Axis 1
Medicinal chemistry of redox biosensors

   Evidence of a glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones has recently been validated as a new strategy to combat malarial parasites. The concept is being applied to the search of novel antischistosmal agents.

   From lead redox-active compounds exhibiting high potencies to specifically kill pathogens (Plasmodium, Schistosoma, Trypanosoma, HIV & HCV virus) work is aimed at producing prodrugs, and/or metabolically-resistant lead analogues with improved pharmacokinetic profile to decrease drug elimination in the host. The preparation of putative metabolites generated in the cells (host cells, pathogens) is also investigated in each lead series, including biaryls, sulfoxides & sulfones, and xanthones.

Axis 2
Total synthesis of (pro-)redox-cyclers

   A platform of exploratory synthetic routes of polysubstituted naphthoquinones, flavones, xanthones, cyclic ketones, and (aza)analogues was established to introduce functionalities at any specific position on the phenyl ring of the lead molecules to improve the pharmacokinetics on demand.

   The control of the regiochemistry of polysubstituted (pseudo)naphthoquinones and their (aza)analogues is made possible by Diels-Alder cycloadditions. The advanced chemistry involves synthetic methodologies for the preparation of starting-blocks applied in large scale by inexpensive “green chemistry” compatible with industrial processes.

Axis 3
Enzymology and redox equilibrium

   Structure-activity relationships are investigated through drug-target interactions. Studies on fluorinated suicide-substrates showed that the glutathione reductase-catalyzed bioactivation of naphthoquinones is essential for the observed antimalarial activity of our lead compounds.

   The results from our interdisciplinary approach provide detailed insight into the understanding of how redox-cyclers interfere with the putative negative cooperativity of the glutathione reductase toward NADPH binding and how this property can be exploited for disulfide reductase-catalyzed drug bioactivation as a general concept to open a new perspective in medicinal chemistry. Mechanism of this negative cooperativity towards NADPH binding orientates the future direction of our investigations to other parasitic diseases.

Axis 4
Physicochemistry & electrochemistry

   The aim of our physico-biochemical approach is to provide deeper insights into the understanding of the mechanism of action of 1,4-naphthoquinone redox cyclers toward parasitic pathogens (Plasmodium, Schistosoma) and of the role of metal ions in the antiviral properties of novel polyphenolic compounds which efficiently targets lipid-enveloped virus (HIV & HCV).

   The physico-biochemical platform is based on complementary analytical tools such as absorption and emission spectrophotometries, fast kinetic methods, electrochemistry and potentiometry.