapeutic opportunity. Leveraging cell-penetrating peptide (CPP)-induced endocytosis and lysosomal delivery, bicyclic CPP-mediated lysosome-targeting chimeras (CPPTACs) were developed to selectively degrade extracellular and cell surface proteins. Constructed by the conjugation of a bicyclic CPP containing the KRK motif with different target protein-binding molecules, these bicyclic peptide-based CPPTACs demonstrate the ability to enhance cellular uptake and facilitate the rapid degradation of protein targets via the endo-lysosomal pathway. These findings support the advancement of bicyclic peptide-based CPPTACs in pharmaceutical drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130496"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719941","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 : 2025-12-08DOI: 10.1016/j.bmcl.2025.130501
Yanlei Su , Yujia Wang , Jianyuan Zhao , Keyu Guo , Xuhong Duan , Honghai Wu , Dianxing Sun , Jing Zhang , Shan Cen
Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential via RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.1) and a novel isoflavone analog (Comp.2), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. In vitro assays demonstrated that Comp.1 exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.2. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.1: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.
{"title":"Identification of flavonoid-based small molecule inhibitors with dual-targeting capability against RdRp and Mpro of SARS-CoV-2","authors":"Yanlei Su , Yujia Wang , Jianyuan Zhao , Keyu Guo , Xuhong Duan , Honghai Wu , Dianxing Sun , Jing Zhang , Shan Cen","doi":"10.1016/j.bmcl.2025.130501","DOIUrl":"10.1016/j.bmcl.2025.130501","url":null,"abstract":"<div><div>Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential <em>via</em> RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.<strong>1</strong>) and a novel isoflavone analog (Comp.<strong>2</strong>), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. <em>In vitro</em> assays demonstrated that Comp.<strong>1</strong> exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.<strong>2</strong>. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.<strong>1</strong>: 0.838 probability) and CYP3A4 inhibition (>0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130501"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719923","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 : 2025-12-08DOI: 10.1016/j.bmcl.2025.130504
Wenjie Zhou , Yanyan Li , Wenli Shi , Binghua Cheng , Jiaming Liang , Zeyu Zhou , Hui Tian , Ximing Shao , Hongchang Li , Lijing Fang , Ke Liu
Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.
{"title":"A self-assembling peptide platform enables plasma membrane protein degradation","authors":"Wenjie Zhou , Yanyan Li , Wenli Shi , Binghua Cheng , Jiaming Liang , Zeyu Zhou , Hui Tian , Ximing Shao , Hongchang Li , Lijing Fang , Ke Liu","doi":"10.1016/j.bmcl.2025.130504","DOIUrl":"10.1016/j.bmcl.2025.130504","url":null,"abstract":"<div><div>Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130504"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719910","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 : 2025-12-08DOI: 10.1016/j.bmcl.2025.130502
Xiu-Jun Wang , Meng-Xin Lu , Qiu-yue Jin , Zi-Yan Lang , Ming-Li Yang , Jing Ji
In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using 1H NMR, 13C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.
{"title":"Synthesis and antitumor activity of derivatives of SKF-83566","authors":"Xiu-Jun Wang , Meng-Xin Lu , Qiu-yue Jin , Zi-Yan Lang , Ming-Li Yang , Jing Ji","doi":"10.1016/j.bmcl.2025.130502","DOIUrl":"10.1016/j.bmcl.2025.130502","url":null,"abstract":"<div><div>In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130502"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719949","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}
Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd 1, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp3 carbons (Fsp3). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd 17. Target specificity studies of Cpd 17 indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd 21, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp3 compared to Cpd 1. These results highlight Cpd 21 as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.
