PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp.

Abstract

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity OPEN ACCESSMolecules 2015, 20 10083 against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol.

Antioxidant and Anti-Inflammatory Activities of the Crude Extracts of Raw and Fermented Tomato Pomace and Their Correlations with Aglycate-Polyphenols

“…This chemometric method was able to identify: (i) molecules with more activity in a mixture, (ii) synergistic and antagonistic effects when testing vegetal extracts as fingerprints vs. bioactivity [16,17].…”

Structure‐activity relationship studies on naphthoquinone analogs. The search for new herbicides based on natural products

“…The molecular mechanisms of naphthoquinones in cells mainly fall into two categories: (i) they induce oxidative stress by generation of reactive oxygen species (ROS) involving processes such as inhibition of electron transport and cellular respiration, and (ii) they interact directly with traditional therapeutic targets in a non‐oxidative mechanism . These chemical properties make naphthoquinones promising leads for new applications and favorable structures in medicinal chemistry, and this has led to a marked increase in the number of studies in recent years .…”

“…The molecular mechanisms of naphthoquinones in cells mainly fall into two categories: (i) they induce oxidative stress by generation of reactive oxygen species (ROS) involving processes such as inhibition of electron transport and cellular respiration, and (ii) they interact directly with traditional therapeutic targets in a non-oxidative mechanism. [7][8][9] These chemical properties make naphthoquinones promising leads for new applications and favorable structures in medicinal chemistry, and this has led to a marked increase in the number of studies in recent years. 10,11 Nevertheless, quinones have been confirmed as Pan Assay INterference compoundS or PAINS due to their multifunctional mechanism of action, which could cause interference in assay readouts used in high-throughput screening (HTS), including target-based assay such as Kv1.3 K + channel or a phenotypic assay.…”

Influence of lipophilicity in O‐acyl and O‐alkyl derivatives of juglone and lawsone: a structure–activity relationship study in the search for natural herbicide models

“…In addition to their properties as natural pigments, a broad range of biological activities have been described for these compounds, for example, antifungal, phytotoxic, anti‐inflammatory, antioxidant and anticancer properties . These effects are mainly ascribed to the ability of naphthoquinones to generate reactive oxygen species (ROS) and also the electrophilicity of the quinone moiety in reactions with different biological targets through a 1,4‐Michael addition involving the nucleophilic thiol species, proteins, DNA and RNA …”

“…[1][2][3][4][5] These effects are mainly ascribed to the ability of naphthoquinones to generate reactive oxygen species (ROS) and also the electrophilicity of the quinone moiety in reactions with different biological targets through a 1,4-Michael addition involving the nucleophilic thiol species, proteins, DNA and RNA. [6][7][8][9][10] Plants that contain naphthoquinones have been used worldwide since ancient times to treat, for example, gastrointestinal disorders or herpes. 11 Within this family of compounds are two interesting biologically active naphthoquinones that are the focus of this work: juglone (5-hydroxy-1,4-naphthoquinone) and lawsone (2-hydroxy-1,4-naphthoquinone).…”