Here, the anti-malarial activity of two gold(I) phosphine compounds auranofin and [Au(d2pype)₂]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with [Au(d2pype)₂]Cl (1 or 2 μM) or auranofin (2 μM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days post inoculation. In some experiments, there was microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type P. chabaudi AS. In experiments where microscopically detectable parasites were observed following in vivo inoculation, mice were subsequently fully protected against a challenge infection with wildtype parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit P. chabaudi AS growth in vivo when administered orally. Gold compounds act via the inhibition of antioxidant systems which are critical in the pathogen's survival from attack by the host oxidants. In vitro, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand, in vivo, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of P. falciparum and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.

中文翻译：

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金（i）膦化合物可作为疟疾疫苗和药物开发的寄生虫减毒剂†

在这里，研究了两种金（I）膦化合物金诺芬和[Au（d2pype）₂ ] Cl（其中d2pype为1,2-双（二-2-吡啶基膦基膦基）乙烷）的抗疟活性。作为潜在的药物和疟疾寄生虫减毒剂。在体外，这些金化合物对恶性疟原虫和诺氏疟原虫以及啮齿类寄生虫chabaudi AS具有活性。观察寄生虫的衰减时小鼠用接种P. chabaudi AS感染处理过的红血细胞在体外与[AU（d2pype）₂] Cl（1或2μM）或金诺芬（2μM）进行2或3 h。定量PCR数据显示，接种后长达8天，寄生虫DNA的含量仍然很低。在一些实验中，接种后存在显微镜下可检测到的寄生虫病，随后清除。接受1或3剂金化合物处理过的寄生红细胞（pRBC）后，当这些小鼠随后受到野生型Chabaudi AS攻击时，未观察到保护作用。在体内接种后观察到显微镜下可检测到的寄生虫的实验中，随后为小鼠提供了全面保护，使其免受野生型寄生虫的攻击感染。在感染和治疗的啮齿动物模型中，金化合物无法抑制沙巴氏假单胞菌的生长口服时在体内。金化合物通过抑制抗氧化剂系统起作用，这对病原体免受宿主氧化剂攻击至关重要。在体外，它们直接抑制寄生虫硫氧还蛋白还原酶，因此具有抑制活性。另一方面，在体内，金化合物可能不容易被吸收，因此需要进行药代动力学研究以进一步检查给药后的药物生物利用度。通过鉴定恶性疟原虫和人类宿主的氧化还原机制的结构差异，可以更好地设计金化合物以更有效地靶向并选择性抑制寄生虫。