Prodrugs of eugenol as antiplasmodial agents and its possible mechanism of action

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

Congreso; RICIFA; 2021

Considering the biological properties of eugenol and its derivatives and the urgency neededof effective drugs for neglected tropical diseases, we report the synthesis of a novel series ofcarbonates of eugenol, using N,N-carbonyldiimidazole and several aliphatic alcohols. The chemicalstructure of the resulting compounds was confirmed by 1H-NMR, 13C-NMR, FTIR and GC/MSspectroscopy. 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 simulationswere used to determine a possible mode of action of eugenol against Plasmodium falciparumdihydroorotate dehydrogenase (PfDHODH). Notably, the docking results showed that not onlyeugenol 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 thateugenol 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.