Redox-active 1,4-naphthoquinones to kill malarial and schistosomal parasites – SCHISMAL

Our previous work led to the selection of potent antimalarial 2-benzyl-3-methyl-1,4-naphthoquinones (benzylNQ) active against various multi-resistant strains of Plasmodium falciparum and in P. berghei-infected mice (intraperitonnally and per os) and not toxic in animals. The compounds are devoid of cytoxicity and do not trigger hemolysis of erythrocytes at more than 1000-fold the effective dose. Our findings suggest that antimalarial lead benzylNQ act as redox-cyclers being biometabolized through a cascade of redox reactions by a heme-catalysed oxidation reaction under the specific conditions found in the food vacuole of the parasites, and then by a glutathione reductase-catalyzed reduction in the cytosol. The biometabolites, the benzoyl analogues (benzoylNQ) were shown to act as the most efficient subversive substrates of the parasitic glutathione reductase (GR) described so far and to redox-cycle methemoglobin(Fe3+) to oxyhemoglobin(Fe2+). Benzxanthones are proposed to be the final biometabolites generated through the cascade of redox reactions. Ultimately, the parent antimalarial benzylNQ are suggested to affect the redox equilibrium resulting in trophozoite development arrest, by drowning the parasite in its own metabolic products. More recently, among the less potent antimalarial benzylNQ, a new set of 1,4-naphthoquinones analogues – distinct chemical functionalities on the 1,4-naphthoquinone core – was discovered to display potent antischistosomal effects in vitro and in vivo.
Lead optimization of the two series of antiparasitic redox-active compounds (antimalarial or antischistosomal) is the focus of the present project including (1) the identification of unproductive biometabolites responsible for drug elimination in the host, (2) Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies, (3) the synthesis of metabolically-resistant analogues, and (4) drug combination studies and advanced parasitological studies including gametocytes of the parasites (malaria) or worms (schistosomiasis), (5) in vivo Pharmacokinetics/Pharmacodynamics studies. The test of the progress of the present project (2 years) will be the preparation of specific drug-candidates with improved antimalarial or antischistosomal effects, respective to the subset of the molecules, leading to complete cure of animal models by oral route, absence of toxicity and absence of hemolysis in G6PDH-deficient populations. A second patent, related to the first patent (2008) describing the total synthesis and therapeutic use of polysubstituted benzylNQ and their biometabolites is planned to be registered at CNRS, with antimalarial or antischistosomal applications for the two sub-set of distinct 1,4-naphthoquinones derivatives. Valuation of the drug-candidates will be optimized in close collaboration with France Innovation Scientifique et Transfert (FIST SA). Cooperative coordination with FIST SA to guide the advancement of the project and communication with industrial partners will be favored to finalize licensing agreements.