Pub Date : 2026-03-11DOI: 10.1021/acs.jmedchem.5c02642
Daniele Pala,Claudio Fiorelli,Paolo Bruno,Charles Baker-Glenn,Hervé Van de Poël,Kim Hirst,Gary Clark,Luca Carlino,Elena Picchi,Barbara Pioselli,Paolo Ronchi,Daniela Pizzirani,Matteo Biagetti
Traditional three-dimensional core-hopping methods aim to substitute the central core of a reference ligand conformer with alternative scaffolds that exhibit similar pharmacophoric features. As such, these algorithms are not trained to perceive the effect of a new core on the conformational equilibrium of ligand substituents. With the aim of evaluating the ability of a new scaffold to preserve the conformational dynamics of the reference compound, we developed DynaCore, a novel bespoke algorithm designed to compute the similarity of conformer ensembles collected from molecular dynamics simulations of a ligand before and after core replacement. DynaCore was subsequently used to prospectively design novel P2X3 antagonists using privileged fragments from previous medicinal chemistry campaigns. The algorithm recapitulated known conformation-activity relationships and successfully distinguished new scaffold replacements that retained or abolished ligand potency, leading to the identification of multiple potent hit series. DynaCore can potentially be applied to any compound pair sharing a common set of substituents.
{"title":"Accurate Prediction of Core-Hopping Transformations Using Molecular Dynamics-Derived Conformational Ensembles: Application to the Discovery of Novel P2X3 Antagonists.","authors":"Daniele Pala,Claudio Fiorelli,Paolo Bruno,Charles Baker-Glenn,Hervé Van de Poël,Kim Hirst,Gary Clark,Luca Carlino,Elena Picchi,Barbara Pioselli,Paolo Ronchi,Daniela Pizzirani,Matteo Biagetti","doi":"10.1021/acs.jmedchem.5c02642","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02642","url":null,"abstract":"Traditional three-dimensional core-hopping methods aim to substitute the central core of a reference ligand conformer with alternative scaffolds that exhibit similar pharmacophoric features. As such, these algorithms are not trained to perceive the effect of a new core on the conformational equilibrium of ligand substituents. With the aim of evaluating the ability of a new scaffold to preserve the conformational dynamics of the reference compound, we developed DynaCore, a novel bespoke algorithm designed to compute the similarity of conformer ensembles collected from molecular dynamics simulations of a ligand before and after core replacement. DynaCore was subsequently used to prospectively design novel P2X3 antagonists using privileged fragments from previous medicinal chemistry campaigns. The algorithm recapitulated known conformation-activity relationships and successfully distinguished new scaffold replacements that retained or abolished ligand potency, leading to the identification of multiple potent hit series. DynaCore can potentially be applied to any compound pair sharing a common set of substituents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung cancer represents a major global health challenge, and the development of new therapeutic agents remains a serious task. This study designed and synthesized 27 novel coumarin-furoxan hybrids. Among them, compound 6o exhibited potent nanomolar-level antiproliferative activity against six nonsmall cell lung cancer (NSCLC) cell lines, including both wild-type and drug-resistant models. Mechanistic investigations revealed that 6o downregulates the expression of ferroptosis-related factors SLC7A11 and GPX4, thereby disrupting redox homeostasis, depleting glutathione, and accumulating lipid peroxides, which collectively trigger ferroptosis. Furthermore, 6o elevated mitochondrial nitric oxide (NO) and reactive oxygen species (ROS) levels, exacerbating cellular damage. 6o also displayed low hERG channel toxicity, favorable in vivo safety, and acceptable solubility. In summary, 6o demonstrates high efficacy against both wild-type and drug-resistant NSCLC cells via a ferroptosis-mediated mechanism, along with a promising safety profile, supporting its potential as a candidate for further development.
