Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla
{"title":"优化 B 环功能化抗疟坦贾明和丙二炔类化合物","authors":"Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla","doi":"10.1021/acs.jmedchem.4c02093","DOIUrl":null,"url":null,"abstract":"Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic <i>Plasmodium</i> parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic <i>Plasmodium yoelii</i> infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage <i>Plasmodium berghei</i> sporozoite-induced infection in mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines\",\"authors\":\"Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla\",\"doi\":\"10.1021/acs.jmedchem.4c02093\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic <i>Plasmodium</i> parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic <i>Plasmodium yoelii</i> infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage <i>Plasmodium berghei</i> sporozoite-induced infection in mice.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c02093\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c02093","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines
Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic Plasmodium parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic Plasmodium yoelii infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage Plasmodium berghei sporozoite-induced infection in mice.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.