Synthesis of plasmodione metabolites and¹³C-enriched plasmodione as chemical tools for drug metabolism investigation

Abstract

Malaria is a tropical parasitic disease threatening populations in tropical and sub-tropical areas. Resistance to antimalarial drugs has spread all over the world in the past 50 years, thus new drugs are urgently needed. Plasmodione (benzylmenadione series) has been identified as a potent antimalarial early lead drug, acting through a redox bioactivation on asexual and young sexual blood stages. To investigate its metabolism, a series of plasmodione-based tools, including a fully 13C-labelled lead drug and putative metabolites, have been designed and synthesized for drug metabolism investigation. Furthermore, with the help of UHPLC-MS/MS, two of the drug metabolites have been identified from urine of drug-treated mice.

A Mild and Versatile Friedel–Crafts Methodology for the Diversity‐Oriented Synthesis of Redox‐Active 3‐Benzoylmenadiones with Tunable Redox Potentials

“…Photo‐Friedel–Crafts acylation of NQs with a large stoichiometric excess of aromatic aldehydes provided the 2‐benzoyl‐dihydronaphthalene derivatives (Scheme ) . Previous work to synthesize 3‐benzoylmenadione derivatives 1 was based on the formation of a carbanion after i) bromination of the reduced and protected form of menadione, that is, the 1,4‐dimethoxy‐2‐methylnaphthalene, ii) halogen/metal exchange, followed by iii) addition of benzoyl chloride to give 2‐benzoyl‐3‐methyl‐1,4‐dimethoxynaphthalene derivatives 2 , and finally, iv) oxidative demethylation by cerium ammonium nitrate (CAN, Scheme ) …”

Free‐radical Initialized Cyclization of 2‐(3‐Arylpropioloyl)benzaldehydes with Toluene Derivatives: Access to Benzylated 1,4‐Naphthoquinones via Copper‐Catalyzed Cascade Reaction

“…Functionalized 1,4‐naphthoquinones represent important heterocyclic structural units that can be found widerly distributed in a variety of natural products and pharmaceuticals, [1] including Vitamin K analogues, P2X7R inhibitors, [2] glutathione reductase inhibitors, [3] and potential anticancer agents [4] . Specifically, benzylated 1,4‐naphthoquinones have demonstrated suitable antimalarial activity, [5] glutathione reductase inhibition, [6] and anti ‐oesophageal cancer [7] activity (Figure 1). Thus, the development of a practical and efficient method to synthesize benzylated 1,4‐naphthoquinones represents a critical goal in synthetic organic chemistry and drug development.…”

A Class of Valuable (Pro-)Activity-Based Protein Profiling Probes: Application to the Redox-Active Antiplasmodial Agent, Plasmodione

“…10–50-fold higher than the corresponding 3-benzylmenadiones. 17 , 21 This may be explained by the very poor internalization of 3-benzoylmenadione metabolites in pRBCs when given externally. Indeed, similar to the 3-benzoylmenadione metabolite PDO , probes 6 – 10 ( Figure 1 ) are more polar and planar than the 3-benzylmenadiones ( PD , probes 5 and 11 ), likely reducing their ability to be internalized in parasites, and in accordance with the same observation in the yeast model.…”

“…Hence, PD activation via PDO -mediated redox-cycling most likely results in the specific removal and clearance of the parasitized RBCs (pRBC). 20 , 21 …”