Abstract :
[en] Owing to its significant impact on the life expectancy for children in developing countries, malaria remains in 2021 a major threat for mankind and more than half of the world population is at daily risk of being infected by Plasmodium species. Annually, more than 200 million of patients are reported for this parasitosis, around 400 000 will die from it, and children under five pays the greater tribute with around 65% of these deaths. However, effective treatments and prevention methods exist for this mosquitoes-transmitted illness, in contrast to other tropical diseases. But, despite them and the significant decrease of cases observed since 2000, malaria remains the main infectious causes of death.
Among the explanations for this situation, the development and spread of resistances to all the current antimalarials is a major one, besides of the resistance of the vectors (Anopheles) against insecticides. Indeed, delayed parasitic clearance has appeared in South-Asia and in Africa for the artemisinin derivatives, the last accepted class of antimalarials. Consequently, in parallel to the development of effective vaccines and prevention campaigns, there is an urgent need of new alternatives in the antimalarial therapeutic arsenal.
Widely distributed polyphenols, including ellagic acid (1), seemed highly promising among the potential candidates identified in natural sources, since they often exhibited an interesting antiplasmodial potency (IC50 = 2.8 μM), even in vivo, combined to the absence of cytotoxicity or reported side effects. However, most of them possess a weak oral bioavailability, which, in case of 1, can be related to its low water solubility (18 μM). Its flat structure, inducing strong inter- and intramolecular bonds, could explain this reduced hydrosolubility, despite a high hydrophilicity (cLogP = 1.05). Modulation around this scaffold could lead to a more complex 3D structure, and thus disturbance of the detrimental crystal packing. This is expected to be linked to a higher solubility and a higher oral bioavailability.
For that purpose, a total synthesis procedure starting from gallic acid (2) has been considered for the synthesis of substituted 1 derivatives. A bench of highly promising dimers of polyhydroxybenzoic acids have then been produced and demonstrated a potent antiplasmodial activity (IC50 ~ 4.5 μM) on several strains of Plasmodium falciparum, sensitive and resistant to the known antimalarials (3D7, W2, and FcB1).
In parallel, most of these open-ring analogues of 1 exhibited no toxicity in several models, including healthy human cells (IC50 > 50 μg/mL) and animals, zebrafish embryos (ED50 > 100 μg/mL) and mice (ED50 > 1.5 g/kg). Moreover, in contrast to 1, they possessed a low to good water solubility, since their equilibrium concentrations were between 2 and 150-fold superior to the lead compound, mainly impacted by the conformation of the product in the solvent because of the used linker.
Finally, N,N’-(propane-1,3-diyl)bis(3,4,5-trihydroxybenzamide) (15) has demonstrated a potent in vivo effect in a murine malaria model, the Peters’ 4d-suppressive test, after both intraperitoneal and oral administration. Contrary to 1 and propane-1,3-diyl bis(3,4,5-trihydroxybenzoate) (8), which only induced a 30% parasitaemia reduction after i.p. administration, 15 was responsible for more than a 50% inhibition in both routes, 70% and 56%, i.p. and per os respectively.
In conclusion, this open-ring amide analogue of 1 could be a promising scaffold for the future developments of new antimalarial candidates. However, further experiments will be needed to confirm its potential, notably with the exploration of its exact mode of action.
