Journal of Medicinal Chemistry最新文献

Optimization of Tambjamines Active against Multiple Stages of Malaria Parasites 抗多期疟原虫的tamjamine优化研究

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-06-01 DOI: 10.1021/acs.jmedchem.5c00597

Amrendra Kumar, Yuexin Li, Xiaowei Zhang, Xiannu Jin, William E. Dennis, Ravi Chetree, Cameron Blount, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Kristina Pannone, Jesse DeLuca, Chau Vuong, Susan Leed, Hieu T. Dinh, Kennedy Mdaki, Rohit Mahato, Priyam Sen, Trisha Mondal, Karabi Phukan, Ankur Saha, Anongruk Chim-Ong, Liwang Cui, Rajachandrasekhar Valmon, Sivanna Chithanna, Rozalia A. Dodean, David H. Peyton, Stephen Orena, Jackson Assimwe, Innocent Tibagambirwa, Patrick Angutoko, Jennifer Legac, Oriana Kreutzfeld, Philip J. Rosenthal, Elodie Chenu, James Duffy, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla

{"title":"Optimization of Tambjamines Active against Multiple Stages of Malaria Parasites","authors":"Amrendra Kumar, Yuexin Li, Xiaowei Zhang, Xiannu Jin, William E. Dennis, Ravi Chetree, Cameron Blount, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Kristina Pannone, Jesse DeLuca, Chau Vuong, Susan Leed, Hieu T. Dinh, Kennedy Mdaki, Rohit Mahato, Priyam Sen, Trisha Mondal, Karabi Phukan, Ankur Saha, Anongruk Chim-Ong, Liwang Cui, Rajachandrasekhar Valmon, Sivanna Chithanna, Rozalia A. Dodean, David H. Peyton, Stephen Orena, Jackson Assimwe, Innocent Tibagambirwa, Patrick Angutoko, Jennifer Legac, Oriana Kreutzfeld, Philip J. Rosenthal, Elodie Chenu, James Duffy, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla","doi":"10.1021/acs.jmedchem.5c00597","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00597","url":null,"abstract":"Malaria remains a major global health challenge, demanding new therapies with novel mechanisms and multistage activity to overcome resistance. Previously, we developed a natural product-inspired novel antimalarial tambjamine chemotype that is potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Herein, we report a rigorous optimization strategy that expanded our chemical library and, more importantly, produced several lead tambjamines with excellent oral efficacy, while exhibiting feasible safety and metabolic profiles. Notably, KAR1123 (109) cured mice with erythrocytic Plasmodium yoelii infection after oral treatment of 25 mg/kg × 4 days or 80 mg/kg × 1 day and also provided partial protection against liver-stage Plasmodium berghei sporozoite-induced infection in mice. Profiling of compound 109 demonstrated a moderately fast in vitro parasite-killing profile. Furthermore, 109 displayed excellent potency against both artemisinin-resistant Plasmodium falciparum parasites and Ugandan P. falciparum clinical isolates.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189021","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}

引用次数: 0

Lysine-Targeted Covalent Strategy Leading to the Discovery of Novel Potent PROTAC-Based PI3Kδ Degraders 赖氨酸靶向共价策略导致发现新的有效的基于protac的PI3Kδ降解物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-31 DOI: 10.1021/acs.jmedchem.5c00408

Bo Yuan, Jiaxin Liu, Yujie Wu, Mengyao Chen, Ying Lai, Hong-Yi Zhao, Zhe Yang, San-Qi Zhang, Minhang Xin

