了解抗药性难治性黄嘌呤喹诺酮 A1 的抗疟作用。

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL ACS Infectious Diseases Pub Date : 2024-05-29 DOI:10.1021/acsinfecdis.4c00232

Jennifer E. Collins, Tiantian Jiang, Jin Woo Lee, Karen Wendt, Flore Nardella, Jin Jeon, Raphaella Paes, Natalia Mojica Santos, Frances Rocamora, Maya Chang, Samuel Schaefer, Robert H. Cichewicz*, Elizabeth A. Winzeler* and Debopam Chakrabarti*,

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引用次数: 0

摘要

我们以前的工作发现了一系列 12 种黄酮类似物和 2 种大黄素二蒽酮类化合物，它们对阴道毛滴虫、生殖器支原体、副隐孢子虫和恶性疟原虫具有广谱活性。本研究中进行的分析表明，活性最强的类似物黄酮喹啉 A1 还能抑制弓形虫速殖体和疟原虫的肝阶段，对已知的抗疟靶标 PfACS、PfCARL、PfPI4K 或 DHODH 没有交叉耐药性。对疟原虫的抑制发生在多核化之前，并在接触化合物 12 小时后诱导寄生虫死亡。黄嘌呤喹诺酮 A1 在淋球菌和恶性疟原虫中都表现出不可抵抗的表型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Understanding the Antiplasmodial Action of Resistance-Refractory Xanthoquinodin A1

Our previous work identified a series of 12 xanthoquinodin analogues and 2 emodin-dianthrones with broad-spectrum activities against Trichomonas vaginalis, Mycoplasma genitalium, Cryptosporidium parvum, and Plasmodium falciparum. Analyses conducted in this study revealed that the most active analogue, xanthoquinodin A1, also inhibits Toxoplasma gondii tachyzoites and the liver stage of Plasmodium berghei, with no cross-resistance to the known antimalarial targets PfACS, PfCARL, PfPI4K, or DHODH. In Plasmodium, inhibition occurs prior to multinucleation and induces parasite death following 12 h of compound exposure. This moderately fast activity has impeded resistance line generation, with xanthoquinodin A1 demonstrating an irresistible phenotype in both T. gondii and P. falciparum.

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来源期刊

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.