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

Abstract

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.

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

“…Over the years, several types of cell line and primary cell culture have been used to determine the cytotoxic activity of new molecules in vitro. Among the most widely used are Cercopithecus aethiops (African green monkey) normal epithelial kidney cells VERO (ATCC® CCL-81 TM ); Maccaca mulata (rhesus monkey) normal epithelial kidney LLC-MK2 (ATCC® CCL-7 TM ); Mus musculus (mouse) embryo fibroblast NIH/3T3 (ATCC® CRL-1658 TM ); Mus musculus (mouse) macrophages from reticulum cell sarcoma J774A.1 (ATTC TIB-67™); Rattus norvegicus myoblast H9c2(2-1) (ATCC® CRL 1446 TM ); Canis familiaris canine macrophage DH82 cell line; Homo sapiens normal tissue lung fibroblast MRC-5 (ATCC® CCL-171™); Homo sapiens epithelial bone osteosarcoma U-2 OS (ATCC® HTB-96™); and Homo sapiens tissue monocytes U-937 (ATCC® CRL-1593.2 TM ) [155][156][157][158].…”

“…A 10 µg/mL concentration is usually incubated, at pH 7.2, in the presence of the candidate compound to be evaluated, and collected during the exponential growth phase. For T. cruzi, the most frequently used strains are Tulahuen strain Discrete Typing Unit (DTU) VI clone C2 and C4, expressing beta-galactosidase gene [155,157,[159][160][161][162][163] or luciferase gene Luc2-Tulahuen [164], Y strain DTU II wild type [165,166] or expressing the firefly luciferase gene [159], Sylvio X10 strain DTU I [156], Dm28c strain DTU I [163], RA strain DTU VI [167][168][169] and VD strain DTU VI [170].…”

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease

“…Over the years, several types of cell line and primary cell cultures have been used to determine the cytotoxic activity of new molecules in vitro. Table 2 summarizes the cell lines most widely used in cytotoxicity assays [ 157 , 158 , 159 , 160 ]. The specific protocol, medium, and nutrients to grow and culture each cell line can be found on the American Type Culture Collection (ATCC) web page ( ; accessed on 1 June 2023).…”

“…A 10 µg/mL concentration is usually incubated at pH 7.2 in the presence of the candidate compound to be evaluated, and it is collected during the exponential growth phase. For T. cruzi , the most frequently used strains are the Tulahuen strain Discrete Typing Unit (DTU) VI clones C2 and C4, which express the beta-galactosidase gene [ 157 , 159 , 161 , 162 , 163 , 164 , 165 ] or the luciferase gene Luc2-Tulahuen [ 166 ]; Y strain DTU II (wild-type [ 167 , 168 ] or expressing the firefly luciferase gene [ 161 ]); Sylvio X10 strain DTU I [ 158 ]; Dm28c strain DTU I [ 165 ]; RA strain DTU VI [ 169 , 170 , 171 ]; and VD strain DTU VI [ 172 ].…”

Bulbiferamide, an Antitrypanosomal Hexapeptide Cyclized via an N-Acylindole Linkage from a Marine Obligate Microbulbifer

“…However, the efficacy of these two old drugs is limited to the acute stage and the early chronic phase . Severe side effects, associated with the long-term administration, often cause patients to abandon the treatment. , Despite decades of research for exploring new anti-Chagas drugs, nothing that can substitute for the two old drugs has been invented . With a pressing need for combatting Chagas disease, development of novel nontoxic and efficacious drugs is strongly awaited. − …”