No abstract

A platform of synthetic methodologies has been established to access a focused library of polysubstituted 3‐benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α‐tetralone or a propiophenone, and 2) the regioselective Diels–Alder reaction, starting from various dienes and two 2‐bromo‐5(or 6)‐methyl‐1,4‐benzoquinones. 6‐Substituted 2‐methylnaphthols were synthesized by using a xanthate‐mediated free‐radical addition/cyclization sequence for the construction of the 6‐substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of 6‐ or 7‐substituted 3‐(substituted‐benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds have allowed structure–activity relationships to be deduced for use as the basis for the development of new antimalarial redox‐active polysubstituted benzylmenadione derivatives.

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.