{"title":"A potent and selective RORγ inhibitor for the treatment of autoimmune diseases","authors":"Taku Ikenogami , Masahiro Yokota , Shingo Fujioka , Naoki Ogawa , Masato Noguchi , Akihiro Nomura , Tsuyoshi Adachi , Yoshiaki Katsuda , Kojo Arita , Naoki Miyagawa , Yusuke Aratsu , Kota Asahina , Paul Crowe , Haiyan Tao , Scott Thacher , Makoto Shiozaki","doi":"10.1016/j.bmcl.2025.130494","DOIUrl":"10.1016/j.bmcl.2025.130494","url":null,"abstract":"<div><div>Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd <strong>1</strong>, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp<sup>3</sup> carbons (Fsp<sup>3</sup>). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd <strong>17</strong>. Target specificity studies of Cpd <strong>17</strong> indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd <strong>21</strong>, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp<sup>3</sup> compared to Cpd <strong>1</strong>. These results highlight Cpd <strong>21</strong> as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130494"},"PeriodicalIF":2.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719970","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 : 2025-12-07DOI: 10.1016/j.bmcl.2025.130499
Shankesh C. Zyate , Nikita V. Awajare , Sanjay S. Gaikwad , Kunal Raut , Vikas Jha , Amardeep R. Jadhao , Poonam T. Agrawal
The surge in fungal infection-related mortality worldwide is being caused by drug resistance to well-established antifungals such azole derivatives (bifonazole, fluconazole, miconazole, and clotrimazole). Finding novel molecules that are structurally different to these could be a useful tactic to get over medication resistance that is currently on the market. In an effort to develop highly potent non-resistance antifungal agents, we reported a series of compounds with benzothiazole, S-benzyl-2,4-isodithiobiuret and thiourea derivatives of 1-hepta-O-benzoyl-β-d-maltose NPs and their antifungal activity against the most infectious fungal strain Candida albicans. Numerous analogues among the synthesized compounds have shown potent antifungal activity. All the synthesized compounds were tested in vitro for determining their anticandidal activity. Almost all the compounds were found to be highly potent than established antifungal drugs (MIC ¼ 0.25–0.125 mg mL−1) against Candida albicans strain. An in silico molecular docking study was also performed to comprehend the mode of action of the active compounds towards prospective target 1EA1 binding protein.
世界范围内真菌感染相关死亡率的激增是由于对唑类衍生物（联苯唑、氟康唑、咪康唑和克霉唑）等公认的抗真菌药物产生耐药性造成的。寻找与这些分子结构不同的新分子可能是克服目前市场上的耐药性的有效策略。为了开发高效的非耐药抗真菌药物，我们报道了一系列含有苯并噻唑、s -苄基-2,4-异硫代比脲和1-庚- o -苯甲酰-β-d-麦芽糖NPs的硫脲衍生物的化合物，以及它们对传染性最强的白色念珠菌的抗真菌活性。合成的化合物中有许多类似物显示出有效的抗真菌活性。所有合成的化合物都在体外测试了它们的抗兴奋剂活性。几乎所有化合物都被发现比已建立的抗真菌药物（MIC 0.25-0.125 mg mL-1）对白色念珠菌菌株具有强效。我们还进行了硅分子对接研究，以了解活性化合物对预期靶标1EA1结合蛋白的作用模式。
{"title":"Design, synthesis, antifungal activity, and molecular docking studies of benzothiazole, S-benzyl-2,4-isodithiobiuret, and thiourea derivatives of 1-hepta-O-benzoyl-β-d-maltose nanoparticles","authors":"Shankesh C. Zyate , Nikita V. Awajare , Sanjay S. Gaikwad , Kunal Raut , Vikas Jha , Amardeep R. Jadhao , Poonam T. Agrawal","doi":"10.1016/j.bmcl.2025.130499","DOIUrl":"10.1016/j.bmcl.2025.130499","url":null,"abstract":"<div><div>The surge in fungal infection-related mortality worldwide is being caused by drug resistance to well-established antifungals such azole derivatives (bifonazole, fluconazole, miconazole, and clotrimazole). Finding novel molecules that are structurally different to these could be a useful tactic to get over medication resistance that is currently on the market. In an effort to develop highly potent non-resistance antifungal agents, we reported a series of compounds with benzothiazole, S-benzyl-2,4-isodithiobiuret and thiourea derivatives of 1-hepta-O-benzoyl-β-<span>d</span>-maltose NPs and their antifungal activity against the most infectious fungal strain <em>Candida albicans</em>. Numerous analogues among the synthesized compounds have shown potent antifungal activity. All the synthesized compounds were tested in vitro for determining their anticandidal activity. Almost all the compounds were found to be highly potent than established antifungal drugs (MIC ¼ 0.25–0.125 mg mL<sup>−1</sup>) against <em>Candida albicans</em> strain. An in silico molecular docking study was also performed to comprehend the mode of action of the active compounds towards prospective target 1EA1 binding protein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130499"},"PeriodicalIF":2.2,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712700","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 : 2025-12-05DOI: 10.1016/j.bmcl.2025.130497
Yeojeong Kim , Jingyang Sun , Kyoungyim Lee , Soobin Kim , Danbi Lee , Bomi Park , Yeji Lee , Inah Hwang , Jae-Sang Ryu
Bruton's tyrosine kinase (BTK) has emerged as a validated therapeutic target for B-cell malignancies and autoimmune disorders, and covalent BTK inhibitors have demonstrated remarkable clinical efficacy. However, because of concerns regarding their off-target effects and safety profiles, there is research interest in developing noncovalent, reversible inhibitors. Herein, we report the design, synthesis, and biochemical evaluation of novel imidazo[4,5-b]pyridine derivatives as noncovalent BTK inhibitors. Through a concise three-step synthetic route, we prepared 16 structurally diverse analogs (6a–p) bearing various substituents on the imidazole scaffold. The results of biochemical evaluation showed that 6b, 6o, and 6p are the most potent inhibitors, with IC₅₀ values of 1.14, 1.54, and 2.46 μM, respectively. The results of structure–activity relationship studies revealed that 2,4-dihydroxyphenyl substitution on the A-ring and extended functionalities (morpholinomethyl or 4-acetamido group) on the B-ring significantly enhanced the inhibition of BTK. The results of molecular docking studies elucidated key binding interactions and showed that the hydroxyl groups form hydrogen bonds with the Thr474 gatekeeper residue and the Met477 hinge region residue, whereas B-ring substituents extend toward the DFG motif. The preliminary kinase selectivity profiling of 6b against 39 kinases demonstrated promising selectivity, with significant inhibition observed primarily for BTK and c-Src. Although these compounds show moderate potency compared with clinically approved BTK inhibitors, their noncovalent, reversible nature offers potential advantages with regard to selectivity, toxicity, and pharmacological effects. Moreover, these compounds represent valuable starting points for further optimization toward developing novel therapeutics for B-cell malignancies and autoimmune disorders with potentially improved safety profiles for long-term treatment.