{"title":"Lysine-Targeted Covalent Strategy Leading to the Discovery of Novel Potent PROTAC-Based PI3Kδ Degraders","authors":"Bo Yuan, Jiaxin Liu, Yujie Wu, Mengyao Chen, Ying Lai, Hong-Yi Zhao, Zhe Yang, San-Qi Zhang, Minhang Xin","doi":"10.1021/acs.jmedchem.5c00408","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00408","url":null,"abstract":"Proteolysis-targeting chimera (PROTAC) technology was employed to achieve the degradation of PI3Kδ in this study, and a series of PROTAC-based PI3Kδ degraders were first developed. Lysine-targeted covalent strategy led to the discovery of novel potent PROTAC-based PI3Kδ degraders. After screening and structure–activity relationship study, B14 was optimal and exhibited strong antiproliferation and selective PI3Kδ inhibition, with a high degradation value (DC50 = 3.98 nM). B14 induced cell cycle arrest in the premitotic phase and prompted cell apoptosis. B14 displayed effective suppression of the tumor growth in the xenograft model and significantly promoted the PI3Kδ degradation in vivo. Most importantly, B14 bound to the Lys779 of PI3Kδ to selectively degrade PI3Kδ by covalent-bonding. Mechanistic studies indicated that the ubiquitin-proteasome pathway was involved in the degradation process. This study provided an effective approach for developing PROTAC-based PI3Kδ degraders, and the lysine-targeted covalent strategy laid the foundation for the further design of potent PI3Kδ-targeting PROTACs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"6 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183901","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}

引用次数: 0

Novel Carbamate-Based o-aminobenzamide Derivatives as Potent Antigastric Carcinoma Agents via Disrupting NAD+ Salvage Synthesis 基于氨基苯甲酰胺的新型氨基苯甲酰胺衍生物通过破坏NAD+补救性合成作为有效的抗胃癌药物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-31 DOI: 10.1021/acs.jmedchem.4c02686

Siyi Zhang, Zhen Li, Bo Li, Zhiyi Li, Huiqian Peng, Lixian Shen, Lejing Zhu, Tong Mo, Jialiang Peng, Linsheng Zhuo, Zhen Wang, Weifan Jiang

{"title":"Novel Carbamate-Based o-aminobenzamide Derivatives as Potent Antigastric Carcinoma Agents via Disrupting NAD+ Salvage Synthesis","authors":"Siyi Zhang, Zhen Li, Bo Li, Zhiyi Li, Huiqian Peng, Lixian Shen, Lejing Zhu, Tong Mo, Jialiang Peng, Linsheng Zhuo, Zhen Wang, Weifan Jiang","doi":"10.1021/acs.jmedchem.4c02686","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02686","url":null,"abstract":"Blocking NAD+ biosynthesis presents an appealing strategy for antitumor therapies. This study developed a series of o-aminobenzamide derivatives with substantial antitumor efficacy against gastric cancer. Notably, compound 9a demonstrated exceptional antitumor activity against undifferentiated gastric cancer HGC27 cells (IC50 = 0.049 μM), and significant inhibitory effects on cellular proliferation, self-renewal, invasion, and migration. Mechanistic investigations revealed that 9a could damage mitochondria, arrest the cell cycle, promote apoptosis, and alter cellular metabolism. Furthermore, the rate-limiting enzyme NAMPT in the NAD+ salvage synthetic pathway was identified as a primary target of 9a. By inhibiting NAMPT, 9a reduced intracellular levels of NAD+ and ATP, while NMN, a natural product of NAMPT, counteracts its antimetabolic and cytotoxic effects. Overall, this study highlights 9a as a promising NAMPT inhibitor with significant activity against undifferentiated gastric cancer, laying the groundwork for developing novel antigastric cancer agents through inhibiting NAD+ biosynthesis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183904","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}

引用次数: 0

Discovery of Novel Potent Molecule for Treating Cisplatin-Induced Acute Kidney Injury Driven by Phenotypic Screening 通过表型筛选发现治疗顺铂所致急性肾损伤的新型有效分子

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-31 DOI: 10.1021/acs.jmedchem.5c00954

Yan Lou, Feilong Zhou, Daxing Shi, Yu Zhang, Jin Dong, Xiaobao Shen, Xing Chen, Xinhua Liu

