Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new ...antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including
,
,
,
,
, and
, along with pure phytochemicals isolated from Asteraceae: mikanolide (
), eupatoriopicrin (
), eupahakonenin B (
), minimolide (
), estafietin (
), 2-oxo-8-deoxyligustrin (
), santhemoidin C (
), euparin (
), jaceidin (
), nepetin (
), jaceosidin (
), eryodictiol (
), eupatorin (
), and 5-demethylsinensetin (
). Results showed that the dichloromethane extracts of
and
and the methanolic extracts prepared from
and
were highly active and selective against DENV-2, affording EC
values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds
,
, and
stand out as the most active (EC
= 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules.
The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against
epimastigotes. ...The aim of this work was to evaluate the activity of these compounds by analyzing their effect against the stages of the parasites that are infective for the human. Even more interesting, we aimed to determine the effect of the most active and selective compound on an
model of
infection. Eupatoriopicrin was the most active against amastigotes and tripomastigotes (IC
= 2.3 µg/mL, and 7.2 µg/mL, respectively) and displayed a high selectivity index. This compound was selected to study on an
model of
infection. The administration of 1 mg/kg/day of eupatoriopicrin for five consecutive days to infected mice produced a significant reduction in the parasitaemia levels in comparison with non-treated animals (area under parasitaemia curves 4.48 vs. 30.47, respectively). Skeletal muscular tissues from eupatopicrin-treated mice displayed only focal and interstitial lymphocyte inflammatory infiltrates and small areas of necrotic; by contrast, skeletal tissues from
infected mice treated with the vehicle showed severe lymphocyte inflammatory infiltrates with necrosis of the adjacent myocytes. The results indicate that eupatoriopicrin could be considered a promising candidate for the development of new therapeutic agents for Chagas disease.
Advancing with our project about the development of new antiparasitic agents, we have enzymatically synthesized a series of amides derived from amlodipine, a calcium channel blocker used as an ...antihypertensive drug. Through lipase-catalyzed acylation with different carboxylic acids, nineteen amlodipine derivatives were obtained, eighteen of which were new compounds. To optimize the reaction conditions, the influence of several reaction parameters was analyzed, finding different requisites for aliphatic carboxylic acids and phenylacetic acids. All synthesized compounds were evaluated as antiproliferative agents against
, the etiological agent of American trypanosomiasis (Chagas' disease). Some of them showed significant activity against the amastigote form of
, the clinically relevant form of the parasite. Among synthesized compounds, the derivatives of myristic and linolenic acids showed higher efficacy and lower cytotoxicity. These results added to the advantages shown by the enzymatic methodology, such as mild reaction conditions and low environmental impact, making this approach a valuable way to synthesize these amlodipine derivatives with an application as promising antiparasitic agents.
Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal ...activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (
), isolated from
(Asteraceae): 11βH,13-dihydroestafietin (
), epoxyestafietin (
and
), 11βH,13-methoxyestafietin, (
) and 11βH,13-cianoestafietin. The antiprotozoal activity against
and
of these compounds was evaluated. Epoxyestafietin was the most active compound against
trypomastigotes and amastigotes (IC
values of 18.7 and 2.0 µg/mL, respectively). Estafietin (
) and 11βH,13-dihydroestafietin (
) were the most active and selective compounds on
promastigotes (IC
values of 1.0 and 1.3 μg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis.
•Effect of eupatoriopicrin and estafietin on different molecular targets of T. cruzi•Eupatoriopicrin causes accumulation of triglycerides and increased lipid droplets•Estafietin produced a large ...decrease in succinate dehydrogenase activity•Experiments carried out with both drugs did not show any interaction between them•For both lactones the kinetoplast is altered and large translucent vacuoles appear
: The sesquiterpene lactones (STLs) eupatoriopicrin (EP) and estafietin (ES), isolated from Stevia alpina Griseb. (Asteraceae) and Stevia maimarensis (Hieron.) Cabrera (Asteraceae) respectively, have previously showed promising trypanocidal activity, both in vitro and in vivo.
: In this work, using biochemical studies and electron microscopy, we aimed at characterizing the mode of action of both STLs on Trypanosoma cruzi.
: The interaction of STLs with hemin was examined by measuring modifications in the Soret absorption band of hemin; the thiol groups interaction was determined spectrophotometrically through its reaction with 5,5’-dithiobis-2-nitrobenzoate; the effect on cruzipain activity was also assayed by spectrophotometry. The synthesis of sterols were qualitatively and quantitatively tested by TLC. Mitochondrial functionality was assessed by measuring mitochondrial membrane potential and the activity of NADH-cytochrome c reductase and succinate-cytochrome c reductase enzymes. The status of the antioxidant system was assessed by quantifying the level of free thiols by spectrophotometry, together with the intracellular oxidative state by flow cytometry. Ultrastructural changes were analyzed by transmission electron microscopy.
: EP and ES were found to impair the functionality and the redox status of the parasite. ES produced a greater decrease in the activity of succinate dehydrogenase than eupatoriopicrin, affecting the functioning of the respiratory chain and the Krebs cycle. EP increased the formation of triglycerides leading to the presence of cytoplasmic lipid droplets. By electron microscopy, alterations in the kinetoplast and the appearance of large translucent vacuoles in the cytoplasm were observed for both compounds.
: Both sesquiterpenelactones proved to act additively on T. cruzi, supporting the hypothesis that each compound would be acting on different primary targets.. The treatment combining eupatoriopicrin and estafietin could be considered a promising alternative for the treatment of Chagas’ disease.