{"title":"Discovery of novel imidazo[4,5-b]pyridine derivatives as noncovalent reversible Bruton’s tyrosine kinase inhibitors","authors":"Yeojeong Kim , Jingyang Sun , Kyoungyim Lee , Soobin Kim , Danbi Lee , Bomi Park , Yeji Lee , Inah Hwang , Jae-Sang Ryu","doi":"10.1016/j.bmcl.2025.130497","DOIUrl":"10.1016/j.bmcl.2025.130497","url":null,"abstract":"<div><div>Bruton's tyrosine kinase (BTK) has emerged as a validated therapeutic target for B-cell malignancies and autoimmune disorders, and covalent BTK inhibitors have demonstrated remarkable clinical efficacy. However, because of concerns regarding their off-target effects and safety profiles, there is research interest in developing noncovalent, reversible inhibitors. Herein, we report the design, synthesis, and biochemical evaluation of novel imidazo[4,5-<em>b</em>]pyridine derivatives as noncovalent BTK inhibitors. Through a concise three-step synthetic route, we prepared 16 structurally diverse analogs (<strong>6a</strong>–<strong>p</strong>) bearing various substituents on the imidazole scaffold. The results of biochemical evaluation showed that <strong>6b</strong>, <strong>6o</strong>, and <strong>6p</strong> are the most potent inhibitors, with IC₅₀ values of 1.14, 1.54, and 2.46 μM, respectively. The results of structure–activity relationship studies revealed that 2,4-dihydroxyphenyl substitution on the A-ring and extended functionalities (morpholinomethyl or 4-acetamido group) on the B-ring significantly enhanced the inhibition of BTK. The results of molecular docking studies elucidated key binding interactions and showed that the hydroxyl groups form hydrogen bonds with the Thr474 gatekeeper residue and the Met477 hinge region residue, whereas B-ring substituents extend toward the DFG motif. The preliminary kinase selectivity profiling of <strong>6b</strong> against 39 kinases demonstrated promising selectivity, with significant inhibition observed primarily for BTK and c-Src. Although these compounds show moderate potency compared with clinically approved BTK inhibitors, their noncovalent, reversible nature offers potential advantages with regard to selectivity, toxicity, and pharmacological effects. Moreover, these compounds represent valuable starting points for further optimization toward developing novel therapeutics for B-cell malignancies and autoimmune disorders with potentially improved safety profiles for long-term treatment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130497"},"PeriodicalIF":2.2,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699419","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 : 2025-12-05DOI: 10.1016/j.bmcl.2025.130498
Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik
Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway via aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using in vitro kinetic assays. Among the tested molecules, compound 4, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with Ki values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.
{"title":"Synthesis of new Pyridazinone derivatives and their dual inhibitory activity on aldose reductase and α-glucosidase","authors":"Mevlüt Akdağ , Merve Güneş Çam , Derya Ergen , Yeliz Demir , Şükrü Beydemir , Azime Berna Özçelik","doi":"10.1016/j.bmcl.2025.130498","DOIUrl":"10.1016/j.bmcl.2025.130498","url":null,"abstract":"<div><div>Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway <em>via</em> aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using <em>in vitro</em> kinetic assays. Among the tested molecules, compound <strong>4</strong>, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with K<sub>i</sub> values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130498"},"PeriodicalIF":2.2,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699488","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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