{"title":"Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents against Wild-Type and Drug-Resistant Nonsmall Cell Lung Cancer Cell Lines.","authors":"Weijie Wang,Xiufan Wu,Fan Cao,La Li,Xuqin Guo,Hongyang Zhao,Mengru Li,Hongrui Liu,Ying Chen","doi":"10.1021/acs.jmedchem.5c03580","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03580","url":null,"abstract":"Lung cancer represents a major global health challenge, and the development of new therapeutic agents remains a serious task. This study designed and synthesized 27 novel coumarin-furoxan hybrids. Among them, compound 6o exhibited potent nanomolar-level antiproliferative activity against six nonsmall cell lung cancer (NSCLC) cell lines, including both wild-type and drug-resistant models. Mechanistic investigations revealed that 6o downregulates the expression of ferroptosis-related factors SLC7A11 and GPX4, thereby disrupting redox homeostasis, depleting glutathione, and accumulating lipid peroxides, which collectively trigger ferroptosis. Furthermore, 6o elevated mitochondrial nitric oxide (NO) and reactive oxygen species (ROS) levels, exacerbating cellular damage. 6o also displayed low hERG channel toxicity, favorable in vivo safety, and acceptable solubility. In summary, 6o demonstrates high efficacy against both wild-type and drug-resistant NSCLC cells via a ferroptosis-mediated mechanism, along with a promising safety profile, supporting its potential as a candidate for further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"62 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1021/acs.jmedchem.6c00059
Steven Panek,Anne-Cécile Van Baelen,Beatrice Dalla Volta,Surjendu Bikash Dutta,Loreen Hericks,Rayen Karoui,Emily Vortmeyer,Yvonne Hannappel,Veronica Isabel Dodero,Thomas Huser,Denis Servent,Olivier Lequin,Aphrodite Kapurniotu,Norbert Sewald,Nicolo Tonali
Amyloid-β (Aβ1–42) prefibrillar aggregates are considered the most neurotoxic amyloid species, yet their transient and heterogeneous nature makes selective detection challenging. Many fluorescent probes also fail to discriminate Aβ from homologous peptides such as IAPP, leading to poor specificity. We report a peptide-guided late-stage diversification strategy to generate BODIPY-based probes highly selective for prefibrillar Aβ1–42. A rationally engineered cyclic peptide derived from the C-terminal region of Aβ1–42 provides conformational rigidity and precise molecular recognition. Conjugation to BODIPY fluorophores afforded peptide–dye hybrids systematically evaluated for selectivity and photophysical response. A controlled aggregation protocol enabling reproducible generation of prefibrillar Aβ species was established to validate probe performance. A Sonogashira-derived conjugate (probe 8) showed strong fluorescence turn-on and selective affinity for prefibrillar Aβ1–42, with no response to IAPP aggregates. In neuronal cells, probe 8 outperformed conventional antibodies, supporting its potential for mechanistic studies and early Alzheimer’s disease diagnostics.
{"title":"Cyclopeptide-Based Fluorescent Conjugates for Monitoring Prefibrillar Aβ Nanostructures","authors":"Steven Panek,Anne-Cécile Van Baelen,Beatrice Dalla Volta,Surjendu Bikash Dutta,Loreen Hericks,Rayen Karoui,Emily Vortmeyer,Yvonne Hannappel,Veronica Isabel Dodero,Thomas Huser,Denis Servent,Olivier Lequin,Aphrodite Kapurniotu,Norbert Sewald,Nicolo Tonali","doi":"10.1021/acs.jmedchem.6c00059","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00059","url":null,"abstract":"Amyloid-β (Aβ1–42) prefibrillar aggregates are considered the most neurotoxic amyloid species, yet their transient and heterogeneous nature makes selective detection challenging. Many fluorescent probes also fail to discriminate Aβ from homologous peptides such as IAPP, leading to poor specificity. We report a peptide-guided late-stage diversification strategy to generate BODIPY-based probes highly selective for prefibrillar Aβ1–42. A rationally engineered cyclic peptide derived from the C-terminal region of Aβ1–42 provides conformational rigidity and precise molecular recognition. Conjugation to BODIPY fluorophores afforded peptide–dye hybrids systematically evaluated for selectivity and photophysical response. A controlled aggregation protocol enabling reproducible generation of prefibrillar Aβ species was established to validate probe performance. A Sonogashira-derived conjugate (probe 8) showed strong fluorescence turn-on and selective affinity for prefibrillar Aβ1–42, with no response to IAPP aggregates. In neuronal cells, probe 8 outperformed conventional antibodies, supporting its potential for mechanistic studies and early Alzheimer’s disease diagnostics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"408 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Histone deacetylase 3 (HDAC3) plays a pivotal role in inflammation by regulating transcriptional programs and promoting NLRP3 inflammasome activation. Here, we report the discovery of GS-1, a covalent HDAC3 degrader derived from a previously reported 18β-glycyrrhetinic acid derivative A18 via structural optimization. It selectively degraded HDAC3 in THP-1 cells, with minimal enzymatic HDAC inhibition and low cytotoxicity. LC–MS/MS analysis revealed covalent modification at Lys367, and molecular simulations indicated that it was located at a noncatalytic site and interacted with surrounding residues. GS-1 demonstrated favorable pharmacokinetics and excellent in vivo tolerability. Mechanistically, GS-1 suppressed NLRP3 inflammasome activation by degrading HDAC3, thereby reducing the maturation of IL-1β and caspase-1. In murine models, GS-1 significantly alleviated inflammation in LPS-induced endotoxic shock, DSS-induced colitis, and MSU-induced gout, showing potent efficacy and excellent safety profiles. These findings establish GS-1 as a promising chemical probe and therapeutic lead for anti-inflammation through HDAC3 degradation.