{"title":"Discovery of Novel Potent Molecule for Treating Cisplatin-Induced Acute Kidney Injury Driven by Phenotypic Screening","authors":"Yan Lou, Feilong Zhou, Daxing Shi, Yu Zhang, Jin Dong, Xiaobao Shen, Xing Chen, Xinhua Liu","doi":"10.1021/acs.jmedchem.5c00954","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00954","url":null,"abstract":"Cisplatin-induced acute kidney injury (cis-AKI) is the primary organ toxicity that occurs during cisplatin-based cancer treatment, and currently, there is a lack of effective treatment methods. The occurrence of cis-AKI involves complex pathophysiological processes, therefore, phenotypic screening-based drug discovery may be more applicable for identifying lead compounds to treat cis-AKI. In this study, a cascading phenotypic screening was designed and implemented. Through this protocol, a potent compound, CX116, was obtained, which exhibits potent anti-inflammatory activity and effectively protects cells from cisplatin toxicity. Mechanism studies indicated that CX116 exerts its effects by inhibiting the inflammatory response, reducing oxidative stress, protecting mitochondrial function, and counteracting apoptosis. In vivo studies showed that CX116 bears acceptable toxicity and appropriate pharmacokinetic properties, and significantly protects renal tissue from cisplatin-induced damage in a cis-AKI animal model. In conclusion, CX116 is a highly promising active molecule and holds great potential for the development of therapeutic drugs for cis-AKI.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184110","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}

引用次数: 0

Rational Design of Novel Quinazolinone–Pyrrolodihydropyrrolone Analogs as PIM/HDAC Dual-Target Inhibitors for the Treatment of Acute Myelocytic Leukemia 新型喹唑啉酮-吡咯二氢吡咯酮类似物作为PIM/HDAC双靶点抑制剂治疗急性髓细胞白血病的合理设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-30 DOI: 10.1021/acs.jmedchem.5c00040

Yabing Xin, Can Xiao, Nan Wang, Huidan Wu, Wenjing Kang, Xuetao Chen, Chihong Liu, Qidong You, Zhengyu Jiang, Xiaoke Guo

{"title":"Rational Design of Novel Quinazolinone–Pyrrolodihydropyrrolone Analogs as PIM/HDAC Dual-Target Inhibitors for the Treatment of Acute Myelocytic Leukemia","authors":"Yabing Xin, Can Xiao, Nan Wang, Huidan Wu, Wenjing Kang, Xuetao Chen, Chihong Liu, Qidong You, Zhengyu Jiang, Xiaoke Guo","doi":"10.1021/acs.jmedchem.5c00040","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00040","url":null,"abstract":"Acute myeloid leukemia (AML) patients usually exhibit suboptimal responses after receiving single target drug therapy. Simultaneously targeting multiple oncogenic pathways is a promising strategy for cancer treatment. Herein, based on the synergistic antiproliferative capacity of the PIM inhibitor C28 and the HDAC inhibitor SAHA in MV4–11 cells, we developed a series of novel dual PIM/HDAC inhibitors. Among them, compound 22 exhibited potent antiproliferative activity in MV4–11 cells, along with robust inhibitory effects against both PIM1 and HDAC6. Flow cytometry analysis showed that 22 dose-dependently induced apoptosis in MV4–11 cells. Mechanistically, treatment with 22 remarkably induced the cleavage of PARP, thereby initiating apoptosis. Furthermore, 22 demonstrated significant anticancer efficacy (TGI = 81.3%; 50 mg/kg, QD) in the MV4–11 xenograft model without notable toxicity. In conclusion, our study established the therapeutic potential of dual PIM/HDAC inhibitors and provided a tool to elucidate synergistic mechanisms underlying the combined inhibition of these targets.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"129 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177257","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}

引用次数: 0

Developing Potent and Selective Anticancer Therapy through Chemical Approaches and the Combination of Cationic Amphipathic Oncolytic Peptides 通过化学方法和阳离子两亲性溶瘤肽的组合开发有效和选择性的抗癌疗法

