Synthesis, In Vitro Antiprotozoal Activity and Cytotoxicity of New Thymol Carbonate Derivatives

Clemente, Camila M.; Ravetti, Soledad; Allemandi, Daniel Alberto; Hergert, Lisandro Yamil; Pineda, Tatiana; Robledo, Sara M.

doi:10.1002/slct.202101461

Cited by 4 publications

(10 citation statements)

References 14 publications

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“…The chromatoplates were observed with UV light at 254 nm. All glassware was oven-dried at 130 °C overnight and cooled in a desiccator over anhydrous CaSO 4 [ 16 , 17 ]. The 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded on a 400 MHz Brüker Advance II spectrometer.…”

Section: Methodsmentioning

confidence: 99%

“…The organic phase was successively washed with water (3 × 20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and the solvent was evaporated under reduced pressure [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Stock solutions at 200 g/mL (v/v) in complete RPMI-1640 medium were prepared and then four-fold serial dilutions of each compound were prepared. At the end, each compound was tested at different concentrations (200, 50, 12.5, 3.125 and 0.78 µg/mL) [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…A blank solution (enriched RPMI-1640 medium plus 0.2% DMSO) was used to correct the absorbance. Each measurement was done in triplicate in two independent experiments [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Continuing our studies on the development of antiparasitic agents using the pharmaceutical strategy of prodrugs [ 14 , 16 , 17 ] and taking into account what has been described above, we report the synthesis and in vitro antiprotozoal evaluation of new menthol carbonates against Trypanosoma cruzi , Leishmania braziliensis and Plasmodium falciparum .…”

Section: Introductionmentioning

confidence: 99%

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Menthol carbonates as potent antiparasitic agents: synthesis and in vitro studies along with computer-aided approaches

Clemente

Robledo

Ravetti

2022

BMC Complement Med Ther

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Introduction Despite the number of deaths and the significant economic and social costs associated with Chagas, Leishmaniasis and Malaria diseases worldwide, available drugs are limited and have serious side effects and high toxicity for the patient. Therefore, there is an urgent need for safe, low-cost, and effective treatments. Natural products are an important source of bioactive compounds and there is current interest in finding natural bioactive molecules that can be used for treating these parasitic diseases. In the present study we proposed to evaluate the in vitro antiparasitic activity of new menthol derivatives against Trypanosoma cruzi, Leishmania braziliensis and Plasmodium falciparum; moreover, we propose to explore their mode of action through in silico approaches. Material and methods A series of carbonate prodrugs (1–9) were synthesized from menthol with different aliphatic alcohols. Spectroscopic techniques were used to confirm the structures of the synthesized compounds. The cytotoxicity of the compounds was assessed using U-937 cells. In vitro trypanocidal, leishmanicidal and antiplasmodial activity were evaluated using a T. cruzi, L. braziliensis and P. falciparum organism, respectively. In addition, in silico studies were also performed through molecular dynamics simulations and MM-PBSA analysis. Results The assay revealed that most of the compounds were highly active against intracellular amastigotes of T. cruzi and L. braziliensis, and had moderate activity against the total forms of P. falciparum. Compound 2 was one of the drugs that showed a high selectivity index (SI) for the three organisms evaluated. The prediction of the ADME properties suggests that all the compounds have drug-like molecular properties and the probability to be lead candidates. Finally, molecular dynamics simulations, and MM-PBSA studies indicate that menthol at the substrate binding site of TcDHODH, LbDHODH and PfDHODH is structurally stable in the same order as the natural substrate; also, interactions of menthol with residues involved in the inhibition of TcDHODH and PfDHODH proteins were predicted. Conclusions The present study demonstrates that menthol prodrugs are promising antiparasitic agents; however, the mechanisms of action proposed in this study need to be experimentally verified by future enzymatic assays.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…A blank solution (enriched RPMI-1640 medium plus 0.2% DMSO) was used to correct the absorbance. Each measurement was done in triplicate in two independent experiments [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Menthol carbonates as potent antiparasitic agents: synthesis and in vitro studies along with computer-aided approaches

Clemente

Robledo

Ravetti

2022

BMC Complement Med Ther

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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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Thymol-Functionalized Hyaluronic Acid as Promising Preservative Biomaterial for the Inhibition of Candida albicans Biofilm Formation

et al. 2023

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Hyaluronic acid (HA) is a naturally occurring biopolymer that has been employed for a plethora of medicinal applications. Nevertheless, as HA is a natural polysaccharide, it can be a substrate able to promote microbial growth and proliferation. Biopolymer−drug conjugates have gained attention over the years to overcome drawbacks of each single component. Within this context, thymol (Thy), a phenolic compound occurring in essential oils (EOs) extracted from Thymus and Origanum, has been largely studied for its antimycotic applications. However, it is characterized by a low water solubility and moderate cytotoxicity. Herein, we report an innovative HA−thymol conjugate (HA-Thy) biomaterial to circumvent the drawbacks of free thymol use by providing the polymer conjugate with the beneficial properties of both components. Preliminary biological tests evidenced the decrease of thymol cytotoxicity for the HA-Thy conjugate, paired with a promising antibiofilm formation activity against Candida albicans, similar to pure thymol, highlighting its potential application as a preservative biomaterial in formulations.

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Synthesis, In Vitro Antiprotozoal Activity and Cytotoxicity of New Thymol Carbonate Derivatives

Cited by 4 publications

References 14 publications

Menthol carbonates as potent antiparasitic agents: synthesis and in vitro studies along with computer-aided approaches

Menthol carbonates as potent antiparasitic agents: synthesis and in vitro studies along with computer-aided approaches

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

Thymol-Functionalized Hyaluronic Acid as Promising Preservative Biomaterial for the Inhibition of Candida albicans Biofilm Formation

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