{"title":"Discovery of a Covalent HDAC3 Degrader with Excellent Anti-Inflammatory Activity and NLRP3 Inflammasome Suppression","authors":"Huanhuan Qin,Yue Shi,Rulong Liu,Bing Wang,Luhao Guo,Guizhou Hao,Guimin Zhang,Dan Liu,Linxiang Zhao,Min Huang","doi":"10.1021/acs.jmedchem.5c02513","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02513","url":null,"abstract":"Histone deacetylase 3 (HDAC3) plays a pivotal role in inflammation by regulating transcriptional programs and promoting NLRP3 inflammasome activation. Here, we report the discovery of GS-1, a covalent HDAC3 degrader derived from a previously reported 18β-glycyrrhetinic acid derivative A18 via structural optimization. It selectively degraded HDAC3 in THP-1 cells, with minimal enzymatic HDAC inhibition and low cytotoxicity. LC–MS/MS analysis revealed covalent modification at Lys367, and molecular simulations indicated that it was located at a noncatalytic site and interacted with surrounding residues. GS-1 demonstrated favorable pharmacokinetics and excellent in vivo tolerability. Mechanistically, GS-1 suppressed NLRP3 inflammasome activation by degrading HDAC3, thereby reducing the maturation of IL-1β and caspase-1. In murine models, GS-1 significantly alleviated inflammation in LPS-induced endotoxic shock, DSS-induced colitis, and MSU-induced gout, showing potent efficacy and excellent safety profiles. These findings establish GS-1 as a promising chemical probe and therapeutic lead for anti-inflammation through HDAC3 degradation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"45 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
GluN2B-NMDARs are promising targets for ischemic stroke therapy, but antagonist development has been limited by poor selectivity and cardiotoxicity. We report NFI23, a novel N-arylindole derivative, as a selective GluN2B-NMDAR antagonist. NFI23 showed potent neuroprotection against NMDA-induced cytotoxicity. Molecular docking revealed its binding to the Ifenprodil site, partial overlap with EVT-101, and unique interactions. NFI23 reduced Ca2+ influx, ROS generation, and neuronal apoptosis, while preserving mitochondrial membrane potential and restoring p-ERK1/2 expression. Competitive binding assays confirmed its low nanomolar affinity. In vitro metabolism indicated high plasma stability and low drug interaction risk, while in vivo pharmacokinetics demonstrated favorable absorption and brain penetration. In a rat MCAO model, NFI23 provided marked neuroprotection. Molecular dynamics simulations confirmed stable receptor binding. Notably, NFI23 exhibited negligible hERG channel inhibition and excellent selectivity over other subtypes and σ1/σ2 receptors, supporting it as a promising and safer therapeutic candidate for ischemic stroke.
