Prodrugs of eugenol as an antiplasmodial agent and its possible mechanism of action

CLEMENTE CAMILA M; HERGERT LISANDRO Y; ALLEMANDI DANIEL A; GARRO ARIEL G; ROBLEDO SARA M; RAVETTI SOLEDAD

CÓRDOBA

Otro; 6ta Reunión Internacional de Ciencias Farmacéuticas; 2021

Universidades Nacionales de Córdoba y Rosario

Considering the biological properties of eugenol and its derivatives and the urgency needed of effective drugs for neglected tropical diseases, we report the synthesis of a novel series of carbonates of eugenol, using N,N-carbonyldiimidazole and several aliphatic alcohols. The chemical structure of the resulting compounds was confirmed by 1H-NMR, 13C-NMR, FTIR and GC/MS spectroscopy. In vitro studies eugenol prodrugs were tested for their antiplasmodial activities and also their cytotoxicity. We found that eugenol was not active against P. falciparum with an EC50 of 665.6 µM (109.29 μg/mL); however, several prodrugs improved the EC50 dose-response against P. falciparum with respect to the parent drug eugenol. Molecular docking and dynamics simulations were used to determine a possible mode of action of eugenol against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Notably, the docking results showed that not only eugenol has binding energy similar to the natural substrate (-7.2 and -7.1, respectively) but it also has interactions with relevant biological residues of PfDHODH. In conclusion, results suggest that eugenol and their carbonate derivatives have promising therapeutic potential as antiplasmodial agents; nonetheless further studies are needed to validate their efficacy as antiparasitic drugs in vivo assays.