tamjamines作为快速多阶段抗疟药

IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL
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*, 
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引用次数: 0

摘要

能够对抗寄生虫生命周期多个阶段的耐受性良好的新型抗疟药是人们所期望的,但发现和开发这种药物却具有挑战性。在此,我们报告了受天然产物启发的新型坦布加明抗疟药物的研究成果。我们发现,它们对肝脏、无性红细胞和有性红细胞寄生虫的生命周期各阶段都有很强的抑制作用。值得注意的是,在人源化恶性疟原虫(NOD-scid)小鼠模型中,我们的主要候选化合物 1(KAR425)显示出卓越的口服疗效,在 50 mg/kg × 4 天的剂量下,72 小时内就能完全清除寄生虫。对化合物 1 的分析表明,其体外杀灭谱速度很快。此外,其他几种坦布加明类似物在小鼠模型中口服 30 毫克/千克和 50 毫克/千克 × 4 天的剂量后,可治愈红细胞疟原虫感染,同时表现出良好的安全性和代谢特征。本研究首次介绍了坦布加明家族中具有快速杀灭特征的多阶段抗疟活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Tambjamines as Fast-Acting Multistage Antimalarials

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.

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来源期刊
ACS Infectious Diseases
ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES
CiteScore
9.70
自引率
3.80%
发文量
213
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.
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