Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB

Abstract

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.

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced Form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone

“…Considering the couple avarone/avarol, we can notice that, as observed for the antiplasmodial effects, the reduced form (3) is substantially more potent than the oxidized form 1 on both investigated Leishmania parasites. This has been reported also for several antileishmanial naphthohydroquinones which resulted more active than the corresponding naphthoquinones [43]. Instead, the hydroquinone metabolite 3 and the thiazinoquinone 2 exhibited similar values of IC 50 in the range of low micromolar; however, avarol (3) showed a significantly higher SI (see Table 4).…”

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

“…Parameters for pophyllotoxin, etoposide, podophyllic aldehyde and 4 were assigned using ParamChem [ 50 , 51 ]. The overall procedure was similar to that used in Reference [ 52 ].…”

Antiprotozoal activity of natural products from Nigerien plants used in folk medicine

“…There are many reports on the Frontiers in Pharmacology frontiersin.org 10 antiparasitic activities and mechanisms of action of quinone derivatives. It was suggested that naphthoquinones could inhibit glycolysis (Prati et al, 2015), mitochondrial respiration (Salomão et al, 2013;Bombaça et al, 2018;Mendonca et al, 2018) and topoisomerase IB (Perez-Pertejo et al, 2019) in parasites. In addition, quinone derivatives are known to be inhibitors of cytochrome b in P. falciparum (Lane et al, 2018).…”