Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability.

中文翻译：

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萜烯醌对婴儿利什曼原虫的抗利什曼活性及其对利什曼原虫拓扑异构酶IB的影响。

利什曼原虫病是引起内脏利什曼病的病原学病原体，内脏利什曼病是一种广泛传播于世界各地的严重的寄生虫传播疾病。抗药性菌株的出现使传统疗法的疗效降低。因此，需要新的更好的药物。萘醌是令人感兴趣的化合物，已针对其描述了许多药理特性，包括杀螨活性。这项工作显示了从天然萜类化合物（如月桂烯和肉豆蔻酸）获得的两个系列的萜烯-1,4-萘醌（NQ）和1,4-蒽醌（AQ）的抗衰老作用。他们针对转基因iRFP-婴儿利什曼原虫菌株进行了体外和离体评估，并在肝HepG2细胞上进行了测试以确定其选择性指数。结果表明，NQ衍生物显示出比AQ类似物更好的抗菌活性，其中，具有二乙酰化氢醌部分的化合物比其相应的醌具有更好的结果。关于萜烯前体，得自单萜类月桂烯的化合物对哺乳动物细胞显示出良好的抗寄生虫功效和低细胞毒性，而衍生自二萜类化合物的化合物显示出更好的无选择性抗菌活性。为了探索其作用机理，已经测试了所有化合物作为利什曼原虫IB型DNA拓扑异构酶的潜在抑制剂，但是只有一些具有醌环的化合物才能在体外抑制重组酶。这一事实以及对LTopIB的对接研究表明存在另一种作用机制，可以替代或补充LTopIB抑制作用。在计算机模拟中，最好的杀菌剂化合物的ADME评估显示出可预测的良好可药物性。