Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials

Londero, Vinicius S.; Costa-Silva, Thaís A.; Tempone, André G.; Namiyama, Gislene Mitsue; Thevenard, Fernanda; Antar, Guilherme Medeiros; Baitello, João Batista; Lago, João Henrique G.

doi:10.1016/j.bioorg.2019.103510

Cited by 17 publications

(16 citation statements)

References 24 publications

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“…In the present study, the plasma membrane permeability of T. cruzi parasites was analyzed spectrofluorimetrically, using the probe SYTOX Green. Our results showed that compound 1 induced no permeabilization of the membrane when compared to the untreated parasites ( Figure 3 ), similar to the eudesmane sesquiterpene costic acid, isolated from Nectandra barbellata (Lauraceae) ( Londero et al, 2020 ).…”

Section: Resultssupporting

confidence: 66%

“…Our data showed an intense hyperpolarization of the mitochondrial membrane, leading to a significant enhance in the BL-2/BL-1 ratio when compared to the untreated parasites ( Figure 5 ). Previous reports of two other natural sesquiterpenes, costic acid isolated from Nectandra barbellata ( Londero et al, 2020 ) and deoxymikanolide isolated from the species of Mikania ( Puente et al, 2019 ), demonstrated an imbalance of the T. cruzi mitochondria, but leading to a depolarization of this organelle. The mitochondria in trypanosomatid are unique and vital organelles, serving as target for several drugs and compounds.…”

Section: Resultsmentioning

confidence: 93%

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(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

et al. 2021

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Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects 6–8 million people worldwide, mainly from developing countries. The treatment is limited to two approved nitro-derivatives, nifurtimox and benznidazole, with several side effects and reduced efficacy. Casearia sylvestris has been used in folk medicine as an antiseptic and cicatrizing in skin diseases. In the present work, the hexane phase from the MeOH extract from the leaves of Casearia sylvestris afforded a fraction composed by the sesquiterpene T-cadinol, which was chemically characterized by NMR and HRMS. The activity of T-cadinol was evaluated against T. cruzi, and IC50 values of 18 (trypomastigotes) and 15 (amastigotes) µM were established. The relation between the mammalian toxicity and the antiparasitic activity resulted in a selectivity index >12. Based on this promising activity, the mechanism of action was investigated by different approaches using fluorescent-based techniques such as plasma membrane permeability, plasma membrane electric potential, mitochondrial membrane electric potential, reactive oxygen species, and the intracellular calcium (Ca2+) levels. The obtained results demonstrated that T-cadinol affected neither the parasite plasma membrane nor the electric potential of the membrane. Nevertheless, this compound induced a mitochondrial impairment, resulting in a hyperpolarization of the membrane potential, with decreased levels of reactive oxygen species. No alterations in Ca2+ levels were observed, suggesting that T-cadinol may affect the single mitochondria of the parasite. This is the first report about the occurrence of T-cadinol in C. sylvestris, and our data suggest this sesquiterpene as an interesting hit compound for future optimizations in drug discovery studies for Chagas disease.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 93%

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

et al. 2021

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“…In continuation of our studies concerning the discovery of new antiprotozoal compounds from Lauraceae species, [18,22,23] the phytochemical analysis from P. fulva leaves yielded three known γ‐lactones: majoranolide B ( 1 ), majorenolide ( 2 ) and majorynolide ( 3 ). Other two known compounds were isolated from the roots of P. americana : lincomolide D ( 4 ) and isolinderanolide E ( 5 ), as well as one new γ‐lactone named perseanolide (3 E ,4 R )‐3‐docosylidene‐4‐hydroxy‐5‐methylideneoxolan‐2‐one; ( 6 ).…”

Section: Introductionmentioning

confidence: 90%

γ‐Lactones from Persea americana and Persea fulva – in Vitro and in Silico Evaluation of Trypanosoma cruzi Activity

Reis

Umehara

Conceição

et al. 2021

Chemistry & Biodiversity

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In the present study, five known γ‐lactones (majoranolide B – 1, majorenolide – 2, majorynolide – 3, lincomolide D – 4, and isolinderanolide E – 5), as well as a new one (perseanolide – 6), were isolated from Persea fulva and P. americana. All isolated compounds exhibited potential activity against trypomastigote forms of Trypanosoma cruzi, whereas compounds 2 (EC50 of 4.8 μM) and 6 (EC50 of 3.6 μM) displayed superior activity than the positive control benznidazole (EC50 of 16.4 μM), with selectivity index (SI) values of 17.8 and >55.6, respectively (benznidazole, SI>12.2). Molecular docking studies were performed for 1–6 against six T. cruzi molecular targets. Using this approach, we observed that, even though perseanolide (6) showed favorable docking to several studied targets, the results were especially promising for hypoxanthine phosphoribosyl transferase (PDB 1TC1). As PDB 1TC1 is associated to the transference of a monophosphorylated ribose from phosphoribosylpyrophosphate (PRPP) in the ribonucleotide synthesis pathway, this interaction may affect the survival of T. cruzi in mammalian cells. The data herein also indicate that possible intermolecular interactions between 6 and PDB 1TC1 derive from (i) hydrogen bonds in the α,β‐unsaturated‐γ‐lactone unity and (ii) hydrophobic interactions in the long‐chain alkyl group. Based on our results, perseanolide (6), reported for the first time in this work, can auspiciously contribute to future works regarding new trypanocidal agents.

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“…The analysis of ΔΨ p alteration was performed by measuring the increase in absorbance of bis(1,3‐diethylthiobarbituric acid)trimethine oxonol [DiSBAC 2 (3)] (Invitrogen), as previously reported [37] …”

Section: Methodsmentioning

confidence: 99%

Aporphine Alkaloids from Ocotea puberula with Anti‐Trypanosoma Cruzi Potential – Activity of Dicentrine‐β‐N‐Oxide in the Plasma Membrane Electric Potentials

Barbosa

Costa-Silva

Conserva

et al. 2021

Chemistry & Biodiversity

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One new aporphine, dicentrine‐β‐N‐oxide (1), together with five related known alkaloids dehydrodicentrine (2), predicentrine (3), N‐methyllaurotetanine (4), cassythicine (5), and dicentrine (6) were isolated from the leaves of Ocotea puberula (Lauraceae). Antiprotozoal activity of the isolated compounds was evaluated in vitro against trypomastigote forms of Trypanosoma cruzi. Among the tested compounds, alkaloid 1 exhibited higher potential with EC50 value of 18.2 μM and reduced toxicity against NCTC cells (CC50>200 μM – SI>11.0), similar to positive control benznidazole (EC50 of 17.7 μM and SI=10.7). Considering the promising results of dicentrine‐β‐N‐oxide (1) against trypomastigotes, the mechanism of parasite death caused by this alkaloid was investigated. As observed, this compound reached the plasma membrane electric potential directly after 2 h of incubation and triggered mitochondrial depolarization, which probably leads to trypomastigote death. Therefore, dicentrine‐β‐N‐oxide (1), reported for the first time in this work, can contribute to future works for the development of new trypanocidal agents.

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Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials

Cited by 17 publications

References 24 publications

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

γ‐Lactones from Persea americana and Persea fulva – in Vitro and in Silico Evaluation of Trypanosoma cruzi Activity

Aporphine Alkaloids from Ocotea puberula with Anti‐Trypanosoma Cruzi Potential – Activity of Dicentrine‐β‐N‐Oxide in the Plasma Membrane Electric Potentials

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