{"title":"Discovery and Evaluation of N-Arylindole-Based GluN2B-NMDAR Antagonists with Reduced Cardiotoxicity for the Treatment of Ischemic Stroke.","authors":"Zhuo Zhang,Ke Du,Zhenlu Liu,Shan Yang,Yu Lu,Xinru Zhou,Xuanhe Xin,Chao Ma,Maosheng Cheng","doi":"10.1021/acs.jmedchem.5c03741","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03741","url":null,"abstract":"GluN2B-NMDARs are promising targets for ischemic stroke therapy, but antagonist development has been limited by poor selectivity and cardiotoxicity. We report NFI23, a novel N-arylindole derivative, as a selective GluN2B-NMDAR antagonist. NFI23 showed potent neuroprotection against NMDA-induced cytotoxicity. Molecular docking revealed its binding to the Ifenprodil site, partial overlap with EVT-101, and unique interactions. NFI23 reduced Ca2+ influx, ROS generation, and neuronal apoptosis, while preserving mitochondrial membrane potential and restoring p-ERK1/2 expression. Competitive binding assays confirmed its low nanomolar affinity. In vitro metabolism indicated high plasma stability and low drug interaction risk, while in vivo pharmacokinetics demonstrated favorable absorption and brain penetration. In a rat MCAO model, NFI23 provided marked neuroprotection. Molecular dynamics simulations confirmed stable receptor binding. Notably, NFI23 exhibited negligible hERG channel inhibition and excellent selectivity over other subtypes and σ1/σ2 receptors, supporting it as a promising and safer therapeutic candidate for ischemic stroke.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1021/acs.jmedchem.5c03822
Yaoguang Huang, Wenwu Liu, Xiaoyu Shi, Yixin Zhang, Xupeng Yang, Lianyu Tang, Shuning Sun, Qingchun Zhao, Jingming Jia, Anhua Wang
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that lacks effective targeted therapies and exhibits strong dependence on CDK9-driven transcription. Here, we report a structure-based drug design strategy exploiting CDK9-specific conformations to discover a novel series of potent inhibitors. This approach yielded HS34, a coumarin-based CDK9 inhibitor with low-nanomolar potency and exceptional selectivity. In cellular assays, HS34 displayed potent antiproliferative activity against TNBC cells, outperforming the reference inhibitor KB-0742. Mechanistically, HS34 suppresses RNAP II Ser2 phosphorylation, leading to the downregulation of short-lived survival and oncogenic proteins such as Mcl-1 and c-Myc, and consequently inducing apoptosis and blocking EMT-associated invasion. Furthermore, HS34 exhibits favorable DMPK properties, including high oral bioavailability and metabolic stability, which align with the significant antitumor efficacy observed in an orally treated xenograft model. Collectively, these findings establish HS34 as a selective CDK9 inhibitor and demonstrate that exploiting target-specific conformational features offers an effective strategy for kinase selectivity.
三阴性乳腺癌（TNBC）是一种高度侵袭性的亚型，缺乏有效的靶向治疗，并表现出对cdk9驱动转录的强烈依赖。在这里，我们报告了一种基于结构的药物设计策略，利用cdk9特异性构象来发现一系列新的有效抑制剂。这种方法产生了HS34，一种基于香豆素的CDK9抑制剂，具有低纳摩尔效力和特殊的选择性。在细胞实验中，HS34对TNBC细胞表现出有效的抗增殖活性，优于参比抑制剂KB-0742。机制上，HS34抑制RNAP II Ser2磷酸化，导致Mcl-1和c-Myc等短寿命存活蛋白和致癌蛋白下调，从而诱导细胞凋亡，阻断emt相关侵袭。此外，HS34具有良好的DMPK特性，包括高口服生物利用度和代谢稳定性，这与在口服治疗的异种移植物模型中观察到的显著抗肿瘤功效一致。总的来说，这些发现证实了HS34是一种选择性CDK9抑制剂，并证明利用靶标特异性构象特征为激酶选择性提供了一种有效的策略。
{"title":"Structure-Based Discovery of HS34: A Highly Selective and Orally Bioavailable CDK9 Inhibitor for Triple-Negative Breast Cancer","authors":"Yaoguang Huang, Wenwu Liu, Xiaoyu Shi, Yixin Zhang, Xupeng Yang, Lianyu Tang, Shuning Sun, Qingchun Zhao, Jingming Jia, Anhua Wang","doi":"10.1021/acs.jmedchem.5c03822","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03822","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a highly aggressive subtype that lacks effective targeted therapies and exhibits strong dependence on CDK9-driven transcription. Here, we report a structure-based drug design strategy exploiting CDK9-specific conformations to discover a novel series of potent inhibitors. This approach yielded <b>HS34</b>, a coumarin-based CDK9 inhibitor with low-nanomolar potency and exceptional selectivity. In cellular assays, <b>HS34</b> displayed potent antiproliferative activity against TNBC cells, outperforming the reference inhibitor KB-0742. Mechanistically, <b>HS34</b> suppresses RNAP II Ser2 phosphorylation, leading to the downregulation of short-lived survival and oncogenic proteins such as Mcl-1 and c-Myc, and consequently inducing apoptosis and blocking EMT-associated invasion. Furthermore, <b>HS34</b> exhibits favorable DMPK properties, including high oral bioavailability and metabolic stability, which align with the significant antitumor efficacy observed in an orally treated xenograft model. Collectively, these findings establish <b>HS34</b> as a selective CDK9 inhibitor and demonstrate that exploiting target-specific conformational features offers an effective strategy for kinase selectivity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"33 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1021/acs.jmedchem.5c03739
Wilmer Villarreal,Helenita Costa Quadros,Legna Colina-Vegas,Sammy Y Aboagye,Godwin Akpeko Dziwornu,Gabriel H Ribeiro,Ariane Isis Barros,Dawid Jakub Kucharski,Mahsa Rahbari,Christina Brandstädter,Sarah D'Alessandro,Nicoletta Basilico,Keabetswe Masike,Nandi Mehlala,Joaquim Araújo Nobrega,Victor M Deflon,Maribel Navarro,Przemysław J Boratyński,Kelly Chibale,David L Williams,Alzir A Batista,Diogo R M Moreira
Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ-metal complexes of the general formula [M(II)(L)(MQ)]PF6 are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a N,O-bidentate ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ-Pt complexes displayed high in vivo efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.
{"title":"Examination of Coligands in Mefloquine-Metal Complexes Reveals the Structural Determinants of Activity against Plasmodium falciparum and Schistosoma mansoni.","authors":"Wilmer Villarreal,Helenita Costa Quadros,Legna Colina-Vegas,Sammy Y Aboagye,Godwin Akpeko Dziwornu,Gabriel H Ribeiro,Ariane Isis Barros,Dawid Jakub Kucharski,Mahsa Rahbari,Christina Brandstädter,Sarah D'Alessandro,Nicoletta Basilico,Keabetswe Masike,Nandi Mehlala,Joaquim Araújo Nobrega,Victor M Deflon,Maribel Navarro,Przemysław J Boratyński,Kelly Chibale,David L Williams,Alzir A Batista,Diogo R M Moreira","doi":"10.1021/acs.jmedchem.5c03739","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03739","url":null,"abstract":"Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ-metal complexes of the general formula [M(II)(L)(MQ)]PF6 are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a N,O-bidentate ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ-Pt complexes displayed high in vivo efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1021/acs.jmedchem.6c00335
Yan Hu,Xiaowei Feng,Jiang Wu,Benqin Xu,Chenhao Liao,Peng Zhou,Jialin Sun,Weijie Xu,Panpan Chen,Feng Wang,Tingyou Li
The limited tissue penetration depth of optical probes based on 2-(2'-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) hindered dynamic monitoring of the actual distribution and metabolism of them in deep tissues. Herein, using fibroblast activating protein (FAP)-activatable dual-modal probes as a prototype, we explored the potential of HPQ as a core scaffold for in vivo imaging probes via stepwise biological characterization. The tumor-to-muscle uptake ratios (T/M) of LWF-1, LWF-2, and LWF-3 were consistently above 4.05 during in vivo fluorescence imaging with sustained tumor visualization exceeding 48 h. All 68Ga-radiolabeled probes exhibited a maximum tumor uptake of up to 12.83 ± 9.37%ID/g in model mice, with the T/M of [68Ga]LWF-3 remaining above 4.89 throughout the PET scanning. The ex vivo biodistribution study revealed that [177Lu]LWF-3 reached the peak uptake in the tumor at 4 h postinjection (10.41 ± 0.68%ID/g). Accordingly, structural design and optimization governing their in vivo metabolism are critical for acquisition of ideal HPQ-based probes.