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-30 DOI: 10.1021/acs.jmedchem.5c00699

Hai Bui Thi Phuong, Bao Loc Nguyen, Linyu Huang, Thi Oanh Oanh Nguyen, Ngoc Duy Le, Beomsu Kim, Basavaraj Rudragouda Patil, Thang Nguyen Quoc, Jeonghwan Kim, Huy Xuan Luong, and Jong Oh Kim

引用次数: 0

Harder than Metal: Challenging Antimicrobial Resistance with Metallo-β-lactamase Inhibitors 比金属更硬：金属β-内酰胺酶抑制剂挑战抗菌素耐药性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-30 DOI: 10.1021/acs.jmedchem.5c00553

Antonietta De Falco, Antonella Ilenia Alfano, Luigi Cutarella, Mattia Mori, Margherita Brindisi

引用次数: 0

Discovery of CYP1A1 Inhibitors for Host-Directed Therapy against Sepsis 发现CYP1A1抑制剂用于败血症的宿主定向治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-29 DOI: 10.1021/acs.jmedchem.5c00493

Fangjie Wang, Sheng-Li Niu, Wei Li, Hong-Yuan Liu, Xue Gong, Xiaoyuan Ma, Bo Zhao, Dongmei He, Jinyu Xia, Liang Gong, Yiqin Cui, Rui Gao, Huaping Liang, Jing Gu, Qin Ouyang

{"title":"Discovery of CYP1A1 Inhibitors for Host-Directed Therapy against Sepsis","authors":"Fangjie Wang, Sheng-Li Niu, Wei Li, Hong-Yuan Liu, Xue Gong, Xiaoyuan Ma, Bo Zhao, Dongmei He, Jinyu Xia, Liang Gong, Yiqin Cui, Rui Gao, Huaping Liang, Jing Gu, Qin Ouyang","doi":"10.1021/acs.jmedchem.5c00493","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00493","url":null,"abstract":"Bacterial sepsis remains a leading cause of death globally, exacerbated by the rise of multidrug resistance (MDR). Host-directed therapy (HDT) has emerged as a promising nonantibiotic approach to combat infections; thus, multiple HDT targets have been identified. However, the translation of HDT targets into therapeutic drugs, particularly small-molecule drugs, remains rare. Our study focuses on cytochrome P4501A1 (CYP1A1), a negative regulator of host antiinfection capabilities. Using deep learning, virtual screening, and biological evaluation, we identified novel small-molecule inhibitors of CYP1A1. After structural optimization, compounds 38 and 47 demonstrated exceptional activity, reducing bacterial loads of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by over 70% by enhancing macrophage phagocytosis. This work highlights CYP1A1 as a valuable HDT target and shows that inhibiting it with a single small-molecule compound can offer a potential solution to treat MDR bacterial-induced sepsis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"166 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177127","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}

引用次数: 0

Correction to “A NIR-II Photoacoustic/NIR-IIa Fluorescent Probe for Targeted Imaging of Glioma under NIR-II Excitation” 修正“NIR-II光声/NIR-IIa荧光探针在NIR-II激发下靶向成像胶质瘤”

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-29 DOI: 10.1021/acs.jmedchem.5c01290

Shuxin Lyu, Siyu Lu, Conghao Gui, Chunyan Guo, Juanjuan Han, Yuling Xiao, Ruiping Zhang, Xuechuan Hong

引用次数: 0

Design of an Oral STING Agonist through Intramolecular Hydrogen Bond Ring Mimicking to Achieve Complete Tumor Regression 通过分子内氢键环模拟设计口服STING激动剂实现肿瘤完全消退

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-05-29 DOI: 10.1021/acs.jmedchem.5c00296

Hong-Yi Zhao, Jinsong Tao, Luchen Zhang, Qiuxia Li, Miao He, Bo Wen, Zhongwei Liu, Hannah Myatt, Duxin Sun

引用次数: 0