Amrendra Kumar, Yuexin Li, Rozalia A. Dodean, Alison Roth, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Patricia J. Lee, Brandon S. Pybus, Monica Martin, Kristina Pannone, Hieu T. Dinh, Cameron Blount, Ravi Chetree, Jesse DeLuca, Martin Evans, Robert Nadeau, Chau Vuong, Susan Leed, Chad Black, Jason Sousa, Christina Nolan, Frida G. Ceja, Stephanie A. Rasmussen, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Matthias Rottmann, Pamela Orjuela-Sanchez, Stephan Meister, Elizabeth A. Winzeler, Michael J. Delves, Holly Matthews, Jake Baum, Robert W. Kirby, Jeremy N. Burrows, James Duffy, David H. Peyton, Kevin A. Reynolds*, Jane X. Kelly* and Papireddy Kancharla*,
{"title":"tamjamines作为快速多阶段抗疟药","authors":"Amrendra Kumar, Yuexin Li, Rozalia A. Dodean, Alison Roth, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Patricia J. Lee, Brandon S. Pybus, Monica Martin, Kristina Pannone, Hieu T. Dinh, Cameron Blount, Ravi Chetree, Jesse DeLuca, Martin Evans, Robert Nadeau, Chau Vuong, Susan Leed, Chad Black, Jason Sousa, Christina Nolan, Frida G. Ceja, Stephanie A. Rasmussen, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Matthias Rottmann, Pamela Orjuela-Sanchez, Stephan Meister, Elizabeth A. Winzeler, Michael J. Delves, Holly Matthews, Jake Baum, Robert W. Kirby, Jeremy N. Burrows, James Duffy, David H. Peyton, Kevin A. Reynolds*, Jane X. Kelly* and Papireddy Kancharla*, ","doi":"10.1021/acsinfecdis.4c0065910.1021/acsinfecdis.4c00659","DOIUrl":null,"url":null,"abstract":"<p >Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Notably, our lead candidate <b>1</b> (KAR425) displays excellent oral efficacy with complete clearance of parasites within 72 h of treatment in the humanized <i>Plasmodium falciparum</i> (NOD-scid) mouse model at 50 mg/kg × 4 days. Profiling of compound <b>1</b> demonstrated a fast <i>in vitro</i> killing profile. In addition, several other tambjamine analogues cured erythrocytic <i>Plasmodium yoelii</i> infections after oral doses of 30 and 50 mg/kg × 4 days in a murine model while exhibiting good safety and metabolic profiles. This study presents the first account of multiple-stage antiplasmodial activities with rapid killing profile in the tambjamine family.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":"10 12","pages":"4291–4300 4291–4300"},"PeriodicalIF":3.8000,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tambjamines as Fast-Acting Multistage Antimalarials\",\"authors\":\"Amrendra Kumar, Yuexin Li, Rozalia A. Dodean, Alison Roth, Diana Caridha, Michael S. Madejczyk, Xiannu Jin, William E. Dennis, Patricia J. Lee, Brandon S. Pybus, Monica Martin, Kristina Pannone, Hieu T. Dinh, Cameron Blount, Ravi Chetree, Jesse DeLuca, Martin Evans, Robert Nadeau, Chau Vuong, Susan Leed, Chad Black, Jason Sousa, Christina Nolan, Frida G. Ceja, Stephanie A. Rasmussen, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Matthias Rottmann, Pamela Orjuela-Sanchez, Stephan Meister, Elizabeth A. Winzeler, Michael J. Delves, Holly Matthews, Jake Baum, Robert W. Kirby, Jeremy N. Burrows, James Duffy, David H. Peyton, Kevin A. Reynolds*, Jane X. Kelly* and Papireddy Kancharla*, \",\"doi\":\"10.1021/acsinfecdis.4c0065910.1021/acsinfecdis.4c00659\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. 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Tambjamines as Fast-Acting Multistage Antimalarials
Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Notably, our lead candidate 1 (KAR425) displays excellent oral efficacy with complete clearance of parasites within 72 h of treatment in the humanized Plasmodium falciparum (NOD-scid) mouse model at 50 mg/kg × 4 days. Profiling of compound 1 demonstrated a fast in vitro killing profile. In addition, several other tambjamine analogues cured erythrocytic Plasmodium yoelii infections after oral doses of 30 and 50 mg/kg × 4 days in a murine model while exhibiting good safety and metabolic profiles. This study presents the first account of multiple-stage antiplasmodial activities with rapid killing profile in the tambjamine family.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.