DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania.

中文翻译：

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拓扑异构酶IB毒物诱导组蛋白H2A磷酸化，作为对婴儿利什曼原虫DNA损伤的反应。

DNA拓扑异构酶被认为是对抗锥虫病所致疾病的巩固药物靶标。几篇报道指出，基于异环喜树碱的拓扑异构酶毒物的茚并异喹啉在内脏利什曼病的小鼠模型中，在体外和体内均具有很强的利什曼杀菌作用。茚并异喹啉的抗衰老作用暗示了几种机制，包括裂解复合物的稳定，组蛋白H2A磷酸化和DNA片段化。在前鞭毛体和从实验鼠感染中获得的巨噬细胞内脾变形虫中都测试了一系列20种化合物，这些化合物具有茚并异喹啉骨架和N6，C3，C8和C9位上的几个取代基。这些化合物中大多数的抗霉菌作用在微摩尔或亚微摩尔范围内。另外，在茚并异喹啉环（7-氮杂茚并异喹啉）中引入N原子产生了最高的选择性指数，以及强烈的DNA拓扑异构酶IB抑制，组蛋白H2A磷酸化和DNA拓扑异构酶IB复合物稳定作用。该报告首次显示了一系列合成的茚并异喹啉对组蛋白H2A磷酸化的影响，这代表利什曼原虫属双链DNA断裂的主要信号。