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species (Asteraceae) have been a rich source of terpenoid compounds, mainly sesquiterpene lactones, several of which show antiprotozoal activity. In the search for new trypanocidal compounds,
var.
...and
were studied. Two sesquiterpene lactones, santhemoidin C and 2-oxo-8-deoxyligustrin, respectively, were isolated. These compounds were assessed in vitro against
stages, showing IC
values of 11.80 and 4.98 on epimastigotes, 56.08 and 26.19 on trypomastigotes and 4.88 and 20.20 µM on amastigotes, respectively. Cytotoxicity was evaluated on Vero cells by the MTT assay. The effect of the compounds on trypanothyone reductase (TcTR),
-sialidase (TcTS) and the prolyl oligopeptidase of 80 kDa (Tc80) as potential molecular targets of
was investigated. Santhemoidin C inhibited oligopeptidase activity when tested against recombinant Tc80 using a fluorometric assay, reaching an IC
of 34.9 µM. Molecular docking was performed to study the interaction between santhemoidin C and the Tc80 protein, reaching high docking energy levels. Plasma membrane shedding and cytoplasmic vacuoles, resembling autophagosomes, were detected by transmission microscopy in parasites treated with santhemoidin C. Based on these results, santhemoidin C represents a promising candidate for further studies in the search for new molecules for the development of trypanocidal drugs.
Austroeupatol, the principal diterpene isolated from the invasive shrub Austroeupatorium inulifolium, holds promise for structural diversification and biological assessment of its derivatives due to ...its abundant availability and high yield isolation. We propose an efficient enzymatic synthesis of a series of austroeupatol esters derived from aliphatic and heterocyclic carboxylic acids. Systematic optimization of reaction parameters, including enzyme type and quantity, acylating agent amount, solvent, and temperature, was conducted. Thermomyces lanuginosus lipase in cyclohexane at 55 °C, yielded esters with favorable conversion rates. Through enzymatic catalysis, mono- and diacylated derivatives were obtained, with a diacylation–monoacylation ratio influenced by temperature and acylating agent amount. The antiprotozoal activity of austroeupatol and all synthesized derivatives was evaluated, observing that acylation improved it. The 19-valeroyl, 19-indolylpropyl, and 19-octyl derivatives were the most potent compounds against Trypanosoma cruzi and Leishmania infantum, highlighting this approach as a valuable method for synthesizing austroeupatol derivatives as potential antiparasitic agents.
Chagas disease is an infection caused by the protozoan
affecting 6-8 million people worldwide. Only two drugs are available for its treatment, having a limited efficacy and adverse side-effects. ...Estafietin is a sesquiterpene lactone isolated from
with
activity against
and low cytotoxicity against mammalian cells. The aim of this work was to predict the toxicologic profile of estafietin by
methods and assess its
activity on a murine model of Chagas disease. Estafietin showed low toxicity according to pkCSM web tool and passed the PAINS filter from PAINS-remover web server. The treatment of infected mice with 1 mg/Kg/day of estafietin for five consecutive days administrated by intraperitoneal route significatively decreased parasitemia levels and reduced inflammatory infiltrates and myocyte damage on muscle tissue. These results suggest that estafietin had effect both on acute and chronic stages of the infection.
The dewaxed dichloromethane extract of Urolepis hecatantha and the compounds isolated from it were tested for their in vitro activity on Trypanosoma cruzi epimastigotes and Leishmania infantum ...promastigotes. The extract of U. hecatantha showed activity against both parasites with IC50 values of 7 µg/mL and 31 µg/mL, respectively. Fractionation of the dichloromethane extract led to the isolation of euparin, jaceidin, santhemoidin C, and eucannabinolide. The sesquiterpene lactones eucannabinolide and santhemoidin C were active on T. cruzi with IC50 values of 10 ± 2 µM (4.2 µg/mL) and 18 ± 3 µM (7.6 µg/mL), respectively. Euparin and santhemoidin C were the most active on L. infantum with IC50 values of 18 ± 4 µM (3.9 µg/mL) and 19 ± 4 µM (8.0 µg/mL), respectively. Eucannabinolide has also shown drug-like pharmacokinetic and toxicity properties.
Advancing with our project about the development of new antiparasitic agents, we have enzymatically synthesized a series of amides derived from amlodipine, a calcium channel blocker used as an ...antihypertensive drug. Through lipase-catalyzed acylation with different carboxylic acids, nineteen amlodipine derivatives were obtained, eighteen of which were new compounds. To optimize the reaction conditions, the influence of several reaction parameters was analyzed, finding different requisites for aliphatic carboxylic acids and phenylacetic acids. All synthesized compounds were evaluated as antiproliferative agents against
Trypanosoma cruzi
, the etiological agent of American trypanosomiasis (Chagas' disease). Some of them showed significant activity against the amastigote form of
T. cruzi
, the clinically relevant form of the parasite. Among synthesized compounds, the derivatives of myristic and linolenic acids showed higher efficacy and lower cytotoxicity. These results added to the advantages shown by the enzymatic methodology, such as mild reaction conditions and low environmental impact, making this approach a valuable way to synthesize these amlodipine derivatives with an application as promising antiparasitic agents.
An efficient lipase-catalyzed method for the amidation of amlodipine with aliphatic and phenylacetic acids in mild reaction conditions is described. Some compounds showed significant activity and selectivity against
Trypanosoma cruzi
amastigotes.
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