Abstract
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.
Highlights
Visceral leishmaniasis (VL) is a serious zoonotic disease caused by parasites of Gen
Indenoisoquinolines belong to a family of non-CPT compounds that were initially synthesized as anticancer drugs, and whose mechanism of action is based on topoisomerase IB (TopIB) poisoning
The battery of indenoisoquinolines studied in this work emphasizes mainly the modifications in the N-6 position of the heterocyclic system, which has been shown to generate better inhibitors of TopIB with antitumor effects (Morrell et al, 2007) and improved trypanocide activity (Bakshi et al, 2009)
Summary
Visceral leishmaniasis (VL) is a serious zoonotic disease caused by parasites of Gen. First-choice drugs are based on organic complexes of pentavalent antimony (SbV), which are losing effectiveness due to excessive use and lack of replacement (Frézard et al, 2009; Bush et al, 2017). A single dose of a liposomal suspension of amphotericin B (AmBisome) (Sundar et al, 2010), and the oral drug miltefosine (Bhattacharya et al, 2007), are being used as second-line treatments, either alone or in combination with SbV (Kimutai et al, 2017). In the case of AmBisome, its use is limited due to, poor chemical stability at the point of care and its mandatory intravenous route of administration (Stone et al, 2016; Jensen, 2017). The urgency of new antileishmanial drugs based on validated objectives is a real need, especially when big pharmaceutical companies are recently committed to invest more funds and efforts in the development of novel treatments
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