Half of the world's population lives in countries at risk of malaria infection, which results in approximately 450,000 deaths annually. Malaria parasites infect erythrocytes in a coordinated manner, with cycle durations in multiples of 24 hours, which reflects a behavior consistent with the host's circadian cycle. Interference in cycle coordination can help the immune system to naturally fight infection. Consequently, there is a search for new drugs that interfere with the cycle duration for combined treatment with conventional antimalarials. Melatonin appears to be a key host hormone responsible for regulating circadian behavior in the parasite cycle. In addition to host factors, there are still unknown factors intrinsic to the parasite that control the cycle duration. In this review, we present a series of reports of indole compounds and melatonin derivatives with antimalarial activity that were tested on several species of Plasmodium to evaluate the cytotoxicity to parasites and human cells, in addition to the ability to interfere with the development of the erythrocytic cycle. Most of the reported compounds had an IC50 value in the low micromolar range, without any toxicity to human cells. Triptosil, an indole derivative of melatonin, was able to inhibit the effect of melatonin in vitro without causing changes to the parasitemia. The wide variety of tested compounds indicates that it is possible to develop a compound capable of safely eliminating parasites from the host and interfering with the life cycle, which is promising for the development of new combined therapies against malaria.

中文翻译：

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褪黑激素在疟原虫感染中的作用：寻找调节无性周期的分子作为削弱寄生虫周期的策略

世界上一半的人口生活在有感染疟疾风险的国家，每年约有 450,000 人因此死亡。疟疾寄生虫以协调的方式感染红细胞，周期持续时间为 24 小时的倍数，这反映了与宿主昼夜节律一致的行为。干扰周期协调可以帮助免疫系统自然地对抗感染。因此，需要寻找干扰与常规抗疟药联合治疗的周期持续时间的新药。褪黑激素似乎是一种关键的宿主激素，负责调节寄生虫周期中的昼夜节律行为。除了寄主因素外，控制周期持续时间的寄生虫固有的未知因素仍然存在。在这次审查中，疟原虫评估对寄生虫和人体细胞的细胞毒性，以及干扰红细胞循环发展的能力。大多数报道的化合物具有低微摩尔范围内的 IC50 值，对人体细胞没有任何毒性。Triptosil 是一种褪黑激素的吲哚衍生物，能够在体外抑制褪黑激素的作用，而不会引起寄生虫血症的变化。测试的化合物种类繁多，表明有可能开发出一种能够安全地从宿主体内消除寄生虫并干扰生命周期的化合物，这对于开发抗疟疾的新联合疗法很有希望。