In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives

Abstract

BackgroundPlasmodium 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.ResultsThe 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 IC50 = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC50 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.ConclusionsThese 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.

PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

“…In addition to MMV085203, GNF-Pf-3600, and atovaquone, the pfmfr3 Q487E single point mutant also showed 3-fold resistance against another compound with a naphthoquinone group, GNF-Pf-3703 (data not shown). If this is indeed the case, MFR3 activity could be a significant correlate of resistance against a multitude of candidate antimalarials given that naphthoquinone derivatives have immense potential as antiplasmodial leader molecules and have been widely used for the development of many compound series. ,− Importantly, polymorphisms in pfmfr3 have been found to naturally exist in parasite populations in the field with over 50% occurring in transmembrane domains . Although none of the genetic alterations that were identified in this study have been documented in clinical isolates, one cannot rule out the possibility of these natural mutations leading to modifications in transporter activity and specificity and eventually contributing to clinical drug resistance.…”

In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in Leishmania spp.

“…Other derivatives also seem to act as inhibitors of P. falciparum isoprenoid biosynthesis. This pathway is formed by menaquinone (vitamin K2) and α-tocopherol (vitamin E) employed in the electron carriage, in the mitochondrial respiratory chain, and protection the membranes against peroxidation, respectively [57]. These vitamins are derived from quinones, indicating a possible mechanism of action for hydroxynaphthoquinone based on their chemical core.…”

A robust computational quest: Discovering potential hits to improve the treatment of pyrazinamide‐resistant Mycobacterium tuberculosis

“…In this study, a variety of in silico tools were selected to investigate the physicochemical and medicinal chemistry properties of the ligands, focusing on their ADMET profile. The selection of these tools was supported by their demonstrated validity and extensive validation in the scientific literature 27–29 . FAF‐Drugs4, Lipinski violations, Veber rule, Egan rule, solubility forecast index, Het/carbon ratio, and total charge analysis, served as a fundamental tool for preliminary filtering of the compound libraries 30–32 .…”