Eugenol carbonate activity against Plasmodium falciparum, Leishmania braziliensis, and Trypanosoma cruzi

Neglected tropical diseases are a major health problem throughout the world, and there are few effective and safe drugs. In this study, we report the design and synthesis of a novel series of carbonates of eugenol using different aliphatic alcohols and N,N‐carbonyldiimidazole. Spectroscopic techniques, including 1H nuclear magnetic resonance (NMR), 13C NMR, Fourier transform infrared, and high‐resolution mass spectrometry, were used to confirm the structures of the synthesized compounds. In vitro and in silico studies of prodrugs of eugenol were performed to determine their antiplasmodial, trypanocidal, and leishmanicidal activities, and also their cytotoxicity. Compounds were highly active against Leishmania braziliensis and Plasmodium falciparum, whereas the activity shown for Trypanosoma cruzi was moderate. Molecular docking was used to determine a possible mode of action of eugenol against the dihydroorotate dehydrogenase of the three parasites (TcDHODH, LbDHODH, and PfDHODH). Notably, the docking results showed that eugenol not only has binding energy similar to that of the natural substrate (−7.2 and −7.1, respectively) but also has interactions with relevant biological residues of PfDHODH. This result indicates that eugenol could act as a substrate for PfDHODH in the pyrimidine biosynthesis pathway of P. falciparum. In conclusion, the combination of certain aliphatic alcohols and eugenol through a carbonate bond could significantly increase the antiparasitic activity of this class of compounds, which merits further studies. Nine carbonate derivatives of eugenol with optimal drug‐like properties were synthesized by combination with aliphatic alcohols and tested for in vitro antileishmanial, antitrypanosomal, and antiplasmodial activities, and cytotoxicity in human U‐937 macrophages. In silico studies indicate that eugenol can interact with the substrate binding‐site of the Plasmodium falciparum dihydroorotate dehydrogenase, an enzyme of the pyrimidine biosynthesis pathway.