{"title":"Systematic Exploration of the Potential of HPQ as the Core Scaffold of Probes for in Vivo Imaging: A Case Study of FAP-Responsive Probes.","authors":"Yan Hu,Xiaowei Feng,Jiang Wu,Benqin Xu,Chenhao Liao,Peng Zhou,Jialin Sun,Weijie Xu,Panpan Chen,Feng Wang,Tingyou Li","doi":"10.1021/acs.jmedchem.6c00335","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00335","url":null,"abstract":"The limited tissue penetration depth of optical probes based on 2-(2'-hydroxyphenyl)-4(3H)-quinazolinone (HPQ) hindered dynamic monitoring of the actual distribution and metabolism of them in deep tissues. Herein, using fibroblast activating protein (FAP)-activatable dual-modal probes as a prototype, we explored the potential of HPQ as a core scaffold for in vivo imaging probes via stepwise biological characterization. The tumor-to-muscle uptake ratios (T/M) of LWF-1, LWF-2, and LWF-3 were consistently above 4.05 during in vivo fluorescence imaging with sustained tumor visualization exceeding 48 h. All 68Ga-radiolabeled probes exhibited a maximum tumor uptake of up to 12.83 ± 9.37%ID/g in model mice, with the T/M of [68Ga]LWF-3 remaining above 4.89 throughout the PET scanning. The ex vivo biodistribution study revealed that [177Lu]LWF-3 reached the peak uptake in the tumor at 4 h postinjection (10.41 ± 0.68%ID/g). Accordingly, structural design and optimization governing their in vivo metabolism are critical for acquisition of ideal HPQ-based probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"237 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ADGRL3 is an important protein mediating neural activities, which is closely associated with various physiological processes including synaptic regulation, motor function, attention, and cognitive behaviors. However, its role in cerebral ischemia has not been investigated to date. In this work, we used CZ-7 which is a pyrano[3,2-a]carbazole alkaloid as hit compound and synthesized 25 nitrone/oxime-bearing derivatives. Pharmacological evaluations showed that 14a and its nano formulation (14a-NPs) mitigated multiple indices of cerebral ischemic injury, outperformed Edaravone-Dexborneol and dl-3-n-butylphthalide (dl-NBP), and displayed a favorable safety profile. Pharmacokinetic results showed that 14a-NPs was highly enriched in the brain compared with plasma. Meanwhile, transcriptomic analysis identified ADGRL3 as its therapeutic target, and the synaptic protective effect of 14a was verified. Collectively, we report for the first time that ADGRL3 is a novel therapeutic target for stroke, and that 14a exerts protective effects against cerebral ischemic injury by targeting ADGRL3 to preserve synaptic function.
{"title":"Discovery of Novel Pyrano[3,2-a]carbazole Alkaloid Derivatives against Ischemic Stroke by Targeting ADGRL3.","authors":"Anhua Tao,Yuzhi Lin,Jing Feng,Haowen Luo,Kai Qu,Yuying Kang,Haibo Yu,Li Chuangjun,Jie Ma,Wei Huang,Li Sheng,Dongming Zhang,Yingda Zang,Ying Peng","doi":"10.1021/acs.jmedchem.5c03301","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03301","url":null,"abstract":"ADGRL3 is an important protein mediating neural activities, which is closely associated with various physiological processes including synaptic regulation, motor function, attention, and cognitive behaviors. However, its role in cerebral ischemia has not been investigated to date. In this work, we used CZ-7 which is a pyrano[3,2-a]carbazole alkaloid as hit compound and synthesized 25 nitrone/oxime-bearing derivatives. Pharmacological evaluations showed that 14a and its nano formulation (14a-NPs) mitigated multiple indices of cerebral ischemic injury, outperformed Edaravone-Dexborneol and dl-3-n-butylphthalide (dl-NBP), and displayed a favorable safety profile. Pharmacokinetic results showed that 14a-NPs was highly enriched in the brain compared with plasma. Meanwhile, transcriptomic analysis identified ADGRL3 as its therapeutic target, and the synaptic protective effect of 14a was verified. Collectively, we report for the first time that ADGRL3 is a novel therapeutic target for stroke, and that 14a exerts protective effects against cerebral ischemic injury by targeting ADGRL3 to preserve synaptic function.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-10DOI: 10.1021/acs.jmedchem.5c03414
Chin Piaw Gwee,Tommaso Felicetti,Kitti Wing Ki Chan,Min Jie Alvin Tan,Muhammad Danial Bin Mohd Mazlan,Ciro Milite,Giacomo Pepe,Chiara Sarnari,Xiao Dan Ng,Wint Wint Phoo,Jasmine Hwee Yee Tan,Marcus G Mah,Satoru Watanabe,Jing Xiu Huang,Serena Massari,Oriana Tabarrini,Stefano Sabatini,Pietro Campiglia,Gianluca Sbardella,Gavin J D Smith,Sylvie Alonso,Alfred Xuyang Sun,Radoslaw M Sobota,Subhash G Vasudevan,Giuseppe Manfroni
Dengue virus (DENV) remains a major global health concern without effective treatments. Previously, we identified sulfonyl anthranilic acid (SAA) derivatives (compounds 1 and 2) as potent pan-DENV inhibitors, likely targeting a primate-specific factor. Here, mass spectrometry-based target deconvolution revealed that SAA compounds downregulate ribosomal protein expression, some of which are essential for DENV replication, as confirmed by siRNA-knockdown studies. This novel mechanism aligns with the broad-spectrum antiviral activity of compounds 1 and 2. Moreover, compound 1 was also effective against the Zika virus in a human brain organoid model. The subsequent medicinal chemistry optimization process resulted in the identification of compound 7, which demonstrated an EC50 value of 50 nM against DENV-2, promising broad-spectrum potential and favorable in vitro ADME properties. Further studies indicated that these compounds modulate the 5'-terminal oligopyrimidine (5'-TOP) motif in ribosomal mRNAs. These findings open a new avenue for antiviral development by targeting a previously unexplored host pathway.
{"title":"Sulfonyl Anthranilic Acid Analogues Display Pan-Serotype Anti-Dengue Activity by Downregulating the Expression of Ribosomal Proteins Encoded by 5'-Terminal Oligopyrimidine Motif-Containing mRNA.","authors":"Chin Piaw Gwee,Tommaso Felicetti,Kitti Wing Ki Chan,Min Jie Alvin Tan,Muhammad Danial Bin Mohd Mazlan,Ciro Milite,Giacomo Pepe,Chiara Sarnari,Xiao Dan Ng,Wint Wint Phoo,Jasmine Hwee Yee Tan,Marcus G Mah,Satoru Watanabe,Jing Xiu Huang,Serena Massari,Oriana Tabarrini,Stefano Sabatini,Pietro Campiglia,Gianluca Sbardella,Gavin J D Smith,Sylvie Alonso,Alfred Xuyang Sun,Radoslaw M Sobota,Subhash G Vasudevan,Giuseppe Manfroni","doi":"10.1021/acs.jmedchem.5c03414","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03414","url":null,"abstract":"Dengue virus (DENV) remains a major global health concern without effective treatments. Previously, we identified sulfonyl anthranilic acid (SAA) derivatives (compounds 1 and 2) as potent pan-DENV inhibitors, likely targeting a primate-specific factor. Here, mass spectrometry-based target deconvolution revealed that SAA compounds downregulate ribosomal protein expression, some of which are essential for DENV replication, as confirmed by siRNA-knockdown studies. This novel mechanism aligns with the broad-spectrum antiviral activity of compounds 1 and 2. Moreover, compound 1 was also effective against the Zika virus in a human brain organoid model. The subsequent medicinal chemistry optimization process resulted in the identification of compound 7, which demonstrated an EC50 value of 50 nM against DENV-2, promising broad-spectrum potential and favorable in vitro ADME properties. Further studies indicated that these compounds modulate the 5'-terminal oligopyrimidine (5'-TOP) motif in ribosomal mRNAs. These findings open a new avenue for antiviral development by targeting a previously unexplored host pathway.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"76 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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