Biological evaluation and molecular modelling of didanosine derivatives

Ravetti, Soledad; Candia, Cristian Ariel de; Gualdesi, María Soledad; Pampuro, Sandra; Turk, Gabriela; Quevedo, Mario Alfredo; Briñón, Margarita C.

doi:10.1039/c4md00003j

Cited by 1 publication

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References 53 publications

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“…[ 15 ] As reported by Parang et al, [ 16 ] more selective compounds can be designed by using the strategy of carbonate substitution. Ravetti et al [ 17,18 ] synthesized and evaluated the anti‐HIV activity of lamivudine and didanosine carbonate prodrugs with the aim of generating derivatives capable of suppressing HIV replication more effectively than their parent drug, with some promising results. Due to the fact that eugenol has poor physicochemical stability, limited aqueous solubility, and poor bioavailability, which hinders its therapeutic use in medicine, [ 19 ] the strategy of designing carbonate prodrugs is a promising alternative.…”

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confidence: 99%

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

Clemente

Pineda

Yepes

et al. 2021

Archiv der Pharmazie

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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.

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