Laboratório de Biologia da Malária e Toxoplasmose - LABMAT, Departmento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
Post-graduate Program in Biochemistry, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.
Malar J. 2018 Dec 19;17(1):482. doi: 10.1186/s12936-018-2615-8.
Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones.
The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol.
These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.
恶性疟原虫已经表现出多种药物耐药性，因此需要开发具有新作用靶点的新药，例如合成异戊烯前体，这是一个很好的靶点，因为该途径与人类宿主相比在多个步骤上存在差异。萘醌衍生物已被描述为具有发展抗疟先导分子的潜力。鉴于此，本工作重点有两个方面：首先，评估萘醌类化合物的体外抗疟活性和细胞毒性；其次，研究两种羟基萘醌衍生物的一种可能作用机制。
两种羟基萘醌衍生物已在体外针对恶性疟原虫进行了测试，使用氯喹敏感（3D7）和氯喹耐药（Dd2）寄生虫株，导致寄生虫生长的 50%抑制浓度在 7 到 44.5μM 之间变化。体外对 RAW 细胞系的细胞活力显示 IC50 值为 483.5 和 714.9μM，而在使用鼠巨噬细胞的原代培养试验中，两种选定化合物的 IC50 值分别为 315.8 和 532.6μM，在测试剂量下不会引起溶血。体内急性毒性试验表明，由于缺乏系统性和行为毒性，安全性显著，高达 300mg/kg 也没有毒性。据推测，该药物似乎抑制了异戊烯化合物的生物合成，特别是甲萘醌和生育酚。
这些衍生物具有开发新型抗疟药物的巨大潜力，因为它们具有低毒性，同时具有令人满意的抗疟活性和可能抑制与哺乳动物宿主中发现的途径不同的代